Understanding the Overlap Between Long-COVID and ME/CFS
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In the 20th century, approximately 70 unexplained outbreaks of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) were documented. A notable incident occurred in 1955 at the Royal Free Hospital in the UK, where 255 healthcare workers fell ill under mysterious circumstances.
This led Dr. Melvin Ramsay to introduce the term ME, which the World Health Organization (WHO) officially recognized as a medical condition by 1969. By the early 2000s, ME began to be regarded as synonymous with chronic fatigue syndrome (CFS), leading to the term ME/CFS to describe the condition collectively.
Viral infections are a common catalyst for ME/CFS, with Covid-19 being a prime example. Although the survival rate for Covid-19 is about 98%, estimates suggest that 10–30% of those who recover may experience long-COVID, a persistent post-viral syndrome that can endure for 6–9 months. Remarkably, the onset of long-COVID does not correlate with the initial severity of the Covid-19 infection, meaning even those who experienced mild cases can face long-term disabilities.
Long-COVID gained considerable attention in May 2020, particularly among support groups, and later among medical professionals. Many speculated that long-COVID could lead to ME/CFS. Nearly ten months later, some predictions held true, as certain cases of long-COVID manifested as ME/CFS. However, does this realization truly provide solutions?
ME/CFS Diagnostic Criteria
There are multiple definitions for diagnosing ME/CFS, but only three are widely accepted:
- The 1994 CDC criteria identify severe fatigue lasting at least six months, accompanied by four or more symptoms: cognitive impairment, tender lymph nodes, sore throat, muscle pain, multi-joint pain, post-exertional malaise, unrefreshing sleep, and headaches.
- The 2003 Canadian Consensus Criteria focus on fatigue, post-exertional malaise, sleep disturbances, muscle or joint pain, and cognitive impairment lasting six months or more.
- The 2015 Institute of Medicine (IOM) criteria emphasize severe, unrelieved fatigue, post-exertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance persisting for a minimum of six months.
These symptoms closely align with those reported in long-COVID cases, suggesting that long-COVID could be classified as ME/CFS based on symptom similarity and duration.
Ultimately, ME/CFS diagnoses rely solely on symptomatic evidence, which can be subjective, leading to potential misdiagnosis. Currently, there are no laboratory tests or biological markers—like blood tests or imaging—to confirm ME/CFS.
Certain Long-COVID Cases Qualify as ME/CFS
Most research on long-COVID typically has a follow-up period of less than six months. Among studies with longer follow-up durations, few have explored the potential for ME/CFS diagnoses among long-haulers. So far, only three studies have conducted formal medical assessments.
Study 1
A recent study published in the Journal of Neurovirology involved 120 Covid-19 survivors who had been discharged from the hospital six months earlier, with an average age of 56 years and a hospital stay of 3.5 days, indicating that most had mild to moderate cases of Covid-19.
Results showed that 21 participants experienced fatigue, with 3 (14.3%) meeting the 1994 CDC criteria for ME/CFS. Additionally, 7 (5.8%) of the 120 survivors were diagnosed with PTSD according to DSM-5 standards.
Study 2
Researchers at University College London gathered questionnaire data from 3,762 Covid-19 survivors across 56 countries, with 41.6% from the U.S. Only 8.4% had been hospitalized, suggesting that most respondents dealt with mild Covid-19.
At 6–7 months post-symptom onset, 77.7% reported fatigue, 77.2% experienced post-exertional malaise, 55.4% suffered cognitive impairment, and 53.6% had headaches. Other symptoms included insomnia, heart palpitations, and muscle aches, with approximately 40% needing to reduce their workload and 22% unable to work.
Out of those surveyed, 1,146 sought medical diagnoses. Among them, 13.5% were diagnosed with POTS, and 10.3% met the 2015 IOM criteria for ME/CFS. An additional 17.2% were diagnosed with long-COVID, potentially overlapping with ME/CFS.
Study 3
Another preprint from the Berlin Institute of Health involved 42 Covid-19 survivors suffering from moderate to severe fatigue lasting at least six months. The median age of participants was 36, with most having experienced mild Covid-19.
Among these fatigued individuals, 41 exhibited post-exertional malaise, 40 had cognitive impairment, 38 reported headaches, and 35 had muscle aches—similar symptoms to previous studies. Notably, 19 (45%) met the 2003 Canadian Consensus Criteria for ME/CFS.
Summary
These studies indicate that roughly 10–45% of Covid-19 long-haulers meet the criteria for ME/CFS. The remaining cases likely present severe fatigue, hinting at another medical condition related to post-Covid fatigue.
For context, the estimated prevalence of ME/CFS in the general population is about 1.4%, suggesting that long-COVID could elevate the risk of ME/CFS by 7–32 times. If 10–30% of Covid-19 cases result in long-COVID, this implies Covid-19 could increase ME/CFS risk by 0.7–9.6 times. However, this calculation may be overly simplistic.
The Many Unknowns
1. Duration and Recovery
A four-year follow-up study of 181 SARS survivors (mean age 43) found that 40% still experienced fatigue, and 27% met the 1994 CDC criteria for ME/CFS. Additionally, 42.5% had at least one psychiatric disorder, predominantly PTSD and depression, as per DSM-IV. Like long-COVID, post-SARS syndrome was unrelated to the severity of the initial infection.
Another study followed 71 SARS survivors discharged from the hospital 15 years ago. While only 7% were over 50, about 6% and 37% still exhibited bone and lung abnormalities on imaging scans, respectively. However, this study did not assess fatigue or ME/CFS.
Thus, it appears that ME/CFS or post-SARS ME/CFS could persist for up to four years (possibly even 15 years). Currently, long-COVID can last up to nine months or more.
2. Biological Causes
To date, the causes of ME/CFS remain elusive. "Multiple models have been proposed to explain the pathogenesis of ME/CFS, but none have been conclusively proven," according to a 2021 research review.
Potential biological models include autoimmunity, hypometabolic states, chronic inflammation, bioenergetic dysfunction, dysautonomia, and the recent persistent brainstem dysfunction hypothesis, which could explain long-COVID.
However, no singular biological cause for ME/CFS has been identified. It's likely that several biological factors contribute to the condition since organ systems are interconnected. For example, chronic inflammation may lead to neuroinflammation, disrupting the brainstem, which regulates autonomic functions and cardiorespiratory systems.
3. Risk Factors
Common triggers for ME/CFS include viral infections, physical or emotional trauma, and exposure to environmental toxins or molds, yet no specific trigger has been recognized.
Genetic predisposition may also play a role, as individuals with relatives suffering from ME/CFS have higher incidence rates. Still, no specific gene has been identified. Other risk factors include older age, female sex, a history of psychiatric disorders, and low socioeconomic status, although these factors have shown inconsistencies in various studies. "None of these factors appear suitable for timely identification of patients at risk of developing CFS/ME in clinical practice," concluded a 2008 systematic review.
4. Treatments
Currently, the treatment landscape for ME/CFS remains unclear. The absence of understanding regarding its causes complicates the development of pharmaceutical treatments. Without a biological explanation, no biological approach can be implemented.
Indeed, randomized clinical trials (RCTs) aimed at identifying treatments for ME/CFS have been largely disappointing. A 2020 systematic review of 56 RCTs found only three evaluating pharmaceutical treatments and five assessing non-pharmacological approaches showed benefits for treating ME/CFS, while 48 trials yielded no statistically significant results.
While some RCTs indicate potential benefits, no treatments are widely accepted or approved for ME/CFS. Non-pharmacological methods—like cognitive-behavioral therapy (CBT), graded exercise therapy (GET), and adaptive pacing therapy (APT)—have shown better outcomes than medications. However, none provide a cure, and their effectiveness is not guaranteed.
As of March 22, 2021, concerns have arisen that CBT and GET may exacerbate symptoms in ME/CFS patients. Indeed, flaws in clinical trials supporting these therapies raise questions about their validity. This may explain why the CDC has not recommended CBT or GET for ME/CFS.
5. Research Funding
Despite the term ME/CFS being coined in 1955, the scientific community still lacks a clear understanding of its biological causes, diagnostic markers, specific triggers, risk factors, and effective treatments.
One significant reason for this lack of progress is the underfunding of ME/CFS research. The U.S. National Institute of Health (NIH) acknowledges this issue and has formed a multi-institute working group to advance research on this debilitating condition.
"Nonetheless, with an overall budget of $42 billion, NIH's allocation for ME/CFS research in 2019 was a mere $15 million, compared to $111 million for multiple sclerosis and $94 million for rheumatoid arthritis, both of which have numerous approved drugs," stated a 2021 research review. Several patient advocacy groups and private foundations have taken the initiative to support ME/CFS research and enhance awareness. However, interest from pharmaceutical companies and investors remains minimal.
Short Abstract
Throughout history, outbreaks of ME/CFS have occurred, often with unknown origins. Given that viral infections are common triggers, it's anticipated that post-Covid-19 outbreaks of ME/CFS may arise. Indeed, 10–30% of Covid-19 cases are expected to develop long-COVID, with 10–45% of these cases qualifying for an ME/CFS diagnosis. However, understanding that certain long-COVID cases represent ME/CFS does little to clarify the situation, given our limited knowledge of ME/CFS itself.
As of February 24, 2021, with 88,266,708 reported Covid-19 recoveries, estimates suggest there could be between 8.8 million to 26.5 million long-COVID cases and 880,000 to 12 million ME/CFS cases. While these calculations may be rough, they highlight the longstanding neglect of ME/CFS and the pressing need to address the consequences we are now witnessing.
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