Are enteroviruses behind mysterious outbreaks of chronic fatigue syndrome?

By Prof Maureen Hanson, Cornell University

Image: Andrea Piacquadio/

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 Adam 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.

Prof Maureen Hanson. Image: Dave Burbank/Cornell University

65m cases of ME/CFS worldwide

ME/CFS is neither a rare nor a trivial illness. Research associate Arnaud Germain and I recently published an estimate of 65m ME/CFS cases worldwide. Most individuals with the disease are unable to work full-time and many are house-bound or bed-bound.

Despite the continuing mystery about the sources of the disease, there is considerable evidence that implicates EVs in many past cases of ME/CFS. In a recent review in Frontiers in Medicine by graduate student Adam O’Neal and myself, we discuss the historical evidence for EVs as causal in outbreaks of ME/CFS.

As well as epidemiological considerations, much evidence comes from antibody tests ordered by perceptive physicians at the time of acute illnesses. Immediate testing following acute illness is critical.

But when tests are conducted in patients many years after onset of chronic illness, results are inconclusive.  Both ME/CFS patients and healthy individuals will be expected to have immunological evidence of past infection, preventing recognition of a prior exposure that might have led to chronic disease.

Is ME/CFS a chronic EV infection?

Our review also explores the possibility that EVs remain actively involved in producing the disease symptoms. A feature of EVs that is often not recognized is their ability to maintain themselves in tissues for long periods of time through down-regulation of replication.

We highlighted past work that has shown that cells can have long-term steady state EV infections. Low amounts in tissues can be detected only if modern PCR and sequencing methods are applied correctly.

But the most important tissues to be interrogated – such as heart or brain – are not readily obtained from living patients. In recent years, serious inquiry into chronic EV infection in ME/CFS has mainly occurred at EVMED through Dr John Chia’s efforts and by Dr Byron Hyde’s publication of important books reviewing the prior evidence for EV involvement in ME/CFS outbreaks and sporadic cases.

Did EVs incite almost all cases of pre-2020 ME/CFS?

The statement is often made that “infection with many different pathogens can lead to ME/CFS”. Whether this is true is actually not known. The majority of individuals with ME/CFS will mention their illness followed a viral-like illness, in which the virus’ identity was not determined.

A significant proportion will say that ME/CFS followed a case of mononucleosis. But did Epstein-Barr Virus result in ME/CFS, or did it merely make an EV infection more likely to have long-term consequences? With six months of new fatigue being required for the diagnosis of ME/CFS, additional infections, symptomatic or not, could have occurred following acute onset of mononucleosis. As we wrote:

“… surveys also indicate that patients ascribe their onset to a variety of other reasons, including emotional stress, life events, recent travel, accidents, toxic substances, or mold. However, some of these events and exposures could merely be coincidental and actually be due to an enteroviral infection that was unnoticed or very mild, given that many enteroviral infections are asymptomatic.”

Are SARS viruses the second class of RNA viruses to cause ME/CFS?

At the time of writing, there are individuals who became ill with relatively mild or even asymptomatic cases of Covid-19 as early as March 2020 who remain ill 16 months later – currently called ‘long Covid’ patients.

Some now exhibit the six months of fatigue, post-exertional malaise, and unrefreshing sleep, and either cognitive problems or orthostatic intolerance, required for diagnosis of ME/CFS according to the National Academy of Medicine. However, many long Covid patients are exhibiting additional symptoms as well that are not typically seen in pre-2020 ME/CFS patients, while others have largely recovered, which is unusual in ME/CFS.

The possibility that ME/CFS patients have persistent EV infection is certainly relevant to long Covid research. Are SARS-CoV-2 RNAs or viral proteins hiding out in tissues, not readily detected by standard methods in use?

In order to draw attention to a neglected area of research, we initiated our review of EVs in ME/CFS well before the long Covid phenomenon was recognized. Hopefully, the heightened interest in post-acute viral syndromes as a result of the pandemic will result in fresh inquiry into the possibility of chronic viral infection in both illnesses.

Prof Maureen Hanson is a Liberty Hyde Bailey Professor in the Department of Molecular Biology and Genetics and Director of the Center for Enervating Neuroimmune Disease at Cornell University, which is supported by private donors and foundations as well as by an NIH ME/CFS Center grant NINDS U54NS105541.

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