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Winter 2023 - Critical Care

Long COVID: Shedding Light on Other Viral Infections

The lingering effects of viral infections are not well-understood, but long COVID is helping shed light on the mysterious phenomenon, particularly in patients with chronic fatigue syndrome.

For many lay people, “long COVID” is the first introduction to a condition caused by a previous infection that has run its course, a condition that lingers indefinitely without an easily identifiable cause and no single test to make a diagnosis. However, among doctors with experience treating myalgic encephalomyelitis (ME), commonly known as chronic fatigue syndrome (CFS), the emergence of long COVID was an “aha” moment.

For decades, a small but committed number of physicians treating patients suffering from ME/CFS have struggled to get their patients’ conditions taken seriously by the larger medical establishment and insurers. Originally dismissed as “yuppie flu”1 and written off by many as a psychological disorder, the few doctors who did treat ME/CFS suspected the condition was likely the aftereffect of a previous viral infection.

The symptoms of long COVID are remarkably similar to those of ME/CFS, with many overlapping. They include post-exertion fatigue, lingering low-grade fever, decreased mental acuity, joint and/or muscle pain, depression and anxiety, digestive issues and dry cough.2 While symptoms of ME/CFS mimic common infectious diseases like influenza or a cold, they tend to be more severe, even debilitating, so much so that patients whose symptoms interfere with daily life are motivated to continue to seek medical help after repeatedly being told nothing is wrong with them. Under existing protocols, a patient had to have these symptoms for six months to be diagnosed with ME/CFS.3

While our studies of long COVID are understandably still in their infancy, one difference between long COVID and ME/CFS is already being noted: Since physicians are more likely to know if a patient has previously contracted COVID-19, even mild symptoms of long COVID are taken seriously, but while the cause of ME/CFS was not — and still is not — known, patients suffering from it are often told nothing is wrong with them.

Historically, there has been little interest in conducting research into ME/CFS, and not much more interest in treating it. (A recent article in The Atlantic noted that only about a dozen physicians attended a 2018 conference intended to found a coalition supporting ME/CFS treatment and research.4)

Contributing to the widespread indifference to ME/CFS is the fact that too many physicians had been taught in medical school that “there has to be an antigen [such as a viral protein] in the system to drive the immune system to make it create sickness, and the immune system should shut off when it’s done,” as Nancy G. Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University in Miami put it in a recent interview.5 Yet in a mere two years, the notion that a viral infection can continue to cause significant, even severe, side effects long after the infection has ended has become broadly accepted, thanks to the avalanche of evidence regarding long COVID. The rise of long COVID is triggering a reexamination of other cases in which patients have presented with seemingly inexplicable symptoms to see if there are more post-acute infection syndromes (PAISs) than had previously been suspected.

While it is too early in the research process to know what will be discovered, it may very well turn out that rather than being an outlier, long COVID is instead a typical post-infection side effect that has mostly gone undetected (and untreated) until now.

A Brief History of PAISs

The history of PAISs is both historic and heavily tilted toward the recent.

In 1750, Sir Richard Manningham described a condition similar to what we know as ME/CFS that he termed “febriclua,” meaning “little fever.” Modern researchers now believe that it is likely that both Florence Nightingale and Charles Darwin suffered from it.6

By the late 1800s, the condition was observed that patients who contracted polio could relapse years — even decades — later, with no sign of a renewed infection and without being contagious. In 1934, staff members at Los Angeles County Hospital exhibited symptoms consistent with ME/CFS. At the time, it was attributed to a variant of polio. Just 21 years later, a similar outbreak occurred among staff at the Royal Free Hospital in London. Post-poliomyelitis syndrome (PPS) was only recognized as an accepted medical condition in 1980, but even today elderly patients who had polio before widespread vaccination was adopted in the 1950s can develop PPS.7

But the symptoms of PPS were fairly similar to the symptoms of polio itself, so making the connection between the poliovirus and PPS was a fairly straightforward process. Trying to determine the cause of, or even argue for the existence of other PAISs, has been more of a struggle.

The medical establishment’s current relationship with PAISs likely began on the shores of Lake Tahoe in 1984 when two physicians noticed an outbreak of what they originally diagnosed as influenza, yet the patients didn’t seem to recover even as weeks and months passed. The patients exhibited a spectrum of symptoms, but common ones were debilitating fatigue that worsened with physical or mental exertion and difficulty sleeping and concentrating. They showed no signs of a current infection, and their physiological test results were normal.

While many of the patients tested positive for antibodies for the Epstein-Barr virus (the virus that causes mononucleosis), most of the patients were adults, and outbreaks of adult-onset mononucleosis are extremely rare. So, the two physicians asked for assistance from the Centers for Disease Control and Prevention (CDC).1 CDC dispatched a team that determined the Epstein-Barr antibody levels weren’t out of the anticipated range for adults who had previously been exposed. High antibody counts for other viruses in the herpes family were also found in some patients, but not in others.

Two years later, a strikingly similar outbreak occurred on the shores of Lake Ontario in New York state, this time affecting mostly children. Again, tests were unable to uncover consistent results across all patients, so the mystery only deepened.

As more and more cases were reported by physicians across the United States, as well as in Canada and Great Britain, CDC finally added CFS to its list of official diseases in 1988 — but no one was any closer to understanding what exactly it is, much less what causes it.
Since then, other PAISs have been identified, including post-dengue fatigue syndrome (PDFS),8 post-Ebola syndrome (PES)9 and post-chikungunya chronic inflammatory rheumatism.10

The Arrival of Long COVID

Within the first year of the COVID-19 pandemic, physicians and researchers noted that some patients who had contracted COVID-19 — even some who were asymptomatic — were exhibiting lingering symptoms months after they were testing negative for an active infection with the SARS CoV-2 virus.11 Symptoms primarily included lingering fever, fatigue and cough.

But nearly three years later, even though long COVID is now accepted as a real condition, it nevertheless remains somewhat fuzzy and undefined. As Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke, part of the U.S. National Institutes of Health, put it recently, “There is no good definition of long COVID, and people define it differently.”

Dr. Nath pointed out that the volume of COVID-19 patients, and the similarities to ME/CFS, have made this a unique opportunity to try to learn more about how the immune system reacts to viral infections and how those reactions can continue to impact patient health even after the infection has abated. He is now heading up a clinical study for the U.S. government to try to answer some basic questions regarding both long COVID and ME/CFS. “People with ME/CFS have been saying for decades that they develop a constellation of persistent new symptoms following some kind of infection. They go to doctors, and they often cannot find anything abnormal. Every test comes back normal. The patients are very frustrated and often say, ‘You think that this is all in my head? This is real. I was perfectly fine before this happened. And now my life is devastated.’”12

Both sides remain frustrated. “The doctors are frustrated because they don’t know what is wrong with the patient, and the patients are frustrated because they think the doctor doesn’t believe their symptoms,” explains Dr. Nath. “So ME/CFS kind of lingers out there in no-man’s land.”12

With regard to COVID-19 and the myriad of people it’s affecting, Dr. Nath observes, “If other infections trigger ME/CFS, then you would think that COVID-19 would surely do it too. And it is true that many of the symptoms that we see in long COVID patients are similar to what we see in ME/CFS patients as well. There is substantial overlap between the two conditions. All clinical studies of long COVID patients would be relevant to ME/CFS.”12

Getting Answers

Now that long COVID is being studied with the kind of resources of which advocates for ME/CFS could have only dreamed, some researchers are also looking at other viral infections to see if they could be responsible for other PAISs — or to perhaps identify the virus or viruses responsible for ME/CFS.13

With nearly one-fifth of all COVID-19 patients developing some level of long COVID, the number of people suffering from a PAIS is obviously increasing dramatically.14 And since doctors can test for a previous SARS-CoV-2 infection, there is a control here that was previously not available, since doctors didn’t even know which virus to test for when studying ME/CFS.

Researchers are looking into two areas right now for long COVID: What are the specific triggers that cause some patients to develop long COVID, and what treatment regimens are most effective? A parallel line of research as outlined by Dr. Nath is trying to determine the cause of ME/CFS. In fact, even before the COVID-19 pandemic, research was slowly proceeding into ME/CFS.

One pre-pandemic study out of Norway looked at the influenza virus as a possible cause of ME/CFS, specifically looking into whether the flu vaccine could be causing it. The study found that although there was no evidence to suggest the vaccine increased the odds of developing ME/CFS, it did find that H1N1, the dominant influenza strain in 2009, was associated with an increase in ME/CFS.15 While not providing a definitive causative link, the study did provide hard evidence for the notion that ME/CFS is a post-viral condition and identified one likely culprit. CDC also notes that there is a correlation between Epstein-Barr virus and ME/CFS, as well as Q fever, a disease caused by the agricultural bacteria Coxiella burnetii.16

One concern for those who treat, study and support patients with ME/CFS is that the first federal bill to provide funding for long COVID research did not include language directing ME/CFS to be part of the studies. Advocates are now working with members of Congress in both houses to try to insert new language into a second bill now making its way through the legislative process, so that at least a portion of the allocation would go toward ME/CFS research.5

Looking Ahead

The existence of PAISs is no longer questioned — neither their existence, nor the importance of learning more about them.
Whether or not Congress specifically funds new research into ME/CFS, the rapid expansion of research into long COVID will definitely have a spillover effect. There are currently 306 studies examining long COVID, another 37 examining post-COVID-19 syndrome and 149 studies evaluating ME/CFS listed on That number would have been unthinkable just three years ago.

With an estimated 146 million Americans having had COVID-19, and one-fifth of those likely to develop long COVID symptoms, there will not be a general practitioner in this country who won’t see a patient for the condition.17

While those suffering from ME/CFS wouldn’t wish their symptoms on anyone and have more sympathy for people with long COVID than anyone else possibly can, they are undoubtedly relieved that moving forward they will never again have to try to convince their physician or insurance carrier that their disease is real, or that any other patient suffering from a PAIS will face the kind of doubtful response from clinicians as they did.


  1. Chronic Fatigue Syndrome. Newsweek, Nov. 11, 1990. Accessed at
  2. Centers for Disease Control and Prevention. Long COVID or Post-COVID Conditions. Accessed at
  3. Centers for Disease Control and Prevention. Symptoms of ME/CFS. Accessed at
  4. Yong, E. Long COVID Has Forced a Reckoning for One of Medicine’s Most Neglected Diseases. The Atlantic, Sept. 26, 2022. Accessed at
  5. Tucker, M. Long COVID Mimics Other Post-Viral Conditions. Web MD, Aug. 24, 2022. Accessed at
  6. Mandal, A. Chronic Fatigue Syndrome History. News Medical, Feb. 26, 2019. Accessed at
  7. Halstead, L. A Brief History of Postpolio Syndrome in the United States. Archives of Physical Medicine and Rehabilitation, August 2011. Accessed at
  8. Umakanth M. Post Dengue Fatigue Syndrome (PDFS) Among Dengue IgM-Antibody Positive Patients at Batticaloa Teaching Hospital, Sri Lanka. Open Access Library Journal, August 2018. Accessed at
  9. Scott, J, Sesay, F, Massaquoi, T, et al. Post-Ebola Syndrome, Sierra Leone. Emerging Infectious Diseases, April 2016. Accessed at
  10. Rodriguez-Morales, A, Gil-Restrepo, A, Acevedo-Mendoza, W, et al. Post-Chikungunya Chronic Inflammatory Rheumatism: Results from a Retrospective Follow-up Study of 283 Adult and Child Cases in La Virginia, Risaralda, Colombia. F1000 Research, April 4, 2016. Accessed at
  11. Perrin, R., Riste, L, Hann, M, et al. Into the Looking Glass: Post-Viral Syndrome Post COVID-19. Medical Hypotheses, November 2020. Accessed at
  12. National Institutes of Health. COVID-19 Research. Studying Long COVID Might Help Others with Post-Viral Fatigue Ailments, Aug. 8, 2022. Accessed at
  13. Choutka, J, Jansari, V, Hornig, M, and Iwasaki, A. Unexplained Post-Acute Infection Syndromes. Nature Medicine, May 2022. Accessed at
  14. Mancini, D, Brunjes, D, Lala, A, et al. Use of Cardiopulmonary Stress Testing for Patients with Unexplained Dyspnea Post–Coronavirus Disease. JACC: Heart Failure, December 2021. Accessed at
  15. Magnus, P, Gunnes, N, Tveito, K, Bakken, I, et al. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) Is Associated with Pandemic Influenza Infection, But Not With an Adjuvanted Pandemic Influenza Vaccine. Vaccine, Nov. 17, 2015. Accessed at
  16. Centers for Disease Control and Prevention. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Causes. Accessed at
  17. Centers for Disease Control and Prevention. Estimated COVID-19 Burden. Accessed at
Jim Trageser
Jim Trageser is a freelance journalist in the San Diego, Calif., area.