The sad thing is how shockingly little we know about myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).
Roughly 70 outbreaks of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) of unknown causes occurred in the 20th Century. One such instance was in 1955 in the U.K. Royal Free Hospital, where 255 medical workers were mysteriously hospitalized.
This event led Melvin Ramsay, M.A., M.D., to coin the term ME, which the World Health Organization (WHO) recognized as an official medical condition by 1969. In early 2000, ME was viewed as synonymous with CFS, so ME/CFS is now used to describe this condition.
A common trigger of ME/CFS is viral infections, of which Covid-19 comes into mind. While the survival rate of Covid-19 is approximately 98%, about 10–30% of survivors will develop long-COVID, a chronic post-viral syndrome that can last up to 6–9 months. Long-COVID is not predicted by initial disease severity or health status, so even mild Covid-19 can leave previously healthy individuals disabled for the long-term.
Long-COVID gained widespread attention around May 2020 among social support groups and later on among the experts. At that time, many predicted that long-COVID would eventually lead to ME/CFS. Nearly 10 months have passed since, and they were partly right. Some cases of long-COVID did turn out to be ME/CFS, but does this knowledge really solve anything?
ME/CFS diagnostic criteria
Although there are many case definitions for ME/CFS, only three are accurate and widely used:
- The 1994 Centers for Disease Control and Prevention (CDC) diagnostic criteria for ME/CFS is severe fatigue lasting for at least six months with at least four of the following 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 for ME/CFS is fatigue, post-exertional malaise, sleep dysfunction, muscle or joint pain, and cognitive impairment for six months or more.
- The 2015 Institute of Medicine (IOM) diagnostic criteria for ME/CFS entail severe fatigue not relieved with rest, post-exertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance (i.e., rapid heart rate, fatigue, and/or lightheadedness upon standing) that last for at least six months.
All of these are also common symptoms of long-COVID that can last for up to six months or more. Thus, judging from the symptomatic resemblance and duration, long-COVID can already qualify as ME/CFS.
Indeed, ME/CFS diagnosis is based on symptomatic criteria only, which can be subjective, leaving more room for misdiagnosis. We still have no laboratory tests or diagnostic biomarkers — such as blood or imaging tests— to confirm ME/CFS biologically.
Certain long-COVID cases are ME/CFS
Most studies involving long-COVID have a follow-up duration of fewer than six months. Of those with a follow-up duration of over 6 months, not many examined for any possible cases of ME/CFS. As few as three studies thus far have sought medical diagnoses among long-haulers.
Study 1
In a study published this month in the Journal of Neurovirology, researchers at Iran recruited 120 survivors of Covid-19 who were discharged from the hospital six months prior. Patients had an average age was 56 years and an average stay of 3.5 days, implying that most had mild-to-moderate Covid-19.
Results revealed that 21 had fatigue, of whom 3 (14.3%) qualified for ME/CFS diagnosis per the 1994 CDC criteria. Moreover, of the 120 survivors, 7 (5.8%) had post-traumatic stress disorder (PTSD) according to the Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5).
Study 2
A study from the University College London, released as a pre-print, collected questionnaire data from 3,762 Covid-19 survivors across 56 countries, with 41.6% being from the U.S. Only 8.4% were hospitalized, indicating that most respondents had mild Covid-19.
At 6–7 months after symptom onset, 77.7% of respondents still had fatigue, 77.2% had post-exertional malaise, 55.4% had cognitive impairment, and 53.6% had headaches. Other less common symptoms included insomnia, heart palpitations, and muscle aches at 40–50%, as well as shortness of breath, joint pain, balance problems, and tachycardia at 30–40%. About 40% had to lessen their workload, and 22% could not work.
In this study, 1,146 respondents sought a medical diagnosis. And 13.5% and 10.3% of them received POTS (postural orthostatic tachycardia syndrome, characterized by orthostatic intolerance) and ME/CFS (following the 2015 IOM criteria) diagnoses, respectively. Another 17.2% were diagnosed with long-COVID, which may have coincided with ME/CFS.
Study 3
Another preprint is from the Berlin Institute of Health in Germany, which recruited 42 Covid-19 survivors with moderate-to-severe fatigue lasting for at least six months. Again, most participants (median age of 36) had mild Covid-19 at baseline.
Of these 42 fatigued long-haulers, 41 also had post-exertional malaise, 40 had cognitive impairment, 38 had a headache, and 35 had muscle ache — symptoms very similar to the abovementioned studies. More importantly, 19 (45%) fulfilled the 2003 Canadian Consensus Criteria for ME/CFS.
Summary
These studies suggest that about 10–45% of Covid-19 long-haulers have met the criteria for ME/CFS. Most of the remaining cases also have severe fatigue, suggesting that another medical condition of post-Covid fatigue may exist.
For reference, the estimated prevalence of ME/CFS in the general population is at 1.4%. So, by a rough calculation, long-COVID could up the risk of ME/CFS by 7–32-fold. If 10–30% of Covid-19 cases lead to long-COVID, that would mean Covid-19 increases the risk of ME/CFS by 0.7–9.6-fold. But please bear in mind that this calculation may be too simplified.
The plethora of unknowns
1. Duration and recovery
In a 4-year follow-up study on 181 SARS survivors (mean age of 43), 40% still had fatigue and 27% met the 1994 CDC criteria for ME/CFS. Moreover, 42.5% of them were diagnosed with at least one psychiatric disorder — most commonly PTSD and depression — following DSM-IV. As with long-COVID, such post-SARS syndrome was unrelated to initial disease severity.
Another study recruited 71 SARS survivors who were discharged from the hospital 15 years ago. Only 7% of them were older than 50 years. Yet about 6% and 37% of them still had bone and lung abnormalities upon imaging scan tests. But this study did not examine fatigue or ME/CFS.
Thus, it seems that ME/CFS or post-SARS ME/CFS could last up to four years (possibly even up to 15 years) and counting. Currently, for long-COVID, we know it can persist up to 9 months and counting.
A 2005 systematic review of 14 studies identified several noteworthy studies on ME/CFS recovery rate. Meta-analysis was not performed as each study has a different follow-up duration. For example, a 3-year follow-up study found that 49% (25 out of 51) of ME/CFS patients recovered. Another study found that 14% (7 out of 50) of ME/CFS patients recovered at a 10-year follow-up after the outbreak of unexplained fatigue in Nevada in 1984–87.
Pooling all the 14 studies irrespective of follow-up duration shows that about 5% of ME/CFS cases recovered, and 39.5% saw improvements in symptoms. “Full recovery from untreated CFS is rare,” stated the systematic review authors. But “the prognosis for an improvement in symptoms is less gloomy.”
Still, it’s an unfortunate reality that ME/CFS rarely heals, and the illness can go on to a decade or more.
2. Biological causes
To this day, we don’t know what causes ME/CFS or how it develops. “Multiple models have been advanced to explain the pathogenesis of ME/CFS. At the present time, however, none of these models has been definitively proven,” stated a 2021 research review.
Such biological models include autoimmunity, hypometabolic state, chronic inflammation, bioenergetic dysfunction, dysautonomia (autonomic nervous system dysfunction), or the more recent persistent brainstem dysfunction hypothesis that I’ve put forward as an explanation for long-COVID.
But science has yet pinpointed any sole biological cause of ME/CFS. The most likely scenario is that many biological factors contribute to ME/CFS. After all, organ systems are interconnected. Chronic inflammation, for instance, may cause neuroinflammation that may disrupt the brainstem, a brain region that regulates the autonomic nervous and cardiorespiratory systems.
3. Risk factors
Common triggers of ME/CFS are viral infections, physical or emotional trauma, and exposure to environmental toxins or mold. But no specific trigger has been identified.
Genetics may also play a role as rates of ME/CFS are higher if one has relatives with ME/CFS. But no specific gene has been pinpointed. Other risk factors of ME/CFS include older age, female sex, a history of psychiatric disorder, and low income or education attainment, but these factors have also been inconsistent among studies. “None of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice,” concluded a 2008 systematic review of 11 studies.
4. Treatments
Presently, nobody knows for sure how to treat ME/CFS. After all, designing pharmaceutical treatments is challenging without first understanding what causes ME/CFS. No biological explanation means no biological approach to tackle the disease.
Indeed, randomized clinical trials (RCTs) to find a treatment for ME/CFS has been incredibly disappointing. A 2020 systematic review looked at 56 RCTs for ME/CFS. Only 3 RCTs examining pharmacological treatments and 5 RCTs examining non-pharma methods found benefits in treating ME/CFS. The other 48 RCTs have found no statistically significant results.
Although some RCTs have found benefit, there are still no approved or widely accepted treatments for ME/CFS.
Overall, non-pharma approaches —such as cognitive-behavioral therapy (CBT), graded exercise therapy (GET), and adaptive pacing therapy (APT) — work better than drugs for ME/CFS. The ME Association, a charitable organization in the U.K., has only recommended CBT and GET. But none of these treatments serves as a cure, and they are not guaranteed to work.
5. Research funding
Although ME/CS was first coined in 1955, we still don’t know its biological cause, let alone its diagnostic biomarkers, precise triggers and risk factors, and treatments.
One prime reason for this neglect is that ME/CFS research is largely underfunded. The U.S. National Institute of Health (NIH) recognizes this problem and has established a multi-institute ME/CFS working group to further research on this debilitating illness in recent years.
“Nonetheless, with an overall budget of ∼$42Bn, NIH’s spend on ME/CFS research in 2019 amounted to only ∼$15 M compared to $111 M on multiple sclerosis and $94 M on rheumatoid arthritis, both conditions for which there are multiple drugs already on the market,” stated a 2021 research review. Several patient groups and private foundations have taken the initiative to support ME/CFS research and raise awareness about ME/CFS. “However, at the current time, interest among pharmaceutical companies and biotech/venture investors appears to be almost non-existent.”
Short abstract
Outbreaks of ME/CFS have happened many times throughout history, often with unknown causes. One common trigger of ME/CFS is viral infections, so it’s expected that we may see ME/CFS outbreaks again following the Covid-19 pandemic declared in March 2020. Indeed, about 10–30% of Covid-19 cases will lead to long-COVID. And 10–45% of long-COVID cases qualify as ME/CFS diagnosis, and the remaining half is likely sub-clinical ME/CFS. But knowing that certain cases of long-COVID is ME/CFS may solve nothing given how little we know about ME/CFS, to begin with.
Given that there are 143,806,836 ‘recovered’ cases of Covid-19 as of 19th May 2021, we may already have 14,400,000 to 43,140,000 cases of long-COVID (i.e., 10–30% of Covid-19 cases) and 1,440,000 to 13,000,000 cases of ME/CFS (i.e., 10–45% of long-COVID cases). Obviously, this is a rough calculation that may not be very accurate. But, if anything, it’s a fact that ME/CFS has long been neglected, and we are seeing its consequences now. We have a huge number of long-COVID and ME/CFS cases that we have no idea how to solve.
This article was originally published in Microbial Instincts with minor modifications.