Viral testing in ME/CFS

From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history

The viruses most commonly found in myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) patients as chronic infections are the two enteroviruses coxsackievirus B and echovirus; the three herpesviruses Epstein-Barr virus, HHV-6 and cytomegalovirus; and the coronavirus SARS-CoV-2. These are the infections that ME/CFS doctors will typically test for. Usually ME/CFS patients will have chronic infections with one or more of these viruses.

More rarely, ME/CFS may involve chronic infections with the following viruses, bacteria and protozoa: varicella zoster virus, parvovirus B19, Chlamydia pneumoniae, HHV-7, Coxiella burnetii, Giardia lamblia, Ross River virus and West Nile virus.

ME/CFS doctors normally employ antibody tests (which measure the immune response to the infection) in order to detect these chronic infections, rather than PCR blood tests (which directly detect the presence of the pathogen in the blood). This is because in ME/CFS, infections may be widespread in the body tissues (and so may elicit an antibody response), but usually very little virus is found in the blood; thus PCR blood tests will often come back negative, even though there may be an ongoing low-level infection in the tissues.

Certainly enterovirus is commonly found in the tissues of ME/CFS patients, as numerous studies have directly detected this virus in muscle, stomach and brain tissue biopsies (whereas the levels of enterovirus in the blood are so low that the virus often cannot be detected by blood PCR). Unfortunately there has been less interest in looking for herpesviruses in ME/CFS patient tissues; so although chronically high antibody levels to enteroviruses and/or herpesviruses are often found in ME/CFS, the bodily locations of the herpesvirus infections that may be eliciting this antibody response are less clear.

The enterovirus infections found in ME/CFS are proven to involve the non-cytolytic form of this virus, rather than just the productive form. Non-cytolytic enterovirus lives inside host cells on a long-term basis, as an intracellular infection of naked viral RNA which does not kill the cell. Similarly, one theory postulates the herpesvirus infections found in ME/CFS could involve an abortive form of herpesvirus (which has some commonalities to non-cytolytic infection), rather than just regular productive or latent/reactivated virus.

Note that ME/CFS doctors may interpret antibody results differently to regular infectious disease specialists: the latter tend to ignore chronic highly elevated IgG, dismissing this as just evidence of a past and now dormant infection (provided IgM is low); whereas ME/CFS doctors may view chronic highly elevated IgG as evidence of an ongoing low-level infection in the body tissues.

In the following sections, the testing protocols employed by leading ME/CFS doctors are detailed for each ME/CFS-associated virus and bacterium.

Coxsackievirus B and echovirus testing[edit | edit source]

Coxsackievirus B and echovirus have been linked to ME/CFS in over 30 studies. There are 6 coxsackievirus B (CVB) serotypes and 32 echovirus (EV) serotypes. All are part of the enterovirus genus. Enterovirus expert Dr John Chia says that the most common enterovirus serotypes found in his ME/CFS patients are CVB3 and CVB4 first and foremost, then CVB2, EV6, EV7 and EV9, and then much less EV11.[1]

Testing for these enteroviruses presents some difficulties, as in ME/CFS, there are hardly any viruses in the blood. Rather the virus is mainly found as a chronic low-level non-cytolytic infection in tissue areas such as the stomach, muscles and brain. Dr Chia finds in whole blood samples, sensitive reverse transcription PCR blood tests are positive only about 30% of the time in patients with enterovirus ME/CFS.[2]

So antibody tests are used to detect enterovirus in ME/CFS patients rather than blood PCR tests. However, Dr Chia found that tests using the neutralisation method of antibody measurement can more reliably detect the chronic low-level enterovirus infections found in ME/CFS, compared to other antibody measurement techniques such as CFT, ELISA and IFA, which may not be sensitive enough (these techniques are fine for acute enterovirus infections, where there is plenty of virus, but detecting low-level chronic infections requires a test with more sensitivity). The CFT test is particularly insensitive for chronic infections.[3] Antibody tests via the neutralisation method however are only offered in a small number of pathology labs worldwide.

For his own ME/CFS patients, Dr Chia uses the ARUP Lab micro-neutralisation tests for coxsackievirus B and echovirus. These are the tests recommended for testing chronic infections by the Enterovirus Foundation. Antibody titers of 1:160 to 1:320 and higher in the ARUP tests are good indicators of chronic infection, Dr Chia found.[4] In this video, Dr Chia explains how he calibrated the ARUP Lab tests to derive this 1:160 to 1:320 threshold for ME/CFS usage.[5] Note that in such neutralisation tests, the levels of IgM and IgG antibodies are usually pooled together, so the test result reflects the combined IgM + IgG antibody level.

Other pathology labs which offer coxsackievirus B or echovirus neutralisation tests include: Institute of Medical Virology, University Hospital Frankfurt am Main, Germany; Hellenic Pasteur Institute in Greece, Torlak Institute of Virology in Serbia, and Fleury Lab in Sao Paulo, Brazil.

Epstein-Barr virus testing[edit | edit source]

Epstein-Barr virus (EBV) has been linked to ME/CFS in many studies. There is a high 95% prevalence of EBV in the general adult population,[6] so most adults will have this virus in their system, but usually in a latent (inactive) state. However, in ME/CFS patients this virus may exist in a reactivated state.

After mononucleosis (glandular fever), which is mostly caused by EBV, ME/CFS was found as a sequelae in 9% of cases.[7] Another study found that at 6, 12 and 24 months after mononucleosis, 13%, 7% and 4% of patients respectively met the criteria for CFS,[8] indicating that in the first year or so, post-mononucleosis ME/CFS can clear up over time in some individuals, though it becomes a permanent illness in others.

Dr Martin Lerner asserts that ME/CFS patients have a chronic EBV infection if there are high antibody levels in the EBV VCA IgM and/or EA IgG diffuse tests;[9] a study[10] confirms that high antibody levels in either of these tests indicates EBV reactivation. Note that: EA = early antigen; VCA = virus capsid antigen (also denoted by CA), EBNA = Epstein-Barr nuclear antigen.

Note that the chronic EBV infections thought to exist in ME/CFS are not the same as those found in the rare and often fatal illness chronic active Epstein-Barr virus (CAEBV). In CAEBV, high EBV viral loads are found in the blood by PCR, whereas in ME/CFS, blood PCR tests are often negative for EBV.

HHV-6 testing[edit | edit source]

Human herpes virus 6 (HHV-6) has been linked to ME/CFS in many studies. HHV-6 is found in nearly 100% of adults, normally in a latent (inactive) state. However, ME/CFS patients may have a reactivated HHV-6 infection. Dr Martin Lerner asserts that if ME/CFS patients have both high HHV-6 IgM antibodies and high HHV-6 IgG antibodies, that indicates a reactivated HHV-6.[9] The HHV-6 Foundation state that in an IFA antibody test, if HHV-6 IgG is highly elevated relative to healthy controls, it indicates a recent infection or a smoldering chronic reactivated infection.[11]

Cytomegalovirus testing[edit | edit source]

Cytomegalovirus (CMV) has been linked to ME/CFS in many studies. CMV is found in around 58% of adults in the US,[12] normally in a latent inactive state. But ME/CFS patients may have a reactivated CMV infection. Dr Martin Lerner states that high levels of CMV IgG antibodies indicate a reactivated infection in ME/CFS. Dr Lerner says testing CMV IgM levels has no relevance in ME/CFS.[13]

SARS-CoV-2 testing[edit | edit source]

Since the COVID pandemic, the SARS-CoV-2 coronavirus has become a new addition to the set of viruses linked to ME/CFS. But no blood testing protocols for SARS-CoV-2 have yet been validated by ME/CFS researchers as a means to associate this virus to ME/CFS patients. However, patients whose ME/CFS appeared immediately after an acute COVID infection (as detected by a COVID lateral flow test or COVID PCR) will naturally assume their illness was triggered by SARS-CoV-2.

Varicella zoster virus testing[edit | edit source]

Varicella zoster virus (VZV) is found in 63% to 100% of the population.[14] VZV causes chickenpox, and VZV can reactivate later in life to cause shingles, a painful or itchy skin rash. Dr John Chia finds a very small percentage of ME/CFS cases are due to reactivated VZV, and this type of ME/CFS can be treated easily with antiviral drugs such as acyclovir, which improve the ME/CFS after just a few weeks.[15]

The shingles rash caused by VZV is distinctive enough on its own to make a diagnosis of VZV reactivation. Even the appearance of just one or two shingles blisters can indicate VZV reactivation. PCR testing of the shingles blister contents can confirm VZV reactivation, if confirmation is needed.[16]

VZV usually lives in a latent state in the nerve ganglia, but when it reactivates it typically leads to shingles; it has been hypothesized VZV reactivation in the nerve ganglia may cause ME/CFS.[17]

Parvovirus B19 testing[edit | edit source]

Parvovirus B19 is a rarer cause of ME/CFS.[18][19] This virus is found in 61% of adults,[20] normally in a latent (inactive) state. But ME/CFS due to parvovirus B19 involves an active infection. Dr John Chia diagnoses active parvovirus B19 infection when the PCR test is positive, or when there are high IgM antibodies.[21]

Note that an acute parvovirus B19 infection can cause false positive IgM antibody test results with blood tests for Epstein-Barr virus, cytomegalovirus, HHV-6, herpes simplex and Borrelia burgdorferi and others.[22][23] This is because parvovirus B19 IgM antibodies cross-react with the IgM antibodies of these other pathogens.

Chlamydia pneumoniae testing[edit | edit source]

Dr John Chia finds the intracellular bacterium Chlamydia pneumoniae is an uncommon but treatable cause of ME/CFS, and says that most ME/CFS patients with active Chlamydia pneumoniae will have high IgG antibody levels, with IgM being negative; however some patients with this infection will have low IgG levels. Thus low IgG levels do not necessarily mean you do not have active Chlamydia pneumoniae.[24]

74% of adults have antibodies to Chlamydia pneumoniae, and about 10% of adults have a persistent active infection, according to an Israeli study.[25]

Incubation periods[edit | edit source]

If the incubation period of the ME/CFS-triggering virus is known, this information can help identify the virus. The incubation period is the time between the initial exposure to the virus, and the appearance of its first acute symptoms (such as a sore throat, gastrointestinal upset or flu-like illness). Some ME/CFS patients may known where and when they contracted their virus, and in these cases, the incubation period may be calculated.

Incubation periods
Pathogen Incubation period Ref
Coxsackievirus B 2 to 6 days [26]
Echovirus 2 to 10 days [27]
Epstein-Barr virus 4 to 6 weeks [28]
Cytomegalovirus 4 to 6 weeks [29]
HHV-6 1 to 2 weeks [30]

Note that HHV-6 is is almost always acquired during infancy.

Learn more[edit | edit source]

Viral testing section of the ME/CFS Roadmap for Testing and Treatment.

See also[edit | edit source]

References[edit | edit source]

  1. Calvin, Patrick W. (October 12, 2014). "Quixotic: My M.E. Blog: Dr. C Recommends New Treatment Plan". Quixotic. Retrieved May 17, 2024.
  2. "Non-cytolytic enterovirus".
  3. Chia, John. "Invest in ME Conference 2009, Dr John Chia's Presentation". Timecode 27m 54s. 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.
  4. "Diagnose & Treat". Enterovirus Foundation. Retrieved May 17, 2024.
  5. Chia, John (June 2008). "The International Symposium on Viruses In Chronic Fatigue Syndrome and Post-Viral Fatigue. June 2008, Baltimore, Maryland, USA". Timecode 10m 34s.
  6. Kuri, Ashvin; Jacobs, Benjamin Meir; Vickaryous, Nikki; Pakpoor, Julia; Middeldorp, Jaap; Giovannoni, Gavin; Dobson, Ruth (June 12, 2020). "Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom". BMC Public Health. 20: 912. doi:10.1186/s12889-020-09049-x. ISSN 1471-2458. PMC 7291753. PMID 32532296.
  7. White, P. D.; Thomas, J. M.; Amess, J.; Crawford, D. H.; Grover, S. A.; Kangro, H. O.; Clare, A. W. (1998-12). "Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever". The British Journal of Psychiatry: The Journal of Mental Science. 173: 475–481. doi:10.1192/bjp.173.6.475. ISSN 0007-1250. PMID 9926075. Check date values in: |date= (help)
  8. Katz, Ben Z.; Shiraishi, Yukiko; Mears, Cynthia J.; Binns, Helen J.; Taylor, Renee (2009-07). "Chronic fatigue syndrome after infectious mononucleosis in adolescents". Pediatrics. 124 (1): 189–193. doi:10.1542/peds.2008-1879. ISSN 1098-4275. PMC 2756827. PMID 19564299. Check date values in: |date= (help)
  9. 9.0 9.1 Lerner, A. Martin; Beqaj, Safedin; Fitzgerald, James T.; Gill, Ken; Gill, Carol; Edington, James (May 24, 2010). "Subset-directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome". Virus Adaptation and Treatment. 2: 47–57. doi:10.2147/VAAT.S10695.
  10. Gold, Jeffrey E.; Okyay, Ramazan A.; Licht, Warren E.; Hurley, David J. (June 17, 2021). "Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation". Pathogens. 10 (6): 763. doi:10.3390/pathogens10060763. ISSN 2076-0817. PMC 8233978. PMID 34204243.
  11. "HHV-6A/B Testing | HHV-6 Foundation | HHV-6 Disease Information for Patients, Clinicians, and Researchers | Apply for a Grant". Retrieved May 17, 2024.
  12. Dollard, Sheila C.; Staras, Stephanie A. S.; Amin, Minal M.; Schmid, D. Scott; Cannon, Michael J. (2011-11). "National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity". Clinical and vaccine immunology: CVI. 18 (11): 1895–1899. doi:10.1128/CVI.05228-11. ISSN 1556-679X. PMC 3209034. PMID 21918114. Check date values in: |date= (help)
  13. Lerner, A. Martin. "ME/CFS Treatment Resource Guide for Practitioners" (PDF). A diagnosis of cytomegalovirus (CMV) infection is made with an elevated CMV IgG titer. The IgM titer for CMV is inaccurate and insensitive. The higher the CMV IgG titer, the greater the viral load.
  14. Eshleman, Emily; Shahzad, Aamir; Cohrs, Randall J (2011-3). "Varicella zoster virus latency". Future virology. 6 (3): 341–355. ISSN 1746-0794. PMC 3118253. PMID 21695042. Check date values in: |date= (help)
  15. "MECFS Alert Episode 38 - Interview with Dr. John Chia, Part 1". Timecode 6m 58s. Retrieved May 17, 2024.
  16. CDC (May 10, 2024). "Laboratory Testing for Varicella-Zoster Virus (VZV)". Chickenpox (Varicella). Retrieved May 18, 2024.
  17. Shapiro, Judith S. (2009-11). "Does varicella-zoster virus infection of the peripheral ganglia cause Chronic Fatigue Syndrome?". Medical Hypotheses. 73 (5): 728–734. doi:10.1016/j.mehy.2009.04.043. ISSN 1532-2777. PMID 19520522. Check date values in: |date= (help)
  18. Kerr, Jonathan R.; Bracewell, Janice; Laing, Ian; Mattey, Derek L.; Bernstein, Robert M.; Bruce, Ian N.; Tyrrell, David A. J. (2002-03). "Chronic fatigue syndrome and arthralgia following parvovirus B19 infection". The Journal of Rheumatology. 29 (3): 595–602. ISSN 0315-162X. PMID 11911112. Check date values in: |date= (help)
  19. Kerr, Jonathan R.; Gough, John; Richards, Selwyn C. M.; Main, Janice; Enlander, Derek; McCreary, Michelle; Komaroff, Anthony L.; Chia, John K. (2010-04). "Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis". The Journal of General Virology. 91 (Pt 4): 893–897. doi:10.1099/vir.0.017590-0. ISSN 1465-2099. PMID 20007355. Check date values in: |date= (help)
  20. Eis-Hübinger, A. M.; Oldenburg, J.; Brackmann, H. H.; Matz, B.; Schneweis, K. E. (1996-07). "The prevalence of antibody to parvovirus B19 in hemophiliacs and in the general population". Zentralblatt Fur Bakteriologie: International Journal of Medical Microbiology. 284 (2–3): 232–240. doi:10.1016/s0934-8840(96)80098-3. ISSN 0934-8840. PMID 8837383. Check date values in: |date= (help)
  21. Chia, John; Chia, Andrew (March 1, 2003). "Diverse Etiologies for Chronic Fatigue Syndrome" (PDF). Clinical Infectious Diseases. 36: 671.
  22. Berth, Mario; Bosmans, Eugene (2009-03). "Acute parvovirus B19 infection frequently causes false-positive results in Epstein-Barr virus- and herpes simplex virus-specific immunoglobulin M determinations done on the Liaison platform". Clinical and vaccine immunology: CVI. 16 (3): 372–375. doi:10.1128/CVI.00380-08. ISSN 1556-679X. PMC 2650871. PMID 19116304. Check date values in: |date= (help)
  23. Woods, Charles R. (2013-03). "False-Positive Results for Immunoglobulin M Serologic Results: Explanations and Examples". Journal of the Pediatric Infectious Diseases Society. 2 (1): 87–90. doi:10.1093/jpids/pis133. ISSN 2048-7193. PMID 26619450. Check date values in: |date= (help)
  24. Chia, John (August 1999). "Chronic Chlamydia pneumoniae Infection: A Treatable Cause of Chronic Fatigue Syndrome" (PDF). Clinical Infectious Diseases. 29.
  25. Ben-Yaakov, M.; Eshel, G.; Zaksonski, L.; Lazarovich, Z.; Boldur, I. (2002-05). "Prevalence of antibodies to Chlamydia pneumoniae in an Israeli population without clinical evidence of respiratory infection". Journal of Clinical Pathology. 55 (5): 355–358. doi:10.1136/jcp.55.5.355. ISSN 0021-9746. PMC 1769655. PMID 11986341. Check date values in: |date= (help)
  26. "Coxsackie B virus". Wikipedia. March 7, 2024.
  27. Canada, Public Health Agency of (September 17, 2001). "Pathogen Safety Data Sheets: Infectious Substances – Echovirus". Retrieved June 19, 2024.
  28. "Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono) Clinical Presentation: History, Causes, Physical Examination". Retrieved June 19, 2024.
  29. Zahid, Maleeha; Ali, Nisha; Saad, Muhammad; Kelly, Paul; Ortiz, Alfonso (July 16, 2020). "Acute Cytomegalovirus (CMV) Hepatitis in an Immunocompetent Adult". The American Journal of Case Reports. 21: e925495–1–e925495-5. doi:10.12659/AJCR.925495. ISSN 1941-5923. PMC 7387041. PMID 32673293.
  30. De Bolle, Leen; Naesens, Lieve; De Clercq, Erik (2005-1). "Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy". Clinical Microbiology Reviews. 18 (1): 217–245. doi:10.1128/CMR.18.1.217-245.2005. ISSN 0893-8512. PMC 544175. PMID 15653828. Check date values in: |date= (help)