Tag: enteroviruses

The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome

ME/CFS is a disabling and often severe disease, so-far incurable, that has long been associated with discrete outbreaks and sporadic incidents of viral-like illness. First, a word about the controversial name. The designation “Myalgic Encephalomyelitis” (abbreviated ME) originated following an outbreak at London’s Royal Free Hospital in 1955. More than 200 members of the hospital staff became disabled [1]. Melvin Ramsay, MD, eventually published important case descriptions in Lancet [2]. He coined “ME” based on predominant symptoms of muscle pain (myalgia) and effects on the brain (encephalo), spinal cord (myel), and inflammation (itis). For 32 years, “ME” was deemed acceptable until, in 1987, the Centers for Disease Control (CDC) convened an extramural committee to change the name. CDC did so in response to a series of outbreaks of a similar, if not identical, illness in the United States, introducing “chronic fatigue syndrome” in 1988 [3].

Because the CDC name trivializes the serious nature of the disease, the patient community and many medical professionals prefer ME, which continues to be widely used in the United Kingdom and Europe. In 2015, a US Institute of Medicine (IOM) committee recommended yet another name, Systemic Exertion Intolerance Disease [4], which has been largely ignored. Should inflammation of the brain and spinal cord be definitively shown with modern methods, the name Myalgic Encephalomyelitis will finally be vindicated. The compromise name ME/CFS is now used most frequently and will be used here despite its faults.

Source: Hanson MR (2023) The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome. PLoS Pathog 19(8): e1011523. https://doi.org/10.1371/journal.ppat.1011523 https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011523 (Full text)

 

Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Over the years, several pathogenic agents have been implicated with no one pathogen being conclusively identified as responsible for induction of a large number of cases. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in chronic infection sites, including the central nervous system, muscle, and heart, potentially resulting in chronic conditions that have symptom constellations like those of ME/CFS.

To gain insight into the association between EVs and ME/CFS, I conducted a comprehensive review of EV studies in ME/CFS and followed this with 1) a broad serological survey of ME/CFS antibody levels to 122 pathogenic antigens and 2) designed and conducted EV-specific targeted RNA sequencing.

A review of prior ME/CFS investigations in ME/CFS revealed a strong prevalence of chronic EV infections across ME/CFS cohorts. The broad survey of anti-pathogen antibody levels in ME/CFS cases did not implicate any one pathogen as a causative factor in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, the results did reveal sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.

Furthermore, I find that our EV-specific probe set allows efficient viral detection when as few as 10 molecules are present in 1ml of blood. However, whether the technology is employed directly on patient samples or following attempts at in vitro biological amplification, EVs were undetected in both ME/CFS and healthy control samples despite all approaches that were pursued.

This work establishes a thorough understanding of the current EV-ME/CFS related literature while simultaneously providing an acutely sensitive and comprehensive approach that will be useful in the future for screening biopsy or cadaver samples from any individuals suspected of having a chronic EV infection.

Source: O’Neal, Adam James. Investigating the enterovirus theory of disease etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Dissertation, Cornell. https://ecommons.cornell.edu/handle/1813/112023 (Full text will be made available)

Polio Vaccination and Chronic Fatigue Syndrome

Abstract:

Background: Previous research has suggested that enteroviruses may be implicated in the development and persistence of Chronic Fatigue Syndrome (CFS). One method of investigating this topic has been to use a polio vaccination challenge, and a previous study showed that CFS patients had more shedding than healthy controls. There was no effect of the vaccination on the clinical condition or wellbeing of the CFS patients.

Methods: In the previous study, the control group were more likely to have had a recent booster vaccination. This was controlled in the present study, where 18 CFS patients were randomly assigned to vaccination or placebo conditions. Nine healthy volunteers were also given the polio vaccination.

Results: The results confirmed that vaccination had no negative effects on the CFS group. Although there was more virus shedding in the CFS polio group than in the control polio group, this difference was not significant.

Conclusion: This study confirms that polio vaccination is not contraindicated in CFS patients but could not confirm that they are more susceptible to enterovirus infection.

Source: Smith AP and Thomas M. Polio Vaccination and Chronic Fatigue Syndrome. Asian Journal of Research in Infectious Diseases 8(4): 43-49. https://orca.cardiff.ac.uk/146095/1/poliocfs.pdf (Full text)

Are enteroviruses behind mysterious outbreaks of chronic fatigue syndrome?

Chronic fatigue syndrome is a long-term illness with a wide range of symptoms, no known treatment, and undetermined origins. However, with as many as 65m people across the world living with the illness, researchers continue to search for answers.

Now, Prof Maureen Hanson of Cornell University discusses how she and graduate student James O’Neal searched through the research archives to see whether a genus of RNA viruses called enteroviruses are the most likely culprits and whether the findings have implications in future ‘long Covid’ research.

Like SARS-CoV-2, which causes Covid-19, viruses, enteroviruses (EVs) are RNA viruses that can lead to cause serious illness and death. One type of EV causes poliomyelitis, which is now largely conquered through near-universal vaccination.

But no vaccine exists against many other types of EVs, which are free to circulate widely. Indeed, the Centers for Disease Control and Prevention estimates between 10m-15m enteroviral infections occur each year in the US.

EVs have long been suspected as causal agents in outbreaks of an illness that is now usually named ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). Outbreaks have been documented since the turn of the previous century and may have occurred earlier.

Many are unaware that ME/CFS can occur in epidemic form. The pathogen(s) inciting most of these outbreaks remain unidentified. One reason for this lamentable situation is that earlier virus identification technology was not as powerful as today’s methods.

Consider how quickly the complete sequence of SARS-CoV-2 was obtained not long after a new illness arose. But another reason that ME/CFS triggers are not known is the existing technology was not deployed to identify the agents causing multiple outbreaks in the mid-1980s. The failure of federal agencies to nor investigate these outbreaks, often dismissed as hysteria or unimportant, is well documented in investigative journalist Hillary Johnson’s Osler’s Web.

Read the rest of this article HERE.

Source: Frontiers Science News, August 12, 2o21. https://blog.frontiersin.org/2021/08/12/chronic-fatigue-syndrome-viruses-maureen-hanson-cornell-university/

The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades.

This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.

Source: O’Neal AJ, Hanson MR. The Enterovirus Theory of Disease Etiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Critical Review. Front Med (Lausanne). 2021 Jun 18;8:688486. doi: 10.3389/fmed.2021.688486. PMID: 34222292; PMCID: PMC8253308. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253308/  (Full text)

Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS) and viral persistence

Abstract:

AIMS: Enteroviruses are well-known causes of acute respiratory and/or gastrointestinal infections and non-specific flu-like illness. Although enterovirus protein, RNA and non-cytopathic viruses have been demonstrated in the stomach biopsies of patients with myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), causality for chronic diseases is difficult to establish without having well-documented cases of acute enterovirus infections. The aim of this study was to link acute enteroviral infection to viral persistence in patients with ME/CFS.

METHOD: Patients admitted to the hospital with acute febrile illnesses were screened for enteroviral infections. Acutely infected patients were followed longitudinally, and those who developed symptoms of ME/CFS underwent oesophagogastroduodenoscopy and biopsies of the antrum to document viral persistence by immunoperoxidase staining for viral protein and viral RNA assay.

RESULTS: Three representative patients with different manifestations of acute enterovirus infections progressed to have chronic symptoms of ME/CFS. Persistent viral infection was demonstrated in the antrum years later.

CONCLUSION: After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.

 

Source: Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb;63(2):165-8. doi: 10.1136/jcp.2009.070466. Epub 2009 Oct 14. https://www.ncbi.nlm.nih.gov/pubmed/19828908

 

Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach

Abstract:

BACKGROUND AND AIMS: The aetiology for chronic fatigue syndrome (CFS) remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastrointestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus (EV) RNA and culturable virus in the stomach biopsy specimens of patients with CFS was evaluated.

METHODS: 165 consecutive patients with CFS underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using EV-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus (CMV). RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for EV.

RESULTS: 135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (p< or =0.001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from six patients at the onset of the CFS/abdominal symptoms, and 2-8 years later showed positive staining in the paired specimens. EV RNA was detected in 9/24 (37%) paraffin-embedded biopsy samples; 1/21 controls had detectable EV RNA (p<0.01); 1/3 patients had detectable EV RNA from two samples taken 4 years apart; 5 patient samples showed transient growth of non-cytopathic enteroviruses.

CONCLUSION: Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsy specimens of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsy.

Comment in: Enterovirus infection of the stomach in chronic fatigue syndrome/myalgic encephalomyelitis. [J Clin Pathol. 2008]

 

Source: Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008 Jan;61(1):43-8. Epub 2007 Sep 13. https://www.ncbi.nlm.nih.gov/pubmed/17872383

 

Special problems of children with myalgic encephalomyelitis/chronic fatigue syndrome and the enteroviral link

Abstract:

Since 1997, it has been known that myalgic encephalomyelitis/chronic fatigue syndrome constitutes the biggest cause of long-term sickness leading to absence from school, in both staff and pupils. The scale of the problem in children is substantial, and the pattern of illness in schools suggests a prominent role for viral infection–for example, the clustering of cases.

The Dowsett-Colby study of 1997, researching long-term sickness, reported on a school roll of 333,024 pupils and 27,327 staff, and found a prevalence of long-term sickness in 70 of 100,000 pupils and 500 of 100,000 staff; 39% of cases were in clusters of three or more. The peak age was 14-16 years. The illness is known to be potentially severe and chronic. In addition, the Tymes Trust has reported that many affected children struggle for recognition of their needs, and are bullied by medical and educational professionals.

Children should have time to recover sufficiently before returning to school; sustainable, energy-efficient and often home-based education is important here to fulfill legal obligations. Research is needed on viruses that trigger childhood myalgic encephalomyelitis–for example, enteroviruses–and on the neurocognitive defects caused by myalgic encephalomyelitis. We should recognise the value of previous biological research and records of outbreaks, and I recommend that myalgic encephalomyelitis be made notifiable owing to the encephalitic nature of the effects commonly reported in this illness.

 

Source: Colby J. Special problems of children with myalgic encephalomyelitis/chronic fatigue syndrome and the enteroviral link. J Clin Pathol. 2007 Feb;60(2):125-8. Epub 2006 Aug 25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1860612/ (Full article)

 

The role of enterovirus in chronic fatigue syndrome

Abstract:

Two and a half decades after coining of the term chronic fatigue syndrome (CFS), the diagnosis of this illness is still symptom based and the aetiology remains elusive. Enteroviruses are well known causes of acute respiratory and gastrointestinal infections, with tropism for the central nervous system, muscles, and heart.

Initial reports of chronic enteroviral infections causing debilitating symptoms in patients with CFS were met with skeptism, and had been largely forgotten for the past decade. Observations from in vitro experiments and from animal models clearly established a state of chronic persistence through the formation of double stranded RNA, similar to findings reported in muscle biopsies of patients with CFS.

Recent evidence not only confirmed the earlier studies, but also clarified the pathogenic role of viral RNA through antiviral treatment. This review summarises the available experimental and clinical evidence that supports the role of enterovirus in chronic fatigue syndrome.

 

Source: Chia JK. The role of enterovirus in chronic fatigue syndrome. J Clin Pathol. 2005 Nov;58(11):1126-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1770761/ (Full article)

 

Enterovirus related metabolic myopathy: a postviral fatigue syndrome

Abstract:

OBJECTIVE: To detect and characterise enterovirus RNA in skeletal muscle from patients with chronic fatigue syndrome (CFS) and to compare efficiency of muscle energy metabolism in enterovirus positive and negative CFS patients.

METHODS: Quadriceps muscle biopsy samples from 48 patients with CFS were processed to detect enterovirus RNA by two stage, reverse transcription, nested polymerase chain reaction (RT-NPCR), using enterovirus group specific primer sets. Direct nucleotide sequencing of PCR products was used to characterise the enterovirus. Controls were 29 subjects with normal muscles. On the day of biopsy, each CFS patient undertook a subanaerobic threshold exercise test (SATET). Venous plasma lactate was measured immediately before and after exercise, and 30 minutes after testing. An abnormal lactate response to exercise (SATET+) was defined as an exercise test in which plasma lactate exceeded the upper 99% confidence limits for normal sedentary controls at two or more time points.

RESULTS: Muscle biopsy samples from 20.8% of the CFS patients were positive for enterovirus sequences by RT-NPCR, while all the 29 control samples were negative; 58.3% of the CFS patients had a SATET+ response. Nine of the 10 enterovirus positive cases were among the 28 SATET+ patients (32.1%), compared with only one (5%) of the 20 SATET- patients. PCR products were most closely related to coxsackie B virus.

CONCLUSIONS: There is an association between abnormal lactate response to exercise, reflecting impaired muscle energy metabolism, and the presence of enterovirus sequences in muscle in a proportion of CFS patients.

Comment in: Enteroviruses in chronic fatigue syndrome: “now you see them, now you don’t”. [J Neurol Neurosurg Psychiatry. 2003]

 

Source: Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Oct;74(10):1382-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1757378/ (Full article)