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Enterovirus

2019-10-08T08:02:31Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [[wikipedia:Auto-brewery_syndrome|auto-brewery syndrome,]] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)[https://www.me-pedia.org/wiki/Endometriosis , endometriosis], [[wikipedia:Type_1_diabetes|Type 1 diabetes]], [[wikipedia:Autoimmune_autonomic_ganglionopathy|autoimmune autonomic ganglionopathy]], [https://me-pedia.org/wiki/Mast_cell_activation_syndrome mast cell activation syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:55:53Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [[wikipedia:Auto-brewery_syndrome|auto-brewery syndrome,]] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)[https://www.me-pedia.org/wiki/Endometriosis , endometriosis], [[wikipedia:Type_1_diabetes|Type 1 diabetes]], [[wikipedia:Autoimmune_autonomic_ganglionopathy|autoimmune autonomic ganglionopathy]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:53:29Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [[wikipedia:Auto-brewery_syndrome|auto-brewery syndrome,]] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)[https://www.me-pedia.org/wiki/Endometriosis , endometriosis], [[wikipedia:Type_1_diabetes|Type 1 diabetes]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:42:47Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [[wikipedia:Auto-brewery_syndrome|auto-brewery syndrome,]] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)[https://www.me-pedia.org/wiki/Endometriosis , endometriosis]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:40:34Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [[wikipedia:Auto-brewery_syndrome|auto-brewery syndrome,]] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:32:50Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)], [[postural orthostatic tachycardia syndrome]] (PoTS)

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:31:13Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia], [https://www.me-pedia.org/wiki/Dysautonomia dysautonomia (autonomic nervous system disorder)]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T07:27:45Z

Commonlyknownasryan:/* Acute and persistent enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute and persistent enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [[wikipedia:Small_fiber_peripheral_neuropathy|small fiber peripheral neuropathy]], [[wikipedia:Metabolic_acidosis|metabolic acidosis]]<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/28592308|title=Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review.|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>, [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

User talk:Commonlyknownasryan

2019-10-08T07:06:50Z

Commonlyknownasryan:/* Enterovirus page edits -- Hip (talk) 02:11, October 8, 2019 (EDT) */

{{Template:Welcome|realName=|name=Commonlyknownasryan}}

-- [[User:New user message|New user message]] ([[User talk:New user message|talk]]) 00:35, October 8, 2019 (EDT)

== Enterovirus page edits -- [[User:Hip|Hip]] ([[User talk:Hip|talk]]) 02:11, October 8, 2019 (EDT) ==

Hi Commonlyknownasryan

You have added things to the enterovirus page which are medically incorrect. There is no evidence that acute enterovirus infections can cause fibromyalgia, small fiber peripheral neuropathy, metabolic acidosis, irritable bowel syndrome, small intestinal bacterial overgrowth, craniocervical instability, tethered cord syndrome, ehlers-danlos syndrome, interstitial cystitis. So why did you add these to the list of acute enterovirus symptoms?

you are nuts and you are medically incorrect

there is evidence it can lead to all those things

You also added "herpangina" and "mouth ulcer" to the respiratory symptoms of acute enterovirus, but these are already included under oral symptoms.

You added "sore throat", but this is already present as "pharyngitis".

Not also that you added "peyer's patches" as an enterovirus symptom, but this is an organ, not a symptom.

If you want to edit MEpedia, make sure the information you add is factually correct, and is backed up by medical references. For every fact that you add to MEpedia, you need to provide a scientific reference.

I am going to revert you changes shortly, because the changes you made are incorrect. [[User:Hip|Hip]] ([[User talk:Hip|talk]]) 02:11, October 8, 2019 (EDT)

===Re: Enterovirus page edits -- [[User:Commonlyknownasryan|Commonlyknownasryan]] ([[User talk:Commonlyknownasryan|talk]]) 03:06, October 8, 2019 (EDT)===

: Replace this text with your reply

Enterovirus

2019-10-08T06:57:28Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], a[[wikipedia:Acute_flaccid_myelitis|cute flaccid myelitis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:52:45Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus], [https://www.me-pedia.org/wiki/Photophobia photophobia]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:51:26Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus],

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:49:57Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Hyperacusis hyperacusis,] [https://www.me-pedia.org/wiki/Tinnitus tinnitus]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:46:41Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus,]] [https://www.me-pedia.org/wiki/Tinnitus tinnitus]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:41:52Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]], [[wikipedia:Dilated_cardiomyopathy|dilated cardiomyopathy]]
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:36:28Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]], [[wikipedia:Ileus#Intestinal_paralysis|paralytic ileus]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:33:32Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral '''— [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:28:06Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis,] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:27:21Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [https://www.me-pedia.org/wiki/Gastroparesis gastroparesis] [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:25:36Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]], [[wikipedia:Autoimmune_gastrointestinal_dysmotility|autoimmune gastrointestinal dysmotility]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:20:49Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] [[wikipedia:Euthyroid_sick_syndrome|euthyroid sick syndrome]]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:19:20Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,] low T3 syndrome

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:18:07Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis,]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:15:57Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome], [https://www.me-pedia.org/wiki/Hashimoto%27s_thyroiditis hashimoto's thyroiditis]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:12:59Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Endometriosis endometriosis,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:06:27Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability,] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:05:52Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] [https://www.me-pedia.org/wiki/Craniocervical_instability craniocervical instability] [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:03:30Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [https://www.me-pedia.org/wiki/Fibromyalgia fibromyalgia], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] craniocervical instability, [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T06:00:49Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]], s[https://www.me-pedia.org/wiki/Small_intestinal_bacterial_overgrowth mall intestinal bacterial overgrowth,] craniocervical instability, [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome], [https://me-pedia.org/wiki/Ehlers-Danlos_syndrome ehlers-danlos syndrome]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:54:47Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]]. craniocervical instability, [https://me-pedia.org/wiki/Tethered_cord_syndrome tethered cord syndrome],

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:50:48Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]]. [https://me-pedia.org/wiki/Craniocervical_instability craniocervical instability]

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:48:02Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]], [[wikipedia:Irritable_bowel_syndrome|irritable bowel syndrome]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:44:52Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:43:18Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — i[[wikipedia:Interstitial_cystitis|interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:42:26Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — i[[wikipedia:Interstitial_cystitis|Interstitial cystitis]], [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:39:40Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]]. [[wikipedia:Fibromyalgia|fibromyalgia]]
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:33:43Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy], [[wikipedia:Metabolic_acidosis|metabolic acidosis]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:29:35Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]], [http://small fiber peripheral neuropathy small fiber peripheral neuropathy].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:23:21Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:22:50Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]],[[wikipedia:Nausea|nausea,]] [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]

Enterovirus

2019-10-08T05:19:45Z

Commonlyknownasryan:/* Acute enterovirus infections */

'''Enterovirus''' is a genus of positive single-stranded [[RNA virus|RNA viruses]]. Viruses in the enterovirus genus include [[Coxsackie A virus|coxsackievirus A]], [[Coxsackie B virus|coxsackievirus B]], [[echovirus]], [[poliovirus]], [[rhinovirus]], and many others. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.<ref>{{Cite web|url=https://emedicine.medscape.com/article/1134374-overview#a5|title=Dermatologic Manifestations of Enteroviral Infections (Medscape article)|last=Alsina-Gibert|first=Mercè|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Enteroviruses spread from person to person by either oral-oral or fecal-oral routes.}}</ref>
[[File:Enterovirus Virion.jpg|thumb|305x305px|Enterovirus is a non-enveloped icosahedral-shaped positive single-stranded RNA virus made from four proteins named VP1 to VP4 (VP4 located in the interior).]]
Enteroviruses are responsible for a range of acute infections and illnesses. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States.<ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/index.html|title=Non-Polio Enterovirus|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=|quote=Non-Polio Enterovirus. Non-polio enteroviruses are very common. They cause about 10 to 15 million infections and tens of thousands of hospitalizations each year in the United States. Most people who get infected with these viruses do not get sick or they only have mild illness, like the common cold.}}</ref> But acute enterovirus [[infection]]<nowiki/>s can often be mild (like a common cold) or [[asymptomatic]] when contracted.<ref>{{Cite web|url=https://emedicine.medscape.com/article/217146-overview|title=Enteroviruses (Medscape article)|last=Schwartz|first=Robert A|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of infections caused by nonpolio entero viruses are asymptomatic or result only in an undifferentiated febrile illness.}}</ref><ref>{{Cite web|url=https://emedicine.medscape.com/article/216564-overview#a5|title=Echovirus Infection (Medscape article)|last=Choudhary|first=Madhu Chhanda|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=More than 90% of echoviral infections are asymptomatic.}}</ref>

Though normally only capable of acute infections, under certain circumstances enteroviruses can create chronic infections, and ongoing enterovirus infections have been found in ME/CFS and several other chronic illnesses in including [[dilated cardiomyopathy]], and type 1 [[diabetes]]. Some researchers posit that such persistent enterovirus infections may be a cause of these diseases.

== Enterovirus species ==
In the new [http://www.picornaviridae.com/enterovirus/enterovirus.htm classification system], the enterovirus genus contains 15 species of enterovirus named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. The [[enterovirus B]] species contains the coxsackievirus B and echovirus serotypes which are associated with ME/CFS.
* Enterovirus A — contains some of the coxsackievirus A serotypes as well as enterovirus A71 (also written enterovirus 71).
* [[Enterovirus B|Enterovirus B]] — includes the six coxsackievirus B and 28 echovirus serotypes, as well as coxsackievirus A9.
* Enterovirus C — contains further coxsackievirus A serotypes as well as the three [[Poliovirus|polioviruses]].
* Enterovirus D — contains enterovirus D68, the virus recently linked to causing childhood [[paralysis]].
* Enterovirus E to L — do not infect humans.
* Rhinovirus A to C — rhinovirus is a common cold virus.
The enterovirus genus is part of the [[picornavirus]] family (Picornaviridae).

== Enterovirus serotypes ==

=== Poliovirus ===
{{Main article | page_name = Poliovirus}}
Poliovirus is the cause of the paralytic disease known as [[poliomyelitis]].<ref>[http://www.virology.ws/2004/08/18/poliovirus/ Poliovirus - Virology Blog]</ref> A study of poliovirus found that polio infection rapidly decreases cellular [[oxygen]] consumption (and thus energy production through [[cellular respiration]]) by inhibiting [[succinate dehydrogenase]] and blocking [[Mitochondria|mitochondrial]] electron transport.<ref>{{Cite journal|url=https://www.ncbi.nlm.nih.gov/pubmed/10814509|title=Poliovirus Induces an Early Impairment of Mitochondrial Function by Inhibiting Succinate Dehydrogenase Activity|last=Koundouris|first=A|date=May 2000|journal=Biochemical and Biophysical Research Communications|volume=271|pages=610-4|via=}}</ref>

=== Coxsackievirus ===
{{Main article | page_name =Coxsackievirus}}

=== Coxsackie A virus ===
{{Main article | page_name =Coxsackie A virus}}

=== Coxsackie B virus ===
{{Main article | page_name =Coxsackie B virus}}

[[Coxsackie B]] (also written coxsackievirus B) is a group of six types of [[enterovirus]], causing symptoms ranging from gastrointestinal distress to pericarditis and myocarditis. Symptoms of infection with viruses in the Coxsackie B grouping include fever, [[headache]], [[sore throat]], gastrointestinal distress, extreme [[fatigue]] as well as [[Chest pain|chest]] and [[muscle pain]]. It can also lead to [[Spasm|spasms]] in arms and legs. Numerous studies have found evidence of persistent infection of Coxsackie B in the [[blood]], muscle, [[gut]] and brain in a subset of patients with diagnosed with myalgic encephalomyelitis and chronic fatigue syndrome.<ref>{{Cite journal|last=Landay|first=AL|date=September 1991|title=Chronic fatigue syndrome: clinical condition associated with immune activation|url=https://www.ncbi.nlm.nih.gov/pubmed/1679864|journal=Lancet|volume=|pages=|via=}}</ref><ref name=":02">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref name="Fegan1983">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder1984">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref><ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=Chronic Enterovirus Infection In Patients With Postviral Fatigue Synfrome|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref><ref name=":03">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref><ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref>

=== Echovirus ===
{{Main article | page_name =Echovirus}}

== Acute enterovirus infections ==
Enteroviruses can infect a wide array of organs in the body, and thus a given enterovirus serotype may cause a variety of different acute infections, and its symptoms in one person can be quite different to the symptoms it creates in the next person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses:<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 1:24.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=}}</ref><ref>{{Cite web|url=https://www.enterovirusfoundation.org/the-symptoms/|title=Symptoms and Signs of an Enterovirus Infection.|last=|first=|date=|website=Enterovirus Foundation|archive-url=|archive-date=|dead-url=|access-date=}}</ref><ref>{{Cite web|url=https://www.cdc.gov/non-polio-enterovirus/about/symptoms.html|title=Non-Polio Enterovirus: Symptoms.|last=|first=|date=|website=CDC Website|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* '''Respiratory''' — [[Sinusitis|rhinosinusitis]], h[[wikipedia:Herpangina|erpangina,]] [[wikipedia:Mouth_ulcer|mouth ulcer]], s[[wikipedia:Sore_throat|ore throat,]] [[wikipedia:Mouth_ulcer|t]][[wikipedia:Tonsillitis|onsillitis]][[wikipedia:Tonsillitis|,]] [[pharyngitis]], [[wikipedia:Croup|croup,]] [[bronchitis]], [[bronchiolitis]], [[pleurisy]], [[pneumonia]].
* '''Gastrointestinal''' — [[wikipedia:Gastroenteritis|gastroenteritis]], [[vomiting]], [[diarrhea]], [[gastritis]], [[wikipedia:Peyer's_patch|peyer's patches,]] terminal [[ileitis]], [[wikipedia:Enterocolitis|enterocolitis]], [[hepatitis]], [[pancreatitis]], [[GERD]], [[Indegestion|functional dyspepsia]].
* '''Oral ''' — [[wikipedia:Herpangina|herpangina,]] [[wikipedia:Mouth_ulcer|mouth ulce]]<nowiki/>rs, [[wikipedia:Enanthem|enanthem]]
* '''Immune manifestations''' — prolonged [[Fever|fevers]] (102 to 104ºF) lasting 3 weeks, [[leukopenia]], [[lymphopenia]], [[bone marrow]] failure.
* '''Central nervous system''' — [[meningitis]], [[encephalitis]], [[myelitis]], [[Guillain-Barré syndrome]], epidemic [[vertigo]] and [[Deaf|deafness]].
* '''Cardiovascular''' — [[myocarditis]], [[pericarditis]], [[myopericarditis]], [[endocarditis]].
* '''Musculoskeletal''' — acute [[myositis]], [[rhabdomyolysis]], [[arthralgia]] and [[arthritis]], pleurodynia ([[Bornholm disease]]).
* '''Genito-urinary tract''' — [[epididymitis]], [[orchitis]], [[salpingitis]] (fallopian tube inflammation), [[prostatitis]].
* '''Skin''' — [[vesicles]], [[maculopapular rash]], [[petechiae]], [[urticaria]], [[vasculitis]].
* '''Oral''' — [[enanthem]] (rash on the mucous membranes), [[herpangina]], tongue and oral [[ulcers]].
* '''Other illnesses''' — [[hand, foot, and mouth disease]], [[hemorrhagic conjunctivitis]], [[poliomyelitis]], acute [[flaccid paralysis]], [[inflammatory muscle disease]].

Note that enterovirus is able to mimic a [[chickenpox]] rash: if a patient previously had chickenpox, and then develops a [[flu-like illness]] with a chickenpox-like [[rash]], that is likely due to enterovirus. But an enterovirus rash can also look like [[measles]], German measles ([[rubella]]) and can look like [[hives]].<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 7:29.|last=Chia|first=John|date=2010|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Enterovirus is the greatest mimicker of chickenpox. If the patient already had chickenpox before and they then develop flu-like illness with chickenpox-like rashes that's enterovirus until proven otherwise. But the rash could look like measles, German measles, it could look like hives.}}</ref> Enteroviruses are the only group of viruses able to routinely infect the [[Muscle|muscles]], [[heart]] and [[central nervous system]]. Other viruses can infect one or two of these organs, but not all three.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 8:08.|last=Chia|first=John|date=2011|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Only one group of viruses that routinely will go to the muscles heart and the brain, and that's enteroviruses.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 2:13.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=These viruses can then spread to the central nervous system, the heart, and also muscles. As a group these are viruses are actually the only virus that can actually to go to all three sites, OK. The other viruses can go to one or two and others.}}</ref>

The incubation period (time between catching the virus and the appearance of its first acute symptoms) for coxsackieviruses is three to five days,<ref>{{Cite web|url=https://www.msdsonline.com/resources/msds-resources/free-safety-data-sheet-index/coxsackievirus/|title=Coxsackievirus — Material Safety Data Sheet - Infectious Substances|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> and the incubation period for echovirus is two to 14 days.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/laboratory-biosafety-biosecurity/pathogen-safety-data-sheets-risk-assessment/echovirus-pathogen-safety-data-sheet.html|title=Pathogen Safety Data Sheets: Infectious Substances – Echovirus|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) [[meningitis]].<ref>{{Cite web|url=https://emedicine.medscape.com/article/215241-clinical#b5|title=Coxsackieviruses Clinical Presentation (Medscape article)|last=Muller|first=Martha L|date=|website=Medscape|archive-url=|archive-date=|dead-url=|access-date=|quote=Coxsackievirus B (serotypes 2-5) and echoviruses account for more than 90% of viral causes of aseptic meningitis.}}</ref> Evidence of enteroviral infection in the myocardium or endocardium tissues of the heart is detected in 40% of those who died suddenly of a [[heart attack]], though it is not clear whether enterovirus causes these heart attacks.<ref>{{Cite journal|last=Andréoletti|first=Laurent|last2=Ventéo|first2=Lydie|last3=Douche-Aourik|first3=Fatima|last4=Canas|first4=Frédéric|last5=Lorin de la Grandmaison|first5=Geoffroy|last6=Jacques|first6=Jérôme|last7=Moret|first7=Hélène|last8=Jovenin|first8=Nicolas|last9=Mosnier|first9=Jean-François|date=2007-12-04|title=Active Coxsackieviral B infection is associated with disruption of dystrophin in endomyocardial tissue of patients who died suddenly of acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/18061067|journal=Journal of the American College of Cardiology|volume=50|issue=23|pages=2207–2214|doi=10.1016/j.jacc.2007.07.080|issn=1558-3597|pmid=18061067}}</ref> Another study found 26% of heart attack patients had serological evidence of a very recent coxsackievirus B infection.<ref>{{Cite journal|last=Nicholls|first=A. C.|last2=Thomas|first2=M.|date=1977-04-23|title=Coxsackie virus infection in acute myocardial infarction|url=https://www.ncbi.nlm.nih.gov/pubmed/67289|journal=Lancet (London, England)|volume=1|issue=8017|pages=883–884|issn=0140-6736|pmid=67289}}</ref>

== Chronic enterovirus infections ==
{{Main article|page_name=Non-cytolytic enterovirus}}Like most RNA viruses, enterovirus is not capable of assuming a latent state within cells, and enterovirus infections are generally considered to be acute and rapidly cleared by the host immune response.<ref name=":6">{{Cite journal|last=Kim|first=K.-S.|last2=Tracy|first2=S.|last3=Tapprich|first3=W.|last4=Bailey|first4=J.|last5=Lee|first5=C.-K.|last6=Kim|first6=K.|last7=Barry|first7=W. H.|last8=Chapman|first8=N. M.|date=Jun 2005|title=5'-Terminal deletions occur in coxsackievirus B3 during replication in murine hearts and cardiac myocyte cultures and correlate with encapsidation of negative-strand viral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/15890942/|journal=Journal of Virology|volume=79|issue=11|pages=7024–7041|doi=10.1128/JVI.79.11.7024-7041.2005|issn=0022-538X|pmc=1112132|pmid=15890942|quote=Picornavirus infections are generally considered to be acute and cleared rapidly by the host adaptive immune response.|via=}}</ref><ref name=":7">{{Cite journal|last=Flynn|first=Claudia T.|last2=Kimura|first2=Taishi|last3=Frimpong-Boateng|first3=Kwesi|last4=Harkins|first4=Stephanie|last5=Whitton|first5=J. Lindsay|date=Dec 2017|title=Immunological and pathological consequences of coxsackievirus RNA persistence in the heart|url=http://linkinghub.elsevier.com/retrieve/pii/S0042682217303264|journal=Virology|volume=512|pages=104–112|doi=10.1016/j.virol.2017.09.017|issn=0042-6822|pmc=5653433|pmid=28950225|quote=until relatively recently, enteroviruses were thought to cause only acute infections, and to be completely eradicated with ~ 2 weeks of the primary infection.|via=}}</ref> Indeed, [[John Chia]] points out that even today, most physicians are taught that enterovirus does not form chronic infections.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC10.shtml|title=Enteroviruses and Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: An Update on Pathogenesis. Presentation at the Invest in ME International ME Conference, London 2015 (available on DVD). Timecode: 3:10.|last=Chia|first=John|date=2015|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

However, it is now understood that enterovirus B serotypes such as coxsackievirus B and echovirus are capable of mutating during the acute infection into an aberrant viral form called [[non-cytolytic enterovirus]] that can cause persistent low-level infections. These persistent non-cytolytic enterovirus infections deriving from mutated enterovirus B serotypes are found in ME/CFS and several other chronic illnesses, including chronic myocarditis, dilated cardiomyopathy, type 1 diabetes, [[motor neuron disease]] and [[Parkinson's disease]].

Non-cytolytic enterovirus consists of mutated naked viral RNA which produces persistent [[intracellular infections]] inside host cells, and does not readily kill the cells in which it resides. Although this infection replicates very slowly, it nevertheless produces all the normal [[Viral protein|viral proteins]], and these proteins may have pathological disease-causing effects in the host. Persistent non-cytolytic enterovirus is resistant to immune clearance, and can thus reside inside host cells for very long periods. Non-cytolytic enterovirus infections are characterized by a decreased ratio of positive to negative strand viral RNA: whereas in normal acute enterovirus infections, this ratio is around 100:1, in persistence non-cytolytic infections, the ratio has a value closer to 1:1.

== Diagnosis of chronic enterovirus infections ==
Dr John Chia uses the following tests to detect chronic enterovirus infection in ME/CFS patients:<ref>{{Cite web|url=https://www.enterovirusfoundation.org/treatments-1/|title=Enterovirus Foundation — Diagnose & Treat|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

'''ARUP Lab micro-neutralization blood tests for enterovirus antibodies'''. Titers of 1:160 to 1:320 or higher on the ARUP Lab [http://ltd.aruplab.com/tests/pub/0060055 coxsackievirus B test] and [http://ltd.aruplab.com/tests/pub/0060053 echovirus test] suggest chronic active infection. These tests use the very sensitive gold standard neutralization method of measuring antibody levels. The ARUP lab test will indicate which particular enterovirus serotypes are present and active in the patient (out of coxsackievirus B1 to B6, and echovirus 6, 7, 9, 11, and 30). Other methods of antibody levels such as ELISA or IFA are less sensitive, and thus may not be reliable. The CFT method of testing for enterovirus antibodies is insensitive and useless for chronic enterovirus infection.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC4.shtml|title=Diagnosis and Treatment of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome Associated with Chronic Enterovirus Infection. Presentation at the Invest in ME International ME Conference, London 2009 (available on DVD). Timecode: 27:51.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=2009|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=The typical antibody that the laboratory would do is called the complement fixation test, which is neither sensitive nor specific. That means if you get a positive test, it's worthless. And if you get a negative test, it's worthless. Well that's wonderful.}}</ref>

'''Stomach biopsy (immunohistochemistry)'''. This test, which requires a sample of stomach tissue obtained by an endoscope and to be sent to [http://www.evmedresearch.com/Immunoperoxidase_Staining_Request_Form250.pdf Dr Chia's lab] for analysis, is the most sensitive for detecting a chronic enteroviral infection, although unlike the ARUP Lab blood tests, the stomach biopsy will not indicate which particular CVB and EV serotypes you have.[[File:Tender spots in enterovirus infection. Dr John Chia Invest in ME Conference London 2009.png|thumb|Pain or tenderness at the X points suggest enterovirus infection of the abdomen. Dr John Chia, Invest in ME Conferences London.]]

Note that PCR testing of the blood is not considered sensitive for chronic enterovirus infections. Since viruses are cleared quickly from the bloodstream, the chance of finding viral gene or RNA in the blood by reverse transcription-PCR technique is low in chronic infection. Dr Chia found that with special techniques and repeated testing, enterovirus RNA can be found in close to thirty percent of whole blood samples taken from chronically infected EV patients.

Dr Chia says that a fairly reliable sign of chronic enterovirus infection of the abdomen in ME/CFS patients is abdominal tenderness or pain in the epigastric area, in the right lower quadrant, and in the left lower quadrant (see the three X's in the abdomen picture). Epigastric pain or tenderness indicates enterovirus infection of the stomach. Right lower quadrant pain or tenderness suggests enterovirus infection of the terminal ileum. Left lower quadrant pain or tenderness suggests enterovirus infection in the small bowel or colon.<ref>{{Cite web|url=http://www.investinme.eu/IIMEC5.shtml|title=Dr John Chia: Enterovirus Infection in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2010 (available on DVD). Timecode: 19:30.|last=Chia|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=Here is a young lady's abdomen: you can notice that there's some viral distention, the patient consistently complaining of epigastric pain, nausea, right lower quadrant pain, and left lower quadrant pain. And when I pushed on it, on these X's, can definitely tell me, the tenderness. This is actually a fairly reliable sign to detect enterovirus infection of the abdomen.}}</ref><ref>{{Cite web|url=http://www.investinme.eu/IIMEC6.shtml|title=Clinical and Research Experience of Enteroviral Involvement in ME/CFS. Presentation at the Invest in ME International ME Conference, London 2011 (available on DVD). Timecode: 14:35.|last=Chia:|first=John|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=|quote=This is actually a very helpful clinical finding. As you know in the definition of ME/CFS, there is sore throat, and ... ... ok, but there is very little attention to the abdominal symptoms, which most patients actually have. Patients often complain of pain up here, here's the rib cage, end of the rib cage, this is where the stomach is. They oftentimes have pain in the right lower quadrant, roughly where the appendix is, and that's the end of the terminal ileum, as I have shown you in the case before. They oftentimes have tenderness in the left lower quadrant, that either the small bowel here, or the colon, which we are actually able to show proteins or viral RNA in these areas.}}</ref>

== Enterovirus in myalgic encephalomyelitis ==
Ever since the [[Epidemic myalgic encephalomyelitis|historic outbreaks]] of ME/CFS in the 1930s-1970s, enteroviruses, especially [[Coxsackie B]] <nowiki/>viruses, have been [[Enteroviral infection hypothesis|posited]] <nowiki/>as a key etiological factor in [[myalgic encephalomyelitis]]. These frequently coincided with outbreaks of [[polio]], another enterovirus. Findings in several outbreaks seemed to suggest that symptoms were caused by a virus distinct from but related to polio including findings of mild, diffuse [[peripheral nervous system]] damage in monkeys infected with the virus; a stronger response to polio [[Vaccine|vaccination]] in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.<ref name=":06">{{Cite journal|last=Parish|first=JG|date=1978|title=Early outbreaks of 'epidemic neuromyasthenia'|url=https://www.ncbi.nlm.nih.gov/pubmed/370810|journal=Postgraduate Medical Journal|volume=54|pages=711-7|via=}}</ref>

In addition to data from ME/CFS outbreaks, there have been over 30 studies on enterovirus infections in ME/CFS (see [[list of enterovirus infection studies]]), and most studies have found enterovirus present in ME/CFS patients' [[Muscle tissue|muscle tissues]], [[Stomach tissue|stomach tissues]], [[Brain tissue|brain tissues]] and [[Blood cell|blood cells]] (though a few studies have failed to find enterovirus in ME/CFS). The chronic enterovirus infections found in ME/CFS have been shown to be of the non-cytolytic form (a reduced ratio of positive to negative strand viral RNA is found in the infections in ME/CFS patients' tissues, which is a signature of non-cytolytic infection).<ref>{{Cite journal|last=Cunningham|first=L.|last2=Bowles|first2=N. E.|last3=Lane|first3=R. J.|last4=Dubowitz|first4=V.|last5=Archard|first5=L. C.|date=Jun 1990|title=Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA|url=https://www.ncbi.nlm.nih.gov/pubmed/2161907|journal=The Journal of General Virology|volume=71 ( Pt 6)|pages=1399–1402|doi=10.1099/0022-1317-71-6-1399|issn=0022-1317|pmid=2161907}}</ref>
===Evidence for enterovirus infection in ME/CFS ===

==== Antibody testing ====
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks.<ref name="Fegan19832">{{Citation
| last1 = Fegan | first1 = KG | authorlink1 = KG Fegan
| last2 = Behan | first2 = PO | authorlink2 = Peter Behan
| last3 = Bell | first3 = EJ | authorlink3 = Eleanor Bell
| title = Myalgic encephalomyelitis — report of an epidemic
| journal = J R Coll Gen Pract | volume = 33| issue = 251| pages = 335–337
| date = 1 Jun 1983
| pmid = 6310104
| url = http://bjgp.org/content/33/251/335
}}</ref><ref name="Calder19842">{{Citation
| last1 = Calder | first1 = BD | authorlink1 = BD Calder
| last2 = Warnock | first2 = PJ | authorlink2 = PJ Warnock
| title = Coxsackie B infection in a Scottish general practice
| journal = Jrnl Royal Coll Gen Pract | volume = 34| issue = 258| pages = 15–19
| date = Jan 1984
| pmid = 6319691
| url = http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1959663/
}}</ref> In a retrospective cohort study<ref name="Dowsett19902">{{Citation
| last1 = Dowsett | first1 = EG | authorlink1 = Elizabeth Dowsett
| last2 = Ramsay | first2 = AM | authorlink2 = Melvin Ramsay
| last3 = McCartney | first3 = RA | authorlink3 = Robert McCartney
| last4 = Bell | first4 = EJ | authorlink4 = Eleanor Bell
| title = Myalgic encephalomyelitis--a persistent enteroviral infection?
| journal = Postgraduate Medical Journal | volume = 66| issue = 777| pages = 526–530
| date = 1 Jul 1990
| pmid = 2170962 | doi = 10.1136/pgmj.66.777.526
| url = http://pmj.bmj.com/content/66/777/526
}}</ref> by [[Melvin Ramsay]] and [[Elizabeth Dowsett]], 31% of the patients were found to have elevated enteroviral IgM antibody levels. Sixteen of these patients were retested annually over three years and all showed persistently elevated Coxsackie B neutralizing antibody levels and intermittently positive enteroviral [[Immunoglobulin M|IgM]], suggesting a persistent infection was present.

Similarly, a study of of 76 patients with [[postviral fatigue syndrome]] (PVFS) found that 76% had detectible IgM responses to enteroviruses. 22% had positive cultures (compared to 7% controls) and [[VP1 antigen]] was detected in 51%, all pointing to a chronic infection in many post-viral patients.<ref>{{Cite journal|last=Yousef|first=G.E.|date=January 1988|title=CHRONIC ENTEROVIRUS INFECTION IN PATIENTS WITH POSTVIRAL FATIGUE SYNDROME|url=https://www.sciencedirect.com/science/article/pii/S0140673688927225|journal=The Lancet|volume=|pages=|via=}}</ref> However, a larger study in Scotland of 243 [[Postviral fatigue syndrome|PVFS]] patients and matched controls found no difference in IgM and [[Immunoglobulin G|IgG]] positivity between patients and controls.<ref>{{Cite journal|last=Miller|first=N A|date=1991|title=Antibody to Coxsackie B virus in diagnosing postviral fatigue syndrome|url=https://www.bmj.com/content/302/6769/140.short|journal=The British Medical Journal|volume=|pages=|via=}}</ref>

Through antibody testing, Dr John Chia [http://quixoticmeblog.blogspot.com/2014/10/dr-c-recommends-new-treatment-plan.html observes] that the coxsackievirus B (CVB) and echovirus (EV) serotypes most often found in ME/CFS are:
* CVB3 and CVB4 first and foremost
* Then CVB2, EV6, EV7 and EV9
* And then much less EV11
Dr Chia finds that ME/CFS patients have antibody titers for the above enterovirus serotypes at significantly levels higher than those found in healthy controls, which is suggestive of chronic active infection. But Dr Chia points out that ME/CFS patients may have chronic infections with enteroviruses that cannot be detected and typed by antibody blood tests (but which are detectable by stomach tissue biopsy).
==== Polymerase chain reaction ====
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by [[Polymerase chain reaction]] (PCR), compared to only 9% of the comparison group.<ref>{{Cite journal|last=Nairn|first=C|date=August 1995|title=Comparison of coxsackie B neutralisation and enteroviral PCR in chronic fatigue patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7595406|journal=Journal of Medical Virology|volume=|pages=|via=}}</ref>

Also using PCR, a study of 236 patients by John Chia found enteroviral [[RNA]] in 48% of patients as compared to 8% of controls.To date, Chia reports finding enteroviral RNA in 35% of 518 patients.<ref name=":04">{{Cite journal|last=Chia|first=John|date=November 2005|title=The role of enterovirus in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/|journal=Journal of Clinical Pathology|volume=|pages=|via=}}</ref>

==== Muscle biopsy ====
Several muscle biopsy studies have also found the presence of Coxsackie B RNA sequences in CFS patients as compared to controls. A study of 60 PVFS patients found 53% had enteroviral RNA in muscle compared to 15% of controls.<ref>{{Cite journal|last=Gow|first=JW|date=|title=Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/1850635|journal=British Medical Journal|volume=|pages=|via=}}</ref> However, a follow-up study comparing CFS patients to patients with other [[Neuromuscular disease|neuromuscular disorders]] failed to find a statistically significant difference.<ref>{{Cite journal|last=Gow|first=JW|date=1994|title=Studies on enterovirus in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8148439/|journal=Clin Infect Dis.|volume=18|pages=S126-9|via=}}</ref>
==== Gut biopsy ====

Research by John Chia and his son, [[Andrew Chia]] has looked for enteroviruses in [[gut biopsies]]. 82% of samples were positive for [[viral capsid protein 1]] (VP1), compared to 20% of controls. Enteroviral RNA was detected in 37% of biopsy samples, compared to 4.7% of controls. They posit that a subset of [[chronic fatigue syndrome]] (CFS) patients have a chronic enteroviral infection.<ref name="ChiaJKS2016" />

==== Brain autopsy ====

{{Main article | page_name =Post-mortem brain studies}}

Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.

== Other conditions ==

=== Type 1 Diabetes ===
Several studies have suggested a relationship between Coxsackie B4 and the onset of [[Type 1 diabetes]].<ref>{{Cite journal|last=Gamble|first=D. R.|last2=Taylor|first2=K. W.|last3=Cumming|first3=H.|date=1973-11-03|title=Coxsackie Viruses and Diabetes Mellitus|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1587352/|journal=British Medical Journal|volume=4|issue=5887|pages=260–262|issn=0007-1447|pmc=1587352|pmid=4753237}}</ref><ref>{{Cite journal|last=Ylipaasto|first=P.|last2=Klingel|first2=K.|last3=Lindberg|first3=A. M.|last4=Otonkoski|first4=T.|last5=Kandolf|first5=R.|last6=Hovi|first6=T.|last7=Roivainen|first7=M.|date=2004-02-01|title=Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells|url=http://link.springer.com/article/10.1007/s00125-003-1297-z|journal=Diabetologia|language=en|volume=47|issue=2|pages=225–239|doi=10.1007/s00125-003-1297-z|issn=0012-186X}}</ref><ref>{{Cite journal|last=Bason|first=Caterina|last2=Lorini|first2=Renata|last3=Lunardi|first3=Claudio|last4=Dolcino|first4=Marzia|last5=Giannattasio|first5=Alessandro|last6=d’Annunzio|first6=Giuseppe|last7=Rigo|first7=Antonella|last8=Pedemonte|first8=Nicoletta|last9=Corrocher|first9=Roberto|date=2013-02-28|title=In Type 1 Diabetes a Subset of Anti-Coxsackievirus B4 Antibodies Recognize Autoantigens and Induce Apoptosis of Pancreatic Beta Cells|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057729|journal=PLOS ONE|language=en|volume=8|issue=2|pages=e57729|doi=10.1371/journal.pone.0057729|issn=1932-6203|pmc=3585221|pmid=23469060}}</ref>

A study of patients with Type 1 [[Diabetes]] found that [[Coxsackie B4]] was found to infect the β cells in the [[pancreatic islets]] of the [[pancreas]] and cause [[inflammation]] mediated by [[natural killer cell]]s (NKC).<ref>http://www.pnas.org/content/104/12/5115.full</ref>

=== Gastroparesis ===
A very small observational study found that nine out of ten patients with symptoms of [[gastroparesis]] had positive [[Gastric tissue biopsy|gastric biopsies]] for enterovirus.<ref name="BarkinJA, 20162">{{Citation
| last1 = Barkin | first1 = JA | authorlink1 =
| last2 = Czul | first2 = F | authorlink2 =
| last3 = Barkin | first3 = JS | authorlink3 =
| last4 = Klimas | first4 = NG | authorlink4 = Nancy Klimas
| last5 = Rey | first5 = IR | authorlink5 = Irma Rey
| last6 = Moshiree | first6 = B | authorlink6 =
| title = Gastric Enterovirus Infection: A Possible Causative Etiology of Gastroparesis
| journal = Digestive Diseases and Sciences | volume = 61 | issue = 8 | page = 2344-50
| date = 2016
| pmid = 27344315
| doi = 10.1007/s10620-016-4227-x
}}</ref>

== Treatment ==

There are no [[U.S. Food and Drug Administration|FDA]] approved treatments for enteroviruses. The drug [[Pleconaril]] has been shown to have activity against a number of enteroviruses<ref name="Rotbart2001" /><ref name="Pevear1999" /><ref name="Bauer2002" /><ref name="Groarke1999" /><ref name="Abzug2016" /> but has not been approved by the FDA.

Treatment usually involves supporting the [[immune response]] particularly in those with documented [[immune dysfunction]]. Dr. Chia treats his patients with enteroviral infection with [[Equilibrant]], [[gammaglobulin]] and [[interferon]].<ref name="evmed-treatment" />

==Talks and interviews==

*2016, [https://youtu.be/mZdG2otpC3w ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD]

==Learn More==
* [http://www.enteroviruses.com/ Enteroviruses: Health, Learn, Live]
* [https://www.enterovirusfoundation.org/the-symptoms/ Enterovirus Foundation: Signs and Symptoms]
* [https://emedicine.medscape.com/article/217146-overview Enteroviruses (Medscape article)]
* [https://www.cdc.gov/non-polio-enterovirus/index.html Non-Polio Enterovirus (CDC article)]
* [https://www.youtube.com/watch?v=Xz7CaxWtCUU Dr John Chia, International Symposium on Viruses In CFS 2008, ''The Role of Enterovirus in ME/CFS'']
* [https://www.youtube.com/watch?v=obHtCwhg3-0 Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 1]
* [https://www.youtube.com/watch?v=BO-yxqZuXTY Dr John Chia, State of Knowledge Workshop on ME/CFS Research 2011 (Day 1) Part 2]
* [http://www.investinme.eu/IIMEC10.shtml Dr John Chia, Invest in ME International ME Conference 2015: ''Enteroviruses and ME/CFS: An Update on Pathogenesis''. Available on DVD]
* [http://www.investinme.eu/IIMEC6.shtml Dr John Chia, Invest in ME International ME Conference 2011: ''Clinical and Research Experience of Enteroviral Involvement in ME/CFS''. Available on DVD]
* [http://www.investinme.eu/IIMEC5.shtml Dr John Chia, Invest in ME International ME Conference 2010: ''Enteroviruses in ME/CFS, Diagnosis and Treatment''. Available on DVD]
* [http://www.anapsid.org/cnd/diffdx/polio1.html ME/CFS and Polio], chapter from book "ME: The New Plague", Jane Colby.<ref name="ColbyJ1996" />

==See Also==

*[[Coxsackie B]]
*[[Enteroviral infection hypothesis]]
*[[Irving Spurr]]
*[[James Mowbray]]
*[[John Chia]]
*[[John Richardson]]
*[[List of enterovirus infection studies]]
*[[Non-cytolytic enterovirus]]
*[[Post-mortem brain studies]]

==References==
<references>
<ref name="Abzug2016">{{Citation
| last1 = Abzug | first1 = Mark J
| last2 = Michaels | first2 = Marian G
| last3 = Wald | first3 = Ellen
| last4 = Jacobs | first4 = Richard F
| last5 = Romero | first5 = José R
| last6 = Sánchez | first6 = Pablo J
| last7 = Wilson | first7 = Gregory
| last8 = Krogstad | first8 = Paul
| last9 = Storch | first9 = Gregory A
| last10 = Lawrence | first10 = Robert
| last11 = Shelton | first11 = Mark
| last12 = Palmer | first12 = April
| last13 = Robinson | first13 = Joan
| last14 = Dennehy | first14 = Penelope
| last15 = Sood | first15 = Sunil K
| last16 = Cloud | first16 = Gretchen
| last17 = Jester | first17 = Penelope
| last18 = Acosta | first18 = Edward P
| last19 = Whitley | first19 = Richard
| last20 = Kimberlin | first20 = David
| last21 = National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group
| display-authors = 3
| title = A Randomized, Double-Blind, Placebo-Controlled Trial of Pleconaril for the Treatment of Neonates With Enterovirus Sepsis
| journal = Journal of the Pediatric Infectious Diseases Society | volume = 5| issue = 1| pages = 53–62
| date = Mar 2016
| pmid = 26407253 | doi = 10.1093/jpids/piv015
| url = http://journals.lww.com/pidj/Abstract/2003/04000/Double_blind_placebo_controlled_trial_of.9.aspx
}}</ref>
<ref name="Bauer2002">{{Citation
| last1 = Bauer | first1 = Sofia
| last2 = Gottesman | first2 = Giora
| last3 = Sirota | first3 = Lea
| last4 = Litmanovitz | first4 = Ita
| last5 = Ashkenazi | first5 = Shay
| last6 = Levi | first6 = Itzhak
| title = Severe Coxsackie virus B infection in preterm newborns treated with pleconaril
| journal = European Journal of Pediatrics | volume = 161| issue = 9| pages = 491–493
| date = 23 Jul 2002
| doi = 10.1007/s00431-002-0929-5
| url = http://link.springer.com/article/10.1007/s00431-002-0929-5
}}</ref>
<ref name="ChiaJKS2016">{{Citation
| last1 = Chia | first1 = JKS | authorlink1 = John Chia
| last2 = Chia | first2 = AY | authorlink2 = Andrew Chia
| title = Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach
| journal = Journal of Clinical Pathology | volume = 61| issue = 1| pages = 43–48
| date = 1 Jan 2008
| pmid = 17872383 | doi = 10.1136/jcp.2007.050054
| url = http://jcp.bmj.com/content/61/1/43
}}</ref>
<ref name="ColbyJ1996">| last1 = Colby | first1 = Jane | authorlink1 = Jane Colby
<nowiki>|</nowiki> title = Chronic Fatigue Syndrome: A polio by another name (chapter)
<nowiki>|</nowiki> journal = ME: The New Plague (book)
<nowiki>|</nowiki> date = 1996
}}</ref>
<ref name="evmed-treatment">{{citation
| title = Treatments for Chronic Fatigue Syndrome
| type = webpage
| journal = EvMed Research
| url = http://www.evmedresearch.com/education/treatment.php
}}</ref>
<ref name="Groarke1999">{{Citation
| last1 = Groarke | first1 = James M
| last2 = Pevear | first2 = Daniel C
| title = Attenuated Virulence of Pleconaril-Resistant Coxsackievirus B3 Variants
| journal = Journal of Infectious Diseases | volume = 179| issue = 6| pages = 1538–1541
| date = 1 Jun 1999
| pmid = 10228078 | doi = 10.1086/314758
| url = http://jid.oxfordjournals.org/content/179/6/1538
}}</ref>
<ref name="Pevear1999">{{Citation
| last1 = Pevear | first1 = Daniel C
| last2 = Tull | first2 = Tina M
| last3 = Seipel | first3 = Martin E
| last4 = Groarke | first4 = James M
| title = Activity of Pleconaril against Enteroviruses
| journal = Antimicrobial Agents and Chemotherapy | volume = 43| issue = 9| pages = 2109–2115
| date = 1 Sep 1999
| pmid = 10471549
| url = http://aac.asm.org/content/43/9/2109
}}</ref>
<ref name="Rotbart2001">{{Citation
| last1 = Rotbart | first1 = HA | authorlink1 = Harley A Rotbart
| last2 = Webster | first2 = AD | authorlink2 = A. David Webster
| title = Treatment of Potentially Life-Threatening Enterovirus Infections with Pleconaril
| journal = Clinical Infectious Diseases| volume = 32| issue = 2| pages = 228–235
| date = 15 Jan 2001
| pmid = 11170912 | doi = 10.1086/318452
| url = http://cid.oxfordjournals.org/content/32/2/228
}}</ref>
</references>


[[Category:Infectious agents]]
[[Category:Triggers and risk factors]]
[[Category:Virology]]
[[Category:Viruses]]
[[Category:Enteroviruses]]