A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS, 2021, Mackay

[Andy]

A significant proportion of COVID-19 patients are suffering from prolonged Post-COVID-19 Fatigue Syndrome, with characteristics typically found in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no clear pathophysiological explanation, as yet, has been provided.

A novel paradigm for a Post-COVID-19 Fatigue Syndrome is developed here from a recent unifying model for ME/CFS. Central to its rationale, SARS-CoV-2, in common with the triggers (viral and non-viral) of ME/CFS, is proposed to be a physiologically severe stressor, which could be targeting a stress-integrator, within the brain: the hypothalamic paraventricular nucleus (PVN). It is proposed that inflammatory mediators, released at the site of COVID-19 infection, would be transmitted as stress-signals, via humoral and neural pathways, which overwhelm this stress-center. In genetically susceptible people, an intrinsic stress-threshold is suggested to be exceeded causing ongoing dysfunction to the hypothalamic PVN's complex neurological circuitry. In this compromised state, the hypothalamic PVN might then be hyper-sensitive to a wide range of life's ongoing physiological stressors. This could result in the reported post-exertional malaise episodes and more severe relapses, in common with ME/CFS, that perpetuate an ongoing disease state. When a certain stress-tolerance-level is exceeded, the hypothalamic PVN can become an epicenter for microglia-induced activation and neuroinflammation, affecting the hypothalamus and its proximal limbic system, which would account for the range of reported ME/CFS-like symptoms.

A model for Post-COVID-19 Fatigue Syndrome is provided to stimulate discussion and critical evaluation. Brain-scanning studies, incorporating increasingly sophisticated imaging technology should enable chronic neuroinflammation to be detected, even at a low level, in the finite detail required, thus helping to test this model, while advancing our understanding of Post-COVID-19 Fatigue Syndrome pathophysiology.

Open access, https://www.frontiersin.org/articles/10.3389/fneur.2021.701419/full

 

[ME/CFS Skeptic]

A "physiologically severe stressor" in "genetically susceptible people" is as unclear as can be.

The gist of the theory revolves around the hypothalamic paraventricular nucleus (PVN). The authors describe it as follows:

The hypothalamic PVN is a complex array of nuclei and neurological circuitry, which functions as a stress-integrator, absorbing, processing and responding to a wide range of physiological stressors, playing an essential role in neuroendocrine and autonomic regulation (23, 24). Incoming stress-signals from all types of infections (via inflammatory mediators, such as cytokines and chemokines), pain, emotional distress and cardiovascular changes from physical exertion, all converge upon the hypothalamic PVN, by a range of humoral and neural routes. This single point of convergence, the hypothalamic PVN, is a potential vulnerable site in genetically susceptible people

The author has previously written about this, this paper seems to add long covid in the mix.

Mackay A, Tate WP. A compromised paraventricular nucleus within a dysfunctional hypothalamus: a novel neuroinflammatory paradigm for ME/CFS. Int J Immunopathol Pharmacol. (2018) 32:1–8. doi: 10.1177/2058738418812342 17.

Mackay A. A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome. J Prim Health Care. (2019) 11:300–7. doi: 10.1071/HC19041​

 

[DokaGirl]

Brain scanning able to detect even low level inflammation, something that seems elusive to pin down in ME.

it would be interesting if some studies included people with Long COVID, another group with ME, plus healthy controls.

 

[Mithriel]

This looks like a way to try to put BPS theory onto a scientific footing while still ignoring the actual symptoms of the disease. It does not reflect my experience of the disease at all.

It is problematic in that it may be close to the truth but still pushing us towards CBT as a treatment.

The findings from CPET testing that our aerobic cellular respiratory output is compromised carries the implication that a lot of our symptoms could be caused by the response of our bodies to the extreme stress of not having enough battery power to work.

For decades, having ME has been described as being similar to a runner at the end of a marathon so any results showing increased stress responses is most likely to be the correct response to that, not a mistake in the signals. The body is sending out the appropriate distress calls for the situation.

 

[Hutan]

Yes, I think Angus is wrong in his BPS-like hypothesis. However, he gives the best summary I have found yet of the evidence for much of Long Covid being ME/CFS. That, I think, has been obvious for a good while, but few papers actually come out and say it.

Here's some of the supporting argument:

As the pandemic has progressed increasing concern has been raised that the loosely defined, but widespread “post-viral fatigue” might in fact represent a much more entrenched and serious form of SARS-CoV-2 triggered “post-viral fatigue syndrome,” in a significant proportion of this cohort (2, 3). Post-Viral Fatigue Syndrome (PVFS) is essentially the same disease as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), originally named simply as Myalgic Encephalomyelitis (ME) after it resulted from an infectious disease outbreak at the Royal Free Hospital in London, in 1955 (7). The World Health Organization lists PVFS and ME/CFS under the same category of neurological disorders (8), while clinical (diagnostic) assessments are the same for each disease. ME/CFS-like illnesses have arisen mainly from a “post-viral fatigue” documented as a consequence of over 75 reported localized outbreaks of infectious disease, since the 1930's (9), but all dwarfed by the pandemic of COVID-19. However, unlike PVFS, the triggers of ME/CFS can sometimes be non-viral (10), which may explain why both terms persist.

Fauci noted that some post-COVID-19 patients' symptoms, such as difficulty in concentrating (“brain fog”) and “fatigue,” were highly suggestive of ME/CFS (3). A UK study estimated that 10% of its patients who had tested positive for COVID-19 remained unwell more than 3 weeks later, and a smaller proportion months later (11). It stated: “The profound and prolonged nature of fatigue in some post-acute COVID-19 patients shares features with chronic fatigue syndrome, described after other serious infections including SARS, MERS, and community acquired pneumonia.” The Irish study, mentioned earlier, also reported a gender bias with 67% of those suffering from “post-viral fatigue” being female (6); ME/CFS has a significant gender bias toward females (10).

Significantly, “chronic fatigue” lasting 6 months or longer, without an alternative explanation, is required to fulfill a diagnosis of ME/CFS (10). Longitudinal studies tracking post-COVID-19patients' symptoms over 6 months or more, are only now emerging, as COVID-19 is still a relatively new, and complex disease, with multiple outcomes. Increasing links between post-COVID-19 patients' symptoms and ME/CFS are becoming evident, as the three recently completed longitudinal studies, following, illustrate.

A Chinese (Wuhan) study of a large patient cohort (n = 1,733), discharged from hospital, found that 76% of them had at least one persistent symptom 6 months after their initial COVID-19 onset (12). The most common symptoms reported were fatigue or muscle weakness (63%), sleep difficulties (26%) and anxiety or depression (23%), which are common in ME/CFS (8). Of the patient cohort, 75% had required supplemental oxygen, with 7% on a ventilator, during their hospital stay, whereas the remaining 25% did not. Consequently, impaired pulmonary diffusion capacity and abnormal chest imaging manifestations were reported (estimated at 22–56% across a scale of severity, and especially evident in the more severe cases). This could also have contributed to the specific symptoms reported in a subset of patients.

An international, web-based survey involved 3,762 participants, aged between 30 and 59 years old (13). Of those with post-COVID-19 issues, 6 months since their infection, 80% were female. The most frequently reported symptoms were fatigue (>75%), post-exertional malaise (>69%) and cognitive dysfunction (“brain-fog”) (>52%), all common core symptoms of ME/CFS. Over 85% experienced health relapses, induced by physical, mental exercise or psychological stress, also key characteristics of ME/CFS (6). Around 67% of the cohort were unable to work or were on a reduced work schedule at the time of the survey. Most of those surveyed (>90%) had not been hospitalized indicating that even relatively mild cases of SARS-CoV-2 infections could trigger ME/CFS-like symptoms.

A comprehensive German study of 42 post-COVID-19 patients, aged between 22 and 62 years old, of which 29 were female, is the first to assess a post-COVID-19 cohort clinically for ME/CFS (14). They were assessed 6 months after initial SARS-CoV-2 infection, which had caused only mild to moderate COVID-19 induced symptoms, thus ruling out interpretations of their long-term symptoms that might be relevant in more severe (hospitalized) cases of COVID-19. The most frequently reported ME/CFS symptoms were chronic fatigue by all 42 patients, post exertional malaise (PEM) (n = 41), cognitive impairment (n = 40), headache (n = 38), and muscle pain (n = 35). The 2003 Canadian Consensus Criteria were the ME/CFS diagnostic criteria used. These were met by 19/42 patients, who were diagnosed with severe fatigue and cognitive impairment, severe stress intolerance, and hypersensitivity to noise, light, and temperature. In particular, the intensity and duration of PEM (symptoms lasting for more than 14 h) was considered to be the main diagnostic criterion for ME/CFS. The remainder of the patients (n = 23), in the study, shared many of these same symptoms, but they were at a lesser severity (in particular PEM duration lasted between 2 and 10 h), and they were categorized as having a closely related “Chronic COVID-19 Syndrome.” This study, again, illustrated that even mildly affected post-COVID-19 patients can develop ME/CFS-like symptoms. The authors concluded: “Our study provides evidence that patients following mild COVID-19 develop a chronic syndrome fulfilling diagnostic criteria of ME/CFS, in a subset. We must anticipate that this pandemic has the potential to dramatically increase numbers of ME/CFS patients.”

 

[Snow Leopard]

LongCOVID is many things (any persistent symptom after SARS-CoV-2 infection), whereas only a minority of people with LongCOVID actually have ME/CFS.

The hypothesis that the illness is caused by hypothalamic paraventricular nucleus dysfunction is weak as there are no consistent neuroendocrine abnormalities (eg related to stress hormones) found - and that has been one of the most investigated avenues since the 1990s (Anthony Cleare and others).