Enterovirus

Enterovirus is a genus of positive single-stranded RNA viruses. Viruses in the enterovirus genus include coxsackievirus A (CVA), coxsackievirus B (CVB), echovirus, poliovirus and rhinovirus, though only CVB and echovirus have been linked to ME/CFS. Person-to-person transmission of enteroviruses occurs through fecal-oral and oral-oral routes.

Enteroviruses are responsible for a range of acute infections and acute illnesses, and but enterovirus infections (including CVB an echovirus) can often be subclinical or asymptomatic when contracted. Though normally only capable of acute infections, under certain circumstances enteroviruses can also create persistent infections, and chronic enterovirus infections have been found in ME/CFS and several other chronic illnesses in including dilated cardiomyopathy and type 1 diabetes, and some researchers posit that persistent enterovirus may be a cause of these diseases.

Enterovirus species
In the new classification system, the enterovirus genus contains 15 species of enterovirus, which are named enterovirus A to L and rhinovirus A to C. Enterovirus A to D infect humans, and are the enterovirus species of clinical significance. And it is the enterovirus B species which contains the CVB 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 — includes the 6 coxsackievirus B and 26 echovirus serotypes, as well as coxsackievirus A9.
 * Enterovirus C — contains further coxsackievirus A serotypes as well as the 3 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.

Acute enterovirus symptoms and illnesses
Enteroviruses can infect almost every organ in the body, and thus the same enterovirus serotype may cause a variety of different acute infections. This means the symptoms a given enterovirus causes in one person can be quite different to the symptoms it creates in another person.

During the acute phase of infection, enteroviruses may produce one or more of the following symptoms and illnesses: Note that enterovirus is able to mimic a chickenpox rash: if a patient previously had chickenpox, and then develops a flu-like illness with chickenpox-like rash, that's likely enterovirus. But the rash can also look like measles, German measles (rubella) and can look like hives. Enteroviruses are the only group of viruses able to routinely infect the muscles, heart and central nervous system. Other viruses can infect one or two of these organs, but not all three.
 * Respiratory — rhinosinusitis, pharyngitis, bronchitis, bronchiolitis, pleurisy, pneumonia.
 * Gastrointestinal — vomiting, diarrhea, gastritis, terminal ileitis, colitis, hepatitis, pancreatitis, GERD, functional dyspepsia.
 * Prolonged fevers (102 to 104ºF) lasting 3 weeks, leukopenia, lymphopenia, bone marrow failure.
 * CNS — meningitis, encephalitis, myelitis, Guillain-Barré syndrome, epidemic vertigo and 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.
 * 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.

Coxsackievirus B (serotypes B2 to B5) and echoviruses account for more than 90% of causes of viral (aseptic) meningitis.

Poliovirus
Poliovirus is the cause of the paralytic disease known as poliomyelitis."

Coxsackie B viruses
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 and muscle pain. It can also lead to 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.

Persistent infection
Some researchers believe that enteroviruses establish a persistent, intracellular, non-cytolytic infection, that is an infection that does not involve the destruction of infected cells. Non-cytolytic infection is difficult to measure in the serum as viral particles remain in the cell walls of tissues.

The molecular mechanisms of non-cytolytic infection were examined in a small study comparing Coxsackie B2 virus cultured in vitro to RNA extracted via muscle biopsy from eight patients with a chronic fatigue syndrome diagnosis. All patients had symptoms of muscle fatiguability. Four of these samples tested positive for enteroviral RNA. In all four patients with enteroviral-specific RNA, the enteroviral RNA had equal amounts of positive sense and negative sense RNA. By contrast, CVB2 virus in culture produced positive sense RNA at a ratio of 100:1. An equal ratio of positive to negative sense RNA would inhibit the translation of virus-specific gene products, explaining the failure to attract a response from the host immune system, and my account for how CVB2 could establish a persistent infection in these four patients.

Models of persistent infection of the heart and brain have also been studied in mice and in thyroid carcinoma.

Metabolic effects
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 mitochondrial electron transport.

Myalgic Encephalomyelitis
Ever since the historic outbreaks of ME in the 1930s-1950s, enteroviruses, especially Coxsackie B viruses, have been posited 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 vaccination in children who had been in epidemic areas; and seasonal patterns of infection resembling polio.

There is no consensus regarding the direct evidence for enteroviral persistence in ME patients, in part to different methods of testing and types of tissue samples. Several researchers have indicated that they have failed to find evidence of enteroviruses in the blood and cerebrospinal fluid of ME patients, whereas others maintain that a persistent infection can only be directly measured in tissue samples, for example muscle biopsies, stomach biopsies, or brain tissue.

Some studies have found evidence of enteroviral infection in muscle biopsies in a subset of patients, while others have failed to replicate those results.

Several studies have patients with ME to have persistently elevated levels of Coxsackie B IgM or IgG antibodies, circulating immune complexes containing viral antigen, or presence of enterovirus by PCR or culture, all indicating the possible presence of a persistent infection. Others studies failed to find a difference in rates of positivity between patients and controls. Differences in study outcomes may be due to the criteria used to define study cohorts as well as the techniques used.

Blood testing
Elevated Coxsackie B antibodies have been found in patients in at least two ME outbreaks. In a retrospective cohort study 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 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. However, a larger study in Scotland of 243 PVFS patients and matched controls found no difference in IgM and IgG positivity between patients and controls.

PCR
In a study of serum samples from 100 CFS patients and 100 healthy controls, 42% of patients were positive for Coxsackie B sequences by PCR, compared to only 9% of the comparison group.

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.

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 post-viral fatigue syndrome patients found 53% had enteroviral RNA in muscle compared to 15% of controls. However, a follow-up study comparing CFS patients to patients with other neuromuscular disorders failed to find a statistically significant difference.

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 patients have a chronic enteroviral infection.

Type 1 Diabetes
Several studies have suggested a relationship between Coxsackie B4 and the onset of Type 1 diabetes.

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 cells.

Gastroparesis
A very small observational study found that nine out of ten patients with symptoms of gastroparesis had positive gastric biopsies for enterovirus.

Treatment
There are no FDA-approved treatments for enteroviruses. The drug Pleconaril has been shown to have activity against a number of enteroviruses    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.

Published Studies

 * 2016, A study on brain tissue samples from a deceased ME patient found evidence of enterovirus specific genomic sequences and enteroviral protein in the patient's cerebral cortex.
 * 2016, A study on stomach tissue samples from CFS patients found that 82% of patients have evidence of chronic enterovirus infection of the stomach.
 * 2010, A longitudinal study found that a percentage of patients presenting to emergency care with acute enterovirus infection would go on to develop symptoms of ME and CFS and had demonstrable evidence of viral persistence.
 * 1996, A Swedish study using the Fukuda criteria was unable to find evidence of any persistent enteroviral infection in fecal samples, muscle biopsies, or cerebrospinal fluid.
 * 1995, In the CFS study group, 42% patients were positive for enteroviral sequences by PCR, compared to only 9% of the comparison group.
 * 1994, A second postmortem tissue study found positive enterovirus PCR sequences in the muscle, heart, brain stem, and hypothalamus of a deceased ME patient.
 * 1990, 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. "This suggests that entrovirus pesistence in muscle is due to a defect in control of viral RNA synthesis."
 * 1990, A retrospective cohort study found that 31% of ME patients had 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 IgM, indicating the possibility of a persistent infection.
 * 1988, A study of 76 postviral fatigue patients and 30 controls found significantly higher numbers of positive cultures and IgM responses to enteroviruses.
 * 1988, In one study, enterovirus-specific RNA three standard deviations greater than controls was found in muscle biopsies of 20% of ME patients studied.

Talks & interviews

 * 2016, - 86. ‪ME and the role of enteroviruses / ME en de rol van enterovirussen - Dr. Byron Hyde‬, MD

Learn More

 * List of enterovirus infection studies


 * ME/CFS and Polio, chapter from book "ME: The New Plague", Jane Colby.