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Do Fatigue and Exercise Intolerance Post-COVID-19 Indicate a Chronic Disease?

  • Authors: News Author: Miriam E. Tucker; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 11/4/2022
  • Valid for credit through: 11/4/2023
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Target Audience and Goal Statement

This activity is intended for primary care physicians, infectious disease specialists, rheumatologists, nurses, nurse practitioners, pharmacists, physician assistants, and other clinicians who care for patients at risk for long COVID or myalgic encephalitis/chronic fatigue syndrome.

The goal of this activity is for learners to be better able to compare long COVID and myalgic encephalitis/chronic fatigue syndrome.

Upon completion of this activity, participants will:

  • Assess the prevalence of long COVID during the Omicron wave of COVID-19
  • Compare long COVID and myalgic encephalitis/chronic fatigue syndrome in terms of symptoms and objective testing
  • Outline implications for the healthcare team


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News Author

  • Miriam E. Tucker

    Freelance writer, Medscape


    Miriam E. Tucker has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor/Compliance Reviewer

  • Yaisanet Oyola, MD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Yaisanet Oyola, MD, has no relevant financial relationships.

Compliance Reviewer/Nurse Planner

  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Do Fatigue and Exercise Intolerance Post-COVID-19 Indicate a Chronic Disease?

Authors: News Author: Miriam E. Tucker; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 11/4/2022

Valid for credit through: 11/4/2023


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

Long COVID can affect up to half of patients with COVID-19, but has the relatively less severe symptomatology associated with the Omicron variant resulted in lower rates of long COVID? A small, single-center study performed in Japan by Morioka and colleagues sought to answer this question, and the results of their research were published in the August 11, 2022, issue of the Journal of Infection and Chemotherapy.[1]

The cross-sectional study compared patients infected with the Omicron variant vs previous strains of COVID-19. Long COVID was defined by the presence of at least 1 symptom for 2 months after the diagnosis of COVID-19. Although hundreds of patients were interviewed for this research protocol, only 18 patients each in the Omicron and other strains groups could be matched to account for demographic variables and vaccination status.

The overall prevalence rates of long COVID in the Omicron and other strain cohorts were 5.6% and 55.6%, a significant difference. However, there was no significant difference between groups in the prevalence of specific symptoms of long COVID, such as fatigue, dyspnea, or dysosmia/dysgeusia.

From its first description, long COVID has been compared with myalgic encephalitis/chronic fatigue syndrome (ME/CFS). The current study assesses how many patients with long COVID meet criteria for ME/CFS.

Study Synopsis and Perspective

A new study provides yet more evidence that a significant subset of people who experience persistent fatigue and exercise intolerance after COVID-19 will meet diagnostic criteria for ME/CFS.

Data from the prospective observational study of 42 patients with "post-COVID-19 syndrome (PCS)," including persistent fatigue and exercise intolerance, suggest that a large proportion will meet strict diagnostic criteria for ME/CFS, including the hallmark postexertional malaise (PEM). Still others may experience similar disability but lack duration and/or severity requirements for the diagnosis.

Moreover, disease severity and symptom burden were found to be similar in those with ME/CFS after COVID-19 and in a group of 19 age- and sex-matched individuals with ME/CFS that was not associated with COVID-19.

"The major finding is that ME/CFS is indeed part of the spectrum of the post-COVID syndrome and very similar to the ME/CFS we know after other infectious triggers," senior author Carmen Scheibenbogen, MD, acting director of the Institute for Medical Immunology at the Charité University Medicine Campus Virchow-Klinikum, Berlin, Germany, told Medscape Medical News.

Importantly, from a clinical standpoint, both diminished hand grip strength and orthostatic intolerance were common across all patient groups, as were several laboratory values, Claudia Kedor, MD, and colleagues at Charité report in the article, published online August 30 in Nature Communications.[2]

Of the 42 patients with PCS, including persistent fatigue and exercise intolerance lasting at least 6 months, 19 met the rigorous Canadian Consensus Criteria (CCC) for ME/CFS, established in 2003, which require PEM, along with sleep dysfunction, significant persistent fatigue, pain, and several other symptoms from neurological/cognitive, autonomic, neuroendocrine, and immune categories that persist for at least 6 months.[3]

Of the 23 who did not meet the CCC criteria, 18 still experienced PEM, but for less than the required 14 hours set by the authors based on recent data.[4] The original CCC had suggested 24 hours as the PEM duration. Eight subjects met all the Canadian criteria except for the neurological/cognitive symptoms. None of the 42 had evidence of severe depression.

The previously widely used 1994 "Fukuda" criteria for ME/CFS are no longer recommended because they don't require PEM, which is now considered a key symptom. The more recent 2015 Institute of Medicine criteria do not define the length of PEM, the authors note in the article.[5]

Dr Scheibenbogen said, "Post-COVID has a spectrum of syndromes and conditions. We see that a subset of patients have similar symptoms of ME/CFS but don't fulfill the CCC, although they may meet less stringent criteria. We think this is of relevance for both diagnostic markers and development of therapy, because there may be different pathomechanisms between the subsets of post-COVID patients."

She pointed to other studies from her group suggesting that inflammation is present early in post-COVID (not yet published), whereas in the subset that goes on to ME/CFS, autoantibodies or endothelial dysfunction play a more important role.[6,7] "At the moment, it's quite complex, and I don't think in the end we will have just 1 pathomechanism. So I think we'll need to develop various treatment strategies."

Asked to comment on the new data, Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School and senior physician at Brigham and Women's Hospital in Boston, Massachusetts, and editor in chief of the Harvard Health Letter, told Medscape Medical News, "This paper adds to the evidence that an illness with symptoms that meet criteria for ME/CFS can follow COVID-19 in nearly half of those patients who have lingering symptoms. This can occur even in people who initially have only mild symptoms from COVID-19, although it is more likely to happen in the people who are sickest when they first get COVID-19. And those who meet criteria for ME/CFS were seriously impaired in their ability to function, [both] at work and at home."

But, Dr Komaroff also cautioned, "the study does not help in determining what fraction of all people who are infected with SARS-CoV-2 go on to develop a condition like ME/CFS, nor how long that condition will last. It is crucial that we get answers to these questions, as the impact on the economy, the healthcare system, and the disability system could be substantial."

He pointed to a recent report from the Brookings Institution finding that "long COVID may be a major contributor to the shortage of job applicants plaguing many businesses."[7]

Biomarkers Include Hand Grip Strength, Orthostatic Intolerance, Lab Measures

Hand grip strength, as assessed by 10 repeat grips at maximum force and repeated after 60 minutes, were lower for all those meeting ME/CFS criteria compared with the healthy controls. Hand grip strength parameters were also positively correlated with laboratory hemoglobin measures in both PCS groups who did and did not meet the Canadian ME/CFS criteria.

A total of 3 patients with PCS who did not meet ME/CFS criteria and 7 with PCS who met ME/CFS criteria had sitting blood pressures of greater than 140 mm Hg systolic and/or greater than 90 mm Hg diastolic. Five patients with PCS (4 who met ME/CFS criteria and 1 who did not) fulfilled criteria for postural orthostatic tachycardia syndrome. Orthostatic hypotension was diagnosed in a total of 7 with PCS, including 1 who did not meet ME/CFS criteria and the rest who did.

Among significant laboratory findings, mannose binding lectin deficiency, which is associated with increased infection susceptibility and found in only about 6% of historical controls, was found more frequently in both of the PCS cohorts (17% of those with ME/CFS and 23% of those without) than it has been in the past among those with ME/CFS compared with historical controls (15%).

There was only slight elevation in C-reactive protein, the most commonly measured marker of inflammation. However, another marker indicating inflammation within the last 3 to 4 months, interleukin 8 assessed in erythrocytes, was above normal in 37% with PCS and ME/CFS and in 48% with PCS who did not meet the ME/CFS criteria.

Elevated antinuclear antibodies, anti-thyroid peroxidase antibodies, vitamin D deficiencies, and folic acid deficiencies were all seen in small numbers of the patients with PCS. Angiotensin converting enzyme 1 (ACE1) levels were below the normal range in 31% of all patients.

"We must anticipate that this pandemic has the potential to dramatically increase the number of ME/CFS patients," Dr Kedor and colleagues write. "At the same time, it offers the unique chance to identify ME/CFS patients in a very early stage of disease and apply interventions such as pacing and coping early with a better therapeutic prognosis. Further, it is an unprecedented opportunity to understand the underlying pathomechanism and characterize targets for specific treatment approaches."

Dr Scheibenbogen and Dr Komaroff have disclosed no relevant financial relationships.

Nature Communications. Published online August 30, 2022. 

Study Highlights

  • Study enrollment took place at a single clinical center in Germany between August and November 2020. All patients included in the study had COVID-19 infection between March and June 2020, when only the original SARS-CoV-2 variant was in circulation.
  • All patients had fatigue and exertion intolerance for at least 6 months after their infection. Patients with a history of previous significant chronic illness were excluded from the study.
  • ME/CFS was defined by postexertional fatigue that lasted at least 14 hours after activity. The main study outcome was the percentage of patients with long COVID who met this criteria.
  • 42 patients were included in the COVID-19 cohort. The median age was 36.5 years, and there were more than twice as many women as men in the study sample;45.2% of the COVID cohort met criteria for ME/CFS. Of those who not meet ME/CFS criteria, 78.3% had postexertional fatigue, but it did not last for 14 hours.
  • Disability was profound and similar among patients with long COVID alone and non-COVID ME/CFS. However, fatigue and stress intolerance were more severe in ME/CFS vs. long COVID.

Figure. ME/CFS Diagnosis and Symptoms in Patients With Long COVID-19

  • Measurements of hand grip strength were reduced with controls, with little difference based on the presence of ME/CFS.
  • 4 patients with ME/CFS attributable to COVID-19 met criteria for postural tachycardia syndrome, as did 1 with long COVID alone; 6 patients with long COVID who met criteria for ME/CFS had postural hypotension, compared with only 1 patient with long COVID alone.
  • C-reactive protein levels were not commonly elevated among patients with long COVID, although interleukin 8 levels were increased in 37% to 48% of patients.
  • Although 8 patients had significant elevations of antinuclear antibodies, none had elevations of double-stranded DNA and extractable nuclear antigen antibodies.

Clinical Implications

  • A previous small study found that long COVID was approximately 10 times less common among patients with infection with the Omicron strain vs previous strains. However, no single symptom of long COVID was more common with previous strains vs the Omicron strain.
  • In the current study, 45.2% of patients with long COVID met criteria for ME/CFS. Disability was profound and similar among patients with long COVID alone and non-COVID ME/CFS. However, fatigue and stress intolerance were more severe in ME/CFS vs long COVID. Half of patients with long COVID had autonomic dysfunction.

Implications for the Healthcare Team

The healthcare team should prepare for the long-term sequelae of COVID-19, including disability, among a substantial minority of patients.


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