Skip to main content

OPINION article

Front. Med., 18 January 2021
Sec. Infectious Diseases – Surveillance, Prevention and Treatment
Volume 7 - 2020 |

Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome?

Anthony L. Komaroff1* Lucinda Bateman2 for the U.S. ME/CFS Clinician Coalition
  • 1Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
  • 2Bateman Horne Center, Salt Lake City, UT, United States


“Recovering” from COVID-19 does not guarantee a return to a person's usual state of health. For one thing, some people with multi-system injury—particularly to the brain, heart and kidneys—may develop permanent dysfunction of those organs.

In addition, a more subtle form of chronic illness may develop. For some people with COVID-19, even those who are only mildly affected at first, the ensuing weeks and months of “recovery” bring a surprise and a betrayal: they do not return to full health. Although nucleic acid tests no longer detect the virus, people still suffer from ongoing symptoms. They call themselves “long haulers,” and the condition is being called “long COVID.”

How Common Is a Lingering Post-COVID-19 Illness?

The Centers for Disease Control and Prevention (CDC) followed nearly 300 people who were PCR-positive for SARS-CoV-2 for several weeks. Three weeks after the positive test, nearly half of the patients still had symptoms, such as fatigue and cough—particularly people who were older or suffered from chronic diseases (1).

Italian investigators studied 143 confirmed COVID-19 patients after the most severe symptoms had ended. Sixty days after the onset of their illness, more than half of the patients continued to have multiple bothersome symptoms, and 41% reported a worsened quality of life (2).

Irish investigators studied 128 patients with PCR-documented SARS-CoV-2 infection and found that, at a median of 10 weeks after the initial COVID-19 symptoms, 52% reported persistent fatigue and 31% had not returned to work. Surprisingly, there was no association of post-COVID fatigue with the severity of the acute illness, nor with routine laboratory markers of inflammation and cell turnover (3).

Between December, 2019 and May, 2020, a group of patients conducted an online survey of patients who, by self-report, experienced symptoms consistent with COVID-19, in collaboration with University College, London; Weill Cornell Medicine, New York, NY; and Oregon Health and Science University, Portland, Oregon. The survey consisted of 257 questions, was translated from English to eight other languages, and was completed by 3,762 patients (age 18 or older) from 56 countries—predominantly white, middle-class, and English-speaking. Of the respondents, 8.4% reported being hospitalized, and 27% reported a laboratory-confirmed diagnosis. At 7 months after the onset of the illness, continue fatigue, post-exertional malaise and cognitive dysfunction (all core symptoms of ME/CFS) remained in 77.9, 71.2, and 56.8%, and 67.5% were unable to work or required a reduced work schedule compared to prior to the illness onset. Systematic physical examination and laboratory diagnostic panel was not performed (4). The data, as reported, don't allow a determination of how many of these people with possible COVID-19 met criteria for ME/CFS, but it is plausible that the majority did.

Post-Infectious Fatigue Syndromes

It is not surprising that some people infected with the COVID-19 coronavirus (SARS-CoV-2) develop a debilitating chronic fatigue. Post-infectious fatigue syndromes follow in the wake of acute infections with several different types of infectious agents: viruses, such as SARS coronavirus (5), Epstein-Barr virus (68), Ross River virus (8), enteroviruses (9), human herpesvirus-6 (10), Ebola virus (11), West Nile virus (12), Dengue virus (13), and parvovirus (14); bacteria, such as Borrelia burgdorferi (15), Coxiella burnetii (16), and Mycoplasma pneumoniae (17); and even parasites, such as Giardia lamblia (18). The acute symptoms of these illnesses, and the organ damage they cause, can be very different. However, the lingering chronic fatiguing illness following each illness appears to be quite similar.

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS)

People with post-infectious fatigue syndromes following these well-documented acute infections share a group of symptoms in common with people who have ME/CFS (originally called just “chronic fatigue syndrome”). Many, but not all, people with ME/CFS note that it began suddenly, with an apparently infectious illness characterized by respiratory symptoms, fever, adenopathy, myalgias, and other symptoms. Because such acute illnesses are common and typically resolve, often no attempt has been made to diagnose the inciting infectious agent. Yet the spectrum of symptoms in ME/CFS that follows an apparently infectious illness due to an undocumented infectious agent is very similar to the illness following a well-documented infectious agent.

Indeed, according to Dr. Anthony Fauci, the Director of the National Institute for Allergy and Infectious Diseases, patients post-COVID-19 can develop “a post-viral syndrome that's very strikingly similar to myalgic encephalomyelitis/chronic fatigue syndrome” (19).

A widely-used case definition of ME/CFS was proposed by the U.S. National Academies of Sciences, Engineering and Medicine (NASEM) (20). This case definition requires that the illness must have lasted for at least 6 months. Since most people who have developed COVID-19 in the U.S. have not yet been ill for 6 months, not enough time has elapsed to know how many will develop an illness that meets the case definition of ME/CFS. We think it is likely that some will.

What is the current burden from ME/CFS in the United States? CDC and NASEM estimate that between 836,000 and 2.5 million Americans suffer from ME/CFS; the direct and indirect economic costs of the illness to society are estimated to be between $17 and $24 billion each year (20).

How Many Additional Cases of ME/CFS Will be Caused by the Pandemic?

One can only guess about the future, but we propose a few conservative estimates. As of late December 2020, nearly 20 million Americans have tested positive for SARS-CoV-2. Based on serological studies the CDC estimates that the true number of infections may be exponentially higher.

To estimate the number of people in the U.S. who may develop “long COVID” we make two conservative assumptions: (1) the introduction of effective vaccines in late 2020 and early 2021 will constrain the total number of people in the U.S. who become infected with SARS-CoV-2 to only 25 million Americans by the end of 2021; and (2) although over 50% of people with confirmed or suspected COVID-19 state that they remain with lingering symptoms at 3 months, we assume that only 10% will be left with an illness that meets the NASEM case definition for ME/CFS. This is consistent with a careful prospective study of the course of symptoms following three quite different acute infections (8). Over the course of 1 year, that would at least double the number of Americans suffering from ME/CFS. The annual incidence of the illness would equal or surpass the point prevalence—a remarkable event in the history of a chronic illness.

What might this mean globally? As of December 2020, COVID-19 has been documented in about 80 million people, globally. Using similar estimates to those we used for the U.S., that number would be predicted to increase to nearly 110 million during 2021, and to generate over 10 million new cases of ME/CFS, globally.

Of course, these number are all rough guesses. But they are informed by well-measured prior experience, and suggest that the U.S. and the world will see a substantial growth in the number of people with ME/CFS. How lasting that illness will be, we cannot know. Most long-term longitudinal studies of people with ME/CFS before the pandemic found that, in most patients, the illness had not abated after many years (21, 22), although the prognosis may be somewhat better in children with ME/CFS (23).

What Causes Post-Infectious Fatigue Syndromes and ME/CFS?

Any acute infectious disease, like COVID-19, that damages multiple organ systems can cause chronic symptoms (along with objective physiological abnormalities) in some people. The symptom of chronic fatigue could be caused by impaired function of the heart, lung, or kidneys. It is too early in the COVID-19 pandemic to know how many will suffer permanent dysfunction of these organs, but it surely is possible. Therefore, in some people with persistent, debilitating fatigue following COVID-19, documentable damage of these organs may be a sufficient explanation of their fatigue. Careful longitudinal studies assessing both symptoms and physiologic function will be necessary to know whether, and how often, this happens.

Experiencing a life-threatening illness, particularly when extreme measures, such as artificial ventilation are required, can lead to post-traumatic stress disorder (PTSD). And if a patient has not been able to return to pre-illness function due to chronic symptoms, the persistent symptoms may also trigger major depression. These psychiatric disorders also may lead to chronic fatigue and related symptoms.

Yet, many cases of post-infectious fatigue follow in the wake of acute infections that are not known to cause permanent damage to the heart, lungs or kidneys—and in people without comorbid PTSD or depression. In the typical case of ME/CFS, in particular, the inciting “infectious-like” illness most often appears to be a transient infection, or a primary infection that becomes permanent but does not typically produce chronic organ dysfunction (such as occurs with Epstein-Barr virus).

What might explain the fatigue and other symptoms if there is no documented heart, lung or kidney damage? Although uncertain, it is likely that the causes of all post-infectious fatigue syndromes share with each other and with ME/CFS many common elements (24). Longitudinal studies of people who develop COVID-19 may help reveal the biological underpinnings of many post-infectious fatigue syndromes.

In people with lingering fatigue post-COVID-19—and without chronic cardiac, pulmonary or renal dysfunction—one likely explanation for the chronic fatigue is a state of chronic low-grade neuroinflammation generated by the disease (25).

SARS-CoV-2 can infect the brain, causing neuroinflammation (26). Moreover, inflammation elsewhere in the body can activate the innate immune system in the brain via both humoral and retrograde neural signals, largely involving the vagus nerve (27, 28). As argued elsewhere (24), neuroinflammation can produce fatigue through the action of various cytokines, perhaps acting on a “fatigue nucleus”—a collection of neurons dedicated to diminishing energy-consuming activities (“sickness behavior”). Such energy-conserving behavior in an organism that is infected or injured would help to focus available energy stores on the process of healing (27, 29). In addition to activation of a “fatigue nucleus” by neuroinflammation, a state of chronic, severe fatigue and related symptoms could also be explained by other abnormalities identified in ME/CFS: impaired energy production (30), oxidative stress (31), ion channelopathies (32), and impaired cerebral perfusion (33).

The longitudinal studies that need to be conducted include repeatedly collecting information on the presence and severity of various symptoms—symptoms common in people with COVID-19 and symptoms that are part of case definitions of ME/CFS. Such studies also should include repeated laboratory studies of the immune system, metabolism, gene structure, and the transcriptome, as well as tests of thinking, sleep, and the functioning of the nervous system, heart, and cardiovascular system.

What Are the Implications for Practicing Physicians?

Although there now is a literature of over 9,000 peer-reviewed studies of ME/CFS, as identified by NASEM (20), it is our experience that many practicing physicians know little about the illness. If a wave of new cases that doubles the number of Americans with ME/CFS is about to emerge, we need to increase efforts to prepare physicians to deal with this burden. A U.S. ME/CFS Clinician Coalition—physicians experienced in the care of people with ME/CFS—has created a website containing useful information1. CDC2 and NIH3 also provide online information.


The COVID-19 pandemic has been a tragedy. It has devastated the health and financial well-being of many people around the world. An unprecedented effort is underway to understand, prevent and treat the disease, including substantial recent funding to study post-COVID illnesses, in the U.S. and elsewhere.

We should not forget the importance of studying all people who become infected with SARS-CoV-2, even those with only mild initial illnesses, and to study the recovery period and the long-term health consequences of COVID-19. We need to know how to prevent and treat “long COVID.” What we learn may apply to the prevention and treatment of ME/CFS, as well.

Author Contributions

AK conceptualized the paper and wrote the original draft. AK and LB reviewed and finalized the paper. All authors contributed to the article and approved the submitted version.

Conflict of Interest

AK reports receiving personal fees from Serimmune Inc., Ono Pharma, and Deallus, and grants from the National Institutes of Health, for activities unrelated to the submitted work. LB is employed by the Bateman Horne Center which receives grants from the National Institutes of Health, and from BHC receives fees from Exagen, Inc., and Teva Pharmaceutical for activities unrelated to the submitted work.


Members of the U.S. ME/CFS Coalition reviewed this manuscript: A. Bested, MD; H. Bonilla, MD: B. Chheda, MD; T. Dempsey, MD, ABIHM; T. Dowell, DNP; D. Felsenstein, MD; D. Kaufman, MD; N. Klimas, MD; C. Lapp, MD; S. Levine, MD; J. Montoya, MD, FACP, FIDSA; B. Natelson, MD; D. Peterson, MD; R. Podell, MD, MPH; I. Ruhoy, MD, PhD; R. Tompkins MD, ScD; M. Vera-Nunez, MD. We also wish to thank L. Chu, MD, MSHS and G. Lange, PhD for their input. Finally, our thanks to Mary Dimmock whose vision and tireless support of people with ME/CFS has meant so much to so many. The U.S. ME/CFS Coalition supported publication costs.



1. Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network. MMWR Morb Mortal Wkly Rep. (2020) 69:993–8. doi: 10.15585/mmwr.mm6930e1

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Carfi A, Bernabei R, Landi F, Group GAC-P-ACS. Persistent symptoms in patients after acute COVID-19. JAMA. (2020) 324:603–4. doi: 10.1001/jama.2020.12603

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Townsend L, Dyer AH, Jones K, Dunne J, Mooney A, Gaffney F, et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS ONE. (2020) 15:e0240784. doi: 10.1371/journal.pone.0240784

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Davis H, Assaf G, McCorkell L, Wei H, Low R, Re'em Y, et al. Symptomatic description of long COVID through 7 months in an international cohort. medRxiv. (2020). doi: 10.1101/2020.12.24.20248802

CrossRef Full Text | Google Scholar

5. Moldofsky H, Patcai J. Chronic widespread musculoskeletal pain, fatigue, depression and disordered sleep in chronic post-SARS syndrome; a case-controlled study. BMC Neurol. (2011) 11:37. doi: 10.1186/1471-2377-11-37

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Jones JF, Ray CG, Minnich LL, Hicks MJ, Kibler R, Lucas DO. Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. Ann Intern Med. (1985) 102:1–7. doi: 10.7326/0003-4819-102-1

PubMed Abstract | CrossRef Full Text | Google Scholar

7. White PD, Thomas JM, Amess J, Crawford DH, Grover SA, Kangro HO, et al. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever. Br J Psychiatry. (1998) 173:475–81. doi: 10.1192/bjp.173.6.475

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. (2006) 333:575–8. doi: 10.1136/bmj.38933.585764.AE

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. (2008) 61:43–8. doi: 10.1136/jcp.2007.050054

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Komaroff AL. Is human herpesvirus-6 a trigger for chronic fatigue syndrome? J Clin Virol. (2006) 37:S39–46. doi: 10.1016/S1386-6532(06)70010-5

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Epstein L, Wong KK, Kallen AJ, Uyeki TM. Post-Ebola signs and symptoms in U.S. survivors. N Engl J Med. (2015) 373:2483–4. doi: 10.1056/NEJMc1506576

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Sejvar JJ, Curns AT, Welburg L, Jones JF, Lundgren LM, Capuron L, et al. Neurocognitive and functional outcomes in persons recovering from West Nile virus illness. J Neuropsychol. (2008) 2:477–99. doi: 10.1348/174866407X218312

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Seet RC, Quek AM, Lim EC. Post-infectious fatigue syndrome in dengue infection. J Clin Virol. (2007) 38:1–6. doi: 10.1016/j.jcv.2006.10.011

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Kerr JR, Gough J, Richards SC, Main J, Enlander D, McCreary M, et al. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. (2010) 91:893–7. doi: 10.1099/vir.0.017590-0

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Sigal LH. Summary of the first 100 patients seen at a Lyme disease referral center. Am J Med. (1990) 88:577–81. doi: 10.1016/0002-9343(90)90520-N

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Morroy G, Keijmel SP, Delsing CE, Bleijenberg G, Langendam M, Timen A, et al. Fatigue following acute Q-fever: a systematic literature review. PLoS ONE. (2016) 11:e0155884. doi: 10.1371/journal.pone.0155884

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Nicolson GL, Gan R, Haier J. Multiple co-infections (mycoplasma, chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. (2003) 111:557–66. doi: 10.1034/j.1600-0463.2003.1110504.x

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Litleskare S, Rortveit G, Eide GE, Hanevik K, Langeland N, Wensaas KA. Prevalence of irritable bowel syndrome and chronic fatigue 10 years after giardia infection. Clin Gastroenterol Hepatol. (2018) 16:1064–72.e4. doi: 10.1016/j.cgh.2018.01.022

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Topol E, Verghese A, Fauci A. Fauci to Medscape: ‘We're All In It Together and We're Gonna Get Through It'. Medscape (2020). Available online at:

Google Scholar

20. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press (2015).

Google Scholar

21. Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A population-based study of the clinical course of chronic fatigue syndrome. Health Qual Life Outcomes. (2003) 1:49. doi: 10.1186/1477-7525-1-49

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). (2005) 55:20–31. doi: 10.1093/occmed/kqi013

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Bell DS, Jordan K, Robinson M. Thirteen-year follow-up of children and adolescents with chronic fatigue syndrome. Pediatrics. (2001) 107:994–8. doi: 10.1542/peds.107.5.994

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Komaroff AL. Advances in understanding the pathophysiology of chronic fatigue syndrome. JAMA. (2019) 322:499–500. doi: 10.1001/jama.2019.8312

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Mueller C, Lin JC, Sheriff S, Maudsley AA, Younger JW. Evidence of widespread metabolite abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. (2019) 14:562–72. doi: 10.1007/s11682-018-0029-4

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Pan R, Zhang Q, Anthony SM, Zhou Y, Zou X, Cassell M, et al. Oligodendrocytes that survive acute coronavirus infection induce prolonged inflammatory responses in the CNS. Proc Natl Acad Sci USA. (2020) 117:15902–10. doi: 10.1073/pnas.2003432117

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Poon DC, Ho YS, Chiu K, Wong HL, Chang RC. Sickness: from the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons. Neurosci Biobehav Rev. (2015) 57:30–45. doi: 10.1016/j.neubiorev.2015.07.015

PubMed Abstract | CrossRef Full Text | Google Scholar

28. VanElzakker MB. Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. (2013) 81:414–23. doi: 10.1016/j.mehy.2013.05.034

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci. (2014) 37:39–46. doi: 10.1016/j.tins.2013.10.003

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, et al. Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci USA. (2016) 113:E5472–80. doi: 10.1073/pnas.1607571113

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ. Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms. Free Radic Biol Med. (2005) 39:584–9. doi: 10.1016/j.freeradbiomed.2005.04.020

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Balinas C, Cabanas H, Staines D, Marshall-Gradisnik S. Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. (2019) 17:401. doi: 10.1186/s12967-019-02155-4

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Campen CLMV, Rowe PC, Visser FC. Reductions in cerebral blood flow can be provoked by sitting in severe myalgic encephalomyelitis/chronic fatigue syndrome patients. Healthcare (Basel). (2020) 8:394. doi: 10.3390/healthcare8040394

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: COVID-19, SARS-CoV-2, post-infectious fatigue syndrome, post-viral fatigue syndrome, myalgic encephalomyelitis/chronic fatigue syndrome

Citation: Komaroff AL and Bateman L (2021) Will COVID-19 Lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? Front. Med. 7:606824. doi: 10.3389/fmed.2020.606824

Received: 29 September 2020; Accepted: 23 December 2020;
Published: 18 January 2021.

Edited by:

Francisco Westermeier, FH Joanneum, Austria

Reviewed by:

Luis Carlos Nacul, University of London, United Kingdom
Elisa Oltra, University of Valencia, Spain

Copyright © 2021 Komaroff and Bateman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Anthony L. Komaroff,