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== 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]] tissues, [[stomach]] tissues, [[brain]] tissues and [[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|issue=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 | author-link1 = 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 = Jun 1, 1983 | pmid = 6310104 | url = http://bjgp.org/content/33/251/335 }}</ref><ref name="Calder19842">{{Citation | last1 = Calder | first1 = BD | author-link1 = 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 | author-link1 = 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 = Jul 1, 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. Eighty-two percent 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">{{Citation | last1 = Chia | first1 = JKS | author-link1 = 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 = Jan 1, 2008 | pmid = 17872383 | doi = 10.1136/jcp.2007.050054 | url = http://jcp.bmj.com/content/61/1/43 }}</ref> ==== Brain autopsy ==== {{Main article | page_name =Autopsy}} Three post-mortem studies have found enterovirus infections in the brains of ME/CFS patients.
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