Earlier Alice penned a thought-provoking blog “No, long COVID is not helping ME/CFS”. Now she and Dr. Naomi Harvey propose that a shift in the language we use to describe both long COVID and ME/CFS would benefit both.
ME (Myalgic Encephalomyelitis) is a severe, immune-mediated illness often triggered by viral infection. Until the emergence of SARS-CoV-2, causing COVID-19, anyone who fit the diagnostic criteria for ME/CFS (often referred to as chronic fatigue syndrome, CFS) would be diagnosed with ME/CFS no matter whether their illness was triggered by viral or bacterial infections, physical or emotional trauma, surgery, childbirth, or allergic reaction.
All of these cases fall together under the umbrella of ME/CFS since they all result in common symptoms including exhaustion, brain fog, PEM/PESE, orthostatic intolerance, and unrefreshing sleep. Common comorbidities include fibromyalgia, irritable bowel syndrome, MCAS, POTS, autoimmune problems, and Ehlers-Danlos Syndrome.
However, the medical community has taken a different approach when ME/CFS is caused by COVID-19. It has been shown on multiple occasions that approximately half of those with the long-term sequelae of SARS-CoV-2, known collectively as long COVID, have ME/CFS. Yet there is a reluctance to categorize these COVID-19-induced ME/CFS sufferers as having ME/CFS.
There are some doctors and patients who believe that long COVID should stand alone. That we shouldn’t consider those with long COVID who fit the diagnostic criteria for ME/CFS as having ME/CFS until it has been unequivocally proven that their disease is the same as those with non-COVID ME/CFS. They think it’s dangerous to conflate the two, and argue that we don’t have enough proof yet that they are the same.
Such arguments may stem from a place of hope and fear. No one wants ME/CFS, as ME/CFS is most often for life, even if the severity varies over time. People want to believe their long COVID is curable, but the commonalities between ME/CFS and long COVID go far beyond a shared symptomatology.
We argue here that the scientific and medical communities should adhere to the precautionary principle. Given the significant overlap in symptoms, viral onset, and a number of biomedical findings, we should accept those with long COVID who meet the ME/CFS criteria as having ME/CFS until proven otherwise.
There are a multitude of reasons why including COVID-19 as a cause of ME/CFS would be beneficial to both communities and reasons why keeping them separate will do harm to both communities. We also do not know enough (or anything) about the risks of progressing to ME/CFS from non-ME post-viral states. Those with long COVID who don’t fit the ME/CFS criteria yet may be at high risk of developing into ME/CFS later, and the precautionary principle means we should at least consider this.
What Does the Science Say?
To our knowledge, every published study on long COVID, bar one, has found the same pathologies that are found in ME/CFS studies. Overwhelmingly, biomedical study results show the same findings between long COVID and ME/CFS. These include but are not limited to: evidence of neuroinflammation; loss of gray matter; cerebral hypoperfusion; dysautonomia; mast cell activation; endothelial dysfunction; the presence of microclots; cardio-pulmonary abnormalities; pro-inflammatory cytokines; impaired TRPM3 ion channel function in NK cells; T cell exhaustion; increased reactive oxygen species; microglial activation; altered fatty acid metabolism and dysfunctional mitochondrial lipid metabolism; lowered cortisol; impaired tryptophan-kynurenine metabolism; impaired glucose metabolism; CPET-evidenced exercise intolerance; small fiber neuropathy; reactivation of EBV and other herpes viruses.
There are a few studies that show quantitative differences in specific abnormal findings between those with long COVID and those with ME. For example, whilst hyperactivated platelets and fibrinaloid microclots are found both in long COVID and ME/CFS, the microclot load was reduced in ME/CFS patients compared to those with long COVID. There have also been suggestions from physicians that the degree of endothelial and cardiovascular damage seen in long COVID outstrips the endothelial damage seen in ME/CFS.
Duration May Make a Difference
These are valid points, and it’s possible that these are differences seen with ME/CFS when induced by SARS-CoV-2, as we would expect to see some minor differences according to the initial trigger. But it’s important to remember when interpreting these differences, that all existing research on long COVID has been done on people in the early stages of the disease.
In contrast, very little research on ME/CFS has ever been done on people in the early years of the disease. In fact, we could only find two studies on people with ME/CFS who were less than 3 years from disease onset, which produced three papers.
So far as we are aware, there is a single study showing a distinct difference between ME/CFS & long COVID, this one. The authors state, “Long-COVID is biochemically distinct from ME/CFS as all 14 vascular transformation biomarkers increased significantly in plasma from Long-COVID patients when compared to healthy control subjects. In contrast, plasma levels of P-SEL, MMP-1, ICAM-1, VEGF-A, and VEGF-D either do not change with ME/CFS or are depressed”. However, as these authors are not ME/CFS specialists, they do not seem to be aware of a very important caveat: ME/CFS pathology changes with time.
ME (Myalgic Encephalomyelitis) is a severe, immune-mediated illness often triggered by viral infection. Until the emergence of SARS-CoV-2 causing COVID-19, anyone who fit the diagnostic criteria for ME/CFS (often referred to as Chronic Fatigue Syndrome, CFS) would be diagnosed with ME/CFS no matter whether their illness was triggered by viral or bacterial infections, physical or emotional trauma, surgery, childbirth, or allergic reaction.
From what little research there is, we know that abnormalities in ME/CFS can and do change with time since onset. For example, people who have had ME/CFS for more than 10 years show less pronounced pulse pressure changes during a NASA Lean Test compared to people who had ME/CFS for <4 years. Additionally, a study led by Dr. Mady Hornig showed that the biochemistry and cytokine signature in ME/CFS changes with illness duration. Dr. Hornig’s team found that those with ME/CFS for <3 years had a distinct immune signature of “activation of both pro- and anti-inflammatory cytokines as well as dissociation of intercytokine regulatory networks”. This research clearly demonstrates that the immunopathology of ME/CFS is dynamic and not fixed.
It’s therefore likely that the few differences that have been found between ME/CFS and long COVID are an artifact of time since illness onset. Additionally, we would expect to see subtle differences in people with ME/CFS depending on the triggering event or virus. As an anecdotal observational example, those whose ME/CFS appeared to be triggered by EBV seem more often to report flares in symptoms such as sore throat and swollen lymph nodes more often than those whose ME/CFS was not EBV-triggered. Such differences do not justify saying EBV-induced ME/CFS is a new disease. Why should COVID-induced ME/CFS be different?
For those of us who know the ME/CFS literature intimately, it is shocking how anyone can argue that long COVID is distinct from ME/CFS. What we are likely seeing in long-COVID research is a terrific insight into the early stages of ME/CFS. And vice versa, we can study ME/CFS veterans and apply existing knowledge in order to better understand the disease course & anticipate problems in those with COVID-induced ME/CFS before they happen.
It is also possible that those with long COVID who do not currently fit the criteria for ME/CFS are at high risk of developing ME/CFS with additional immune challenges such as repeat infections or vaccinations. There has only ever been one prospective study of ME/CFS from before its onset and we know next to nothing about whether people with non-ME post-viral illness or POTS, MCAS, EDS etc. may go on to develop ME/CFS further down the line.
By separating ME/CFS from long COVID now, we are missing a unique opportunity to study a cohort of people with post-viral illness long term to see what their risk of ME/CFS is and what biochemical and immune changes mediate this.
The Risks of Treating Long COVID as Distinct to ME/CFS
How Problematic Language Surrounding Long COVID Harms Those with ME
Consider the term “long COVID”, which encompasses several health conditions rolled into one. Definitions of long COVID vary and often include any new symptoms or conditions lasting sufficiently long following a Covid-19 infection.
Some conditions counted as long COVID are conventional non-syndromic issues that can be tested for and have existing guidelines, such as kidney injury pulmonary fibrosis, or cardiac pathologies. However, long COVID also includes those with syndromes like ME/CFS, dysautonomia, and chronic autoimmune conditions, as well as people with pre-existing complex chronic illness that are worsened by SARS-CoV-2 infection.
Some of these long-COVID conditions include ME/CFS, Post-ICU syndrome, lingering COVID symptoms (such as cough, loss of smell, and taste), organ damage, neurological symptoms, and arthritis. Often, the increased risk for things like heart attack, stroke, and diabetes following a COVID-19 infection is also considered to be part of long COVID.
The use of the term long COVID enables all the effects of SARS-CoV-2 to be discussed and quantified as a whole, and it has allowed the patient community to come together as one. There are many reasons why this term has been effective and needs to be kept at least as an overall umbrella term.
The fact that long COVID encompasses so many conditions makes it harder to talk about the different needs of those with different subtypes, as well as to talk about the long-COVID ME/CFS subgroup. We cannot say that long COVID and ME/CFS are the same because long COVID includes too many other issues, yet they are more than just “similar” or “linked”.
Unfortunately, many people new to the world of chronic illness and ME/CFS seem to be under the illusion that ME/CFS is “just fatigue” and that the problems that come with it including hypercoagulable blood, vascular and orthostatic dysfunction, dysautonomia, immune dysregulation including mast cell activation syndrome, are separate comorbidities seen only in long COVID.
This is what we call the “comorbidity problem” – where people fail to understand that ME/CFS is far more than “just fatigue”. Essentially, people end up conflating a number of different conditions together all under the umbrella of long COVID to make it look like long COVID = ME/CFS + POTS + autoimmune problems + MCAS + Post ICU Syndrome + Loss of Smell + etc. This, in turn, makes it easier for people to consider ME/CFS as “just fatigue” & makes it seem like those with “Long COVID” have much more numerous & severe health problems than those with non-COVID ME/CFS, which is simply not true.
Once ME/CFS is viewed as “just fatigue”, it becomes much harder for it to be taken seriously, and the reluctance to group COVID-induced ME/CFS with other ME/CFS begins to make sense.
Those with long COVID know their problems go far beyond “just fatigue”. They see the gaslighting & dismissal people with ME/CFS have faced for decades & understandably do not want to have to face the same thing, so many further encourage the division between long COVID & ME/CFS.
Unfortunately, this does not protect them from such a fate, as the proponents of the psychosocial model of ME/CFS are already working on long COVID, trying the same things they did with ME/CFS, including recommending treatments such as the Lightning Process and Graded Exercise Therapy which will only serve to harm sufferers.
Failing to acknowledge that up to 50% of people with long COVID have ME/CFS also makes it difficult to understand the risks that long COVID poses. Estimates of the prevalence of long COVID following COVID-19 infections vary wildly across studies using varying definitions of long COVID, as well as various methods of estimating its prevalence
Without diagnoses that allow us to appropriately stratify the long-COVID branch of diseases, we cannot estimate the true risks and consequences of having long COVID; i.e. what percentage of those with “long COVID” have something relatively minor, such as a lingering cough, or fatigue that will disappear over time, vs something more severe like an ME/CFS case, which can leave one functionally disabled for life. That vagueness has allowed the public to minimize the severity of long COVID. (Checking out the comments on any long-COVID media piece will make that clear.)
For people to better understand the risk long COVID poses, we need to break “long COVID” down into distinct conditions, each of which will have different impacts, risk levels, and prognoses.
Additionally, it’s clear that some people who see reports claiming a high risk of long COVID following COVID-19 infection exists, combine that with a personal experience of knowing few or zero people who (publicly) report being severely affected by long COVID, and then conclude that the high risk of long COVID is made up.
Indeed, it’s possible that most people initially labeled with “long COVID” will either have relatively minor symptoms that simply take some time to disappear. People whose functionality is more impaired (the ME/CFS-like long-COVID group) are likely fewer in numbers, may either not wish to be public about their condition, or may lack the energy to do so – leaving them largely invisible.
Splitting up long-COVID risk by condition, (e.g. – the risk of developing ME/CFS following COVID risk of developing loss of smell following COVID, etc.), would reduce the gaslighting the ME/CFS-like long-COVID cohort faces, educate the public about the seriousness of the disorder, and make it harder to dismiss or minimize.
Talking about COVID-induced ME/CFS will also benefit those with ME/CFS by helping to undo the decades of gaslighting and stigmatism they’ve endured while making it clear, once again, that “chronic fatigue syndrome” or ME/CFS is not “just fatigue”.
The Wider Dangers of Separating COVID ME/CFS from Others with ME
By pretending that COVID-19-induced ME/CFS is a new condition, and by failing to make clear that long COVID is just the latest iteration of post-infectious ME/CFS-like illness states, we allow governments and research funders to continue dragging their feet on ME/CFS research, leaving ME/CFS one of the most underfunded diseases in the NIH.
We saw this recently at the National Institutes of Health (NIH) when support for ME/CFS actually dropped at a time when the NIH was engaged in spending over a billion congressionally mandated dollars on long-COVID research.
This allows the media the state things like treatments for brain fog are lacking because brain fog is a “still relatively new” phenomenon, when brain fog has been a significant problem in ME/CFS, POTS, fibromyalgia, and cancer fatigue, for decades.
Keeping Long COVID Distinct from ME/CFS Will Further Hinder Research on Both Diseases
Whilst the term long COVID was created by patients themselves and is the preferred colloquial name, failing to appropriately screen and categorize the sub-types of Long COVID in research studies will also introduce methodological errors and weaken the research.
Treating long COVID as a uniform condition in research studies means that important differences will be missed, at best lending to confusion as to what long COVID is, perpetuating ideas that long COVID is ‘mysterious’, at best, and invalidating research findings and delaying treatment progress, at worst. This, however, is currently the norm as very few long-COVID studies to date have differentiated out their ME/CFS-like or other subsets.
The reason so many long-COVID studies produce the same abnormal findings as ME studies may be because at least 50% of their participants have undiagnosed ME/CFS. That, of course, would hamper our understanding of those whose long COVID does not fit the ME/CFS criteria.
Failure to account for subtypes and differential diagnoses means not only failing to appropriately stratify for disease subtypes but leads to failures to link up with the existing literature on those conditions, leaving researchers to keep “rediscovering” findings that previously showed up in ME/CFS and other conditions. While some studies cite ME/CFS findings, others – even in cases where ME/CFS citation would help to validate a finding or hypothesis – do not.
The search for effective treatments will surely be hampered, as well, by having a mishmash of patients in clinical trials. A treatment that works for one particular subset of long COVID may not work for the rest – resulting in false negatives and treatments wrongly being discarded as ineffective.
Consider PEM (Post Exertional Malaise), the cardinal symptom of ME. Patients with PEM exhibit exercise intolerance and can be harmed by exercise but long-COVID patients without PEM may actually benefit from exercise. There are ample cases within the long-COVID community of this harm happening already. The authors personally know people who suffered severe worsening after exercise, who were seeing a doctor who did not diagnose them with COVID-19-induced ME/CFS, and failed to treat them properly.
- Alice Kennedy’s first blog on Health Rising, “No, Long Covid is Not Helping People with ME…” triggered a lot of discussion. Now she’s back, teamed up with Dr. Naomi Harvey with another thought-provoking blog.
- The authors noted that prior to long COVID, the term ME/CFS included many different types of ME/CFS – post-infectious (viral/bacteria) ME/CFS, emotional/stress-induced ME/CFS, post-surgical ME/CFS, no known trigger ME/CFS. That changed with long COVID: instead of long COVID being a part of ME/CFS, there was long COVID – and ME/CFS.
- While the term long COVID has been helpful in bringing attention and resources to the illness, Alice and Naomi believe it’s imperative that the ME/CFS cohort be singled out and grouped under the term ME/CFS.
- Many studies now suggest that the pathophysiology of the two diseases is nearly identical. (See list at the bottom of the blog.) Alice and Naomi argue that the small differences found thus far could be due to the longer duration of illness seen in ME/CFS.
- Because long COVID contains so many subsets – from the large ME/CFS-like cohort to the people with lung or heart or kidney damage – the fact that the term long COVID suggests it’s one thing is misleading…
- It includes, for instance, people with one or two symptoms that either resolve themselves over time or aren’t particularly significant. Including people with significant functional problems such as the ME/CFS-like cohort in the same group causes confusion – and can cause some to minimize the severity of their illness.
- When ME/CFS gets grouped in the long-COVID basket with diseases like POTS, MCAS, lung, heart or kidney problems, etc., it tends to get viewed as “just fatigue” rather than the complex disease it is.
- Not filtering out the ME/CFS cohort from other long-COVID cohorts will impede efforts to understand and find treatments for all the cohorts.
- Not doing so leaves some researchers oblivious to the fact that decades of research on ME/CFS exist which could help inform their understanding.
- It leaves the ME/CFS group of long-COVID patients prey to potentially harmful techniques like graded exercise therapy.
- The authors suggest we find new ways of referring to the different types of long COVID such as COVID-induced ME/CFS”, “COVID-induced autoimmunity”, “lingering COVID symptoms”, “COVID-induced asthma”, etc.
In short, keeping ME/CFS and long COVID separate will hinder progress in research on both diseases.
Using the term “long COVID” whilst failing to identify subdiagnoses and specifying which groups are being discussed, is confusing & actively harmful both in scientific research and in a wider context. Failure to appropriately diagnose ME/CFS amongst those with long COVID is detrimental to those suffering from it, as well as those with non-COVID ME/CFS and the general public.
Failing to correctly diagnose ME/CFS in those with long COVID is actively harmful to individual patients, as it leaves them exposed to false ‘treatments’ such as graded exercise therapy, which have been widely discredited and found to be harmful to people with ME/CFS. One of the benefits of receiving an appropriate ME/CFS diagnosis is the limited protection such a diagnosis gives through guidelines such as the NICE guidelines on diagnosis and management of ME/CFS in the UK, which prohibit graded exercise therapy or cognitive behavioral therapy from being offered to ME/CFS patients as a treatment.
The SARS-CoV-2 virus appears to be acting as a ‘super-trigger’ that can produce all sorts of serious and severe diseases – including ME/CFS. The reality is that we are in the midst of the largest outbreak of ME/CFS ever recorded. Failure to acknowledge this, alongside all of the other long-term consequences of COVID, is a failure of public health.
The medical community’s neglect of conditions like ME/CFS and POTS has left our medical systems ill prepared to handle the massive wave of coronavirus-triggered ME/CFS-like other sequelae. Specialty departments in post-infectious illness or dysautonomia are largely lacking and few physicians are even marginally fluent in these conditions. Likewise, few clinics can offer thorough testing and diagnostics, and there are no licensed treatments for ME/CFS. None of this will change until there is widespread recognition that ME/CFS is part and parcel of long COVID.
I hope we can start a discussion around the use of the term “long COVID” and begin using more specific language to describe the conditions it comprises. Doing this will speed up research, and improve understanding of long COVID and associated conditions. A good starting point, for people with long COVID, is to start with yourself. Instead of describing yourself as having “long COVID”, you might describe yourself as having “COVID-induced ME/CFS”, “COVID-induced autoimmunity”, “lingering COVID symptoms”, etc. If enough people adopt this, it will go a long way toward solving these problems.
Table 1. A non-exhaustive selection of findings that have been replicated between ME/CFS and long COVID (one example of each type of pathology has been shown for brevity).
Reduced gray matter
Brainstem volume changes
Postural orthostatic tachycardia
Small fiber neuropathy
|Nakatomi et al. 2014||Kavanagh 2022|
T cell exhaustion
Mast cell activation
Impaired TRPM3 ion channel function in NK cells
|Nijhof et al. 2014||Klein et al .2022|
Reduced cardiac output
Chest pain & dyspnea
|Miwa 2016||Brown et al. 2022|
|Sandvik et al. 2023||Charfeddine et al. 2021|
|Latent viral reactivation (EBV, HHV6 etc)||Schikova et al. 2020||Rohrhofer et al. 2022|
|Exertion intolerance||Moore et al. 2023||Joseph et al. 2023|
|Impaired glucose metabolism
Altered fatty acid metabolism
Impaired tryptophan-kyneurenine metabolism
|Brown et al. 2018||Montefusco et al. 2021|