Post-COVID Fatigue, Exercise Intolerance Signal ME/CFS

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A new study provides yet more evidence that a significant subset of people who experience persistent fatigue and exercise intolerance following COVID-19 will meet diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (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 post-exertional 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 similar in those with ME/CFS following COVID-19 and in a group of 19 age- and sex-matched individuals with ME/CFS that wasn't associated with COVID-19.

Dr Carmen Scheibenbogen

"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 (HGS) and orthostatic intolerance were common across all patient groups, as were several laboratory values, Claudia Kedor, MD, and colleagues at Charité report in the paper, published online August 30 in Nature Communications.

Of the 42 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.

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. 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 (now Academy) of Medicine criteria don't define the length of PEM, the authors note in the paper.

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), while in the subset that goes on to ME/CFS, autoantibodies or endothelial dysfunction play a more important role. "At the moment, it's quite complex, and I don't think in the end we will have just one pathomechanism. So I think we'll need to develop various treatment strategies."

Dr Anthony Komaroff

Asked to comment on the new data, Anthony L. Komaroff, MD, professor of medicine at Harvard Medical School, senior physician at Brigham and Women's Hospital in Boston, 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, 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."

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 didn't meet the Canadian ME/CFS criteria.

A total of three patients with PCS who didn't meet ME/CFS criteria and seven 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 — four who met ME/CFS criteria and one who didn't — fulfilled criteria for postural orthostatic tachycardia syndrome. Orthostatic hypotension was diagnosed in a total of seven with PCS, including one 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 3-4 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 PCS patients. 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," 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."

Scheibenbogen and Komaroff reported no relevant financial relationships.

Nature Communications. Published online August 30, 2022. Full text

Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter @MiriamETucker.

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