‘We are going to have difficulty’: Untangling causes of fatigue, long COVID remains elusive
Key takeaways:
- Among adults infected with SARS-CoV-2, 4.5% developed ME/CFS vs. 0.6% of uninfected individuals.
- Rheumatologists should assess patients who have had COVID-19 for autoimmune or preclinical diseases.
Developing myalgic encephalomyelitis/chronic fatigue syndrome is significantly more likely after a case of COVID-19, an important connection for rheumatologists as they sort through symptoms and medical histories for a diagnosis, data show.
“Rheumatologists have often seen patients with post-infectious symptoms, but we have never had this magnitude of people becoming infected in a short amount of time,” Nora G. Singer, MD, professor of medicine and pediatrics at the Case Western Reserve University School of Medicine, told Healio.
In a study funded by the NIH and published in the Journal of General Internal Medicine, Singer and colleagues used data from the NIH’s Researching COVID to Enhance Recovery (RECOVER) initiative to compare the development of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) among 11,785 people infected with SARS-CoV-2 vs. 1,439 uninfected individuals.
The researchers found that, months later, 4.5% of those infected — compared with 0.6% of those not infected — met Institute of Medicine criteria for ME/CFS.
In addition, compared with uninfected individuals, patients who had been infected with COVID-19 demonstrated a hazard ratio for ME/CFS of 4.93 (95% CI, 3.62-6.71). Among those with ME/CFS, 88.7% also met RECOVER’s criteria for long COVID.
For more on what these findings mean for rheumatologists, Healio reached out to Singer, who directs the division of rheumatology at the MetroHealth system in Ohio.
Healio: What role should rheumatologists play in diagnosing and managing ME/CFS, especially in patients who have had COVID-19?
Singer: I think rheumatologists, number one, need to determine, at the time that the patient is seen, whether or not they think there is an autoimmune disease that has expressed itself, or if there are indications that there might be pre-clinical disease evolving.
After COVID, B cells produce more autoantibodies than in people who are uninfected. That, combined with the highly sensitive assays we use to detect these antibodies, detects a lot of things that may or may not have a positive correlation with clinical disease, especially when the autoantibodies are low titer. As I tell my patients, diagnoses of autoimmune disease still require a clinician’s assessment.
In terms of ME/CFS, rheumatologists do treat fatigue that accompanies a number of rheumatic diseases. The evidence base for therapies that work is still evolving. Clinicians in general need to do a detailed sleep history, because helping patients fix their sleep is very important to reducing pain.
I think rheumatologists will self-select with regard to caring for patients with post-COVID syndrome that is not organ specific. For interstitial lung disease, for example, which associates with autoantibodies seen in muscle disease, many rheumatologists are willing to collaborate with the pulmonologist caring for the patients. For the group of patients who have exercise intolerance, we may recognize it, but we may not ultimately be the ones who treat it.
Rheumatologists are very qualified to sort out complex and sometimes vague symptoms just because they take histories from patients every day with complex medical issues and think analytically.
With regard to post-COVID, I think first and foremost we need to validate what patients are experiencing and exclude other conditions for which there are evidenced-based therapies. We also need to understand which patients do and don't have dysautonomia.
Healio: What should rheumatologists know about connections between ME/CFS and long COVID?
Singer: I think that, until we understand the mechanism(s) by which long COVID sets in, we are going to have difficulty distinguishing causes of ME/CFS. Clinically, the timing of when long COVID symptoms occurred, and whether or not ME/CFS was present prior to COVID, is helpful information. For example, COVID toes, which are seen mostly in mild cases of COVID and resemble lupus chilblains — both appear to occur because of the same secreted cell mediator, type 1 interferons. Currently, we don't have that level of precision for either long COVID or ME/CFS.
There are patients with ME/CFS whose symptoms came before COVID, and a few of those patients have not had COVID that they know of. We need to compare a variety of parameters, including, but not limited to, those found in a variety of types of blood cells, to the blood cells of those patients who had COVID-associated ME/CFS. By comparing these subsets of patients, we would like to try to understand if ME/CFS is the same if ME/CFS was, or was not, triggered by COVID — or at least the timing is suspicious for COVID as the trigger.
It would be ideal to be able to pair these types of studies with treatment studies, so we know what improves in both long COVID with and without ME/CFS, and also to study ME/CFS that appears to be unrelated to COVID — eg, was present prior to the pandemic. We would like to know what things in the blood need to change for patients to feel like their old selves and to have therapeutics that can help us cure ME/CFS and long COVID symptoms.
Healio: How does ME/CFS overlap with or differ from other rheumatologic conditions, such as fibromyalgia?
Singer: In my clinical experience, fibromyalgia waxes and wanes more and may have a more pronounced component of disordered sleep. ME/CFS seems like it is always there. Many patients with fibromyalgia are helped by daily exercise, which in ME/CFS is often not tolerated. We as a community don't completely understand to what extent dysautonomia figures into both of these conditions.
Healio: Are there any multidisciplinary approaches or referrals you would recommend?
Singer: I think it does take a team or virtual team to address all the needs. An individual patient's team, besides their primary care physician, may need cardiologists, pulmonologists, rehabilitation clinicians, endocrinologists, gastroenterologists, etc. Not every patient needs every service, and it is both fatiguing and costly for patients to have to see a number of clinicians, so we ought to think about which services an individual patient needs.
We were involved with the clinical trials that the Duke Clinical Research Institute oversaw for long COVID. The data will be fully analyzed once the last patient completes their final visit in late March. There is a clinical trials network that NIAID plans to start that will address some of the unmet needs of patients with long COVID, and patients are very organized and are participating with NIAID and clinicians in informing what therapies should be tested.
The patient community appears dedicated to participating in trials to cure long COVID, and rheumatologists can help by being a clinical trial site if they are approached.
Healio: What should rheumatologists communicate to patients about the potential risk for ME/CFS after COVID-19 infection?
Singer: Honestly, the patient community is more effective at communicating these issues than we have been. I think we as clinicians need to validate symptoms that patients are feeling. Some clinicians who are too busy already or are less interested in post-COVID may choose to refer to colleagues with more interest in this disorder.
References:
Vernon SD, et al. J Gen Intern Med. 2025;doi:10.1007/s11606-024-09290-9.
For more information:
Nora G. Singer, MD, can be reached at nsinger@metrohealth.org.
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