No Causal Effects Detected in COVID-19 and ME/CFS: A Two Sample Mendelian Randomization Study 2023 Xu et al

Abstract

New clinical observational studies suggest that Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a sequela of COVID-19 infection, but whether there is an exact causal relationship between COVID-19 and ME/CFS remains to be verified. To investigate whether infection with COVID-19 actually causes ME/CFS, this paper obtained pooled data from the Genome Wide Association Study (GWAS) and analyzed the relationship between COVID susceptibility, hospitalization and severity of COVID and ME/CFS, respectively, using two-sample Mendelian randomization (TSMR). TSMR analysis was performed by inverse variance weighting (IVW), weighted median method, MR-Egger regression and weighted mode and simple mode methods, respectively, and then the causal relationship between COVID-19 and ME/CFS was further evaluated by odds ratio (OR). Eventually, we found that COVID-19 severity, hospitalization and susceptibility were all not significantly correlated with ME/CFS (OR:1.000,1.000,1.000; 95% CI:0.999–1.000, 0.999–1.001, 0.998–1.002; p = 0.333, 0.862, 0.998, respectively). We found the results to be reliable after sensitivity analysis. These results suggested that SARS-CoV-2 infection may not significantly contribute to the elevated risk of developing CFS, and therefore ME/CFS may not be a sequela of COVID-19, but may simply present with symptoms similar to those of CFS after COVID-19 infection, and thus should be judged and differentiated by physicians when diagnosing and treating the disease in clinical practice.

Open access, https://www.mdpi.com/1660-4601/20/3/2437

 

I can believe that self-reported chronic fatigue syndrome in sample of patients that hasn't undergone sufficient quality control has no particular relationship (probably to anything) because there is so much misdiagnosis and confusion of fatigue with ME/CFS.

Whether that is what is happening here I don't know, but it seems like a possibility.

Edit: the data of ME/CFS was obtained from the UK bio bank (not the other ME/CFS specific biobank).

To believe what this paper claims, we would have to believe that ME/CFS is not triggered by infections, or that it is triggered by infections but not by infection with SARS-CoV-2, or that the ME/CFS-like form of LC is radically different from ME/CFS in terms of underlying biological disruption despite having high similarity in terms of symptoms.

Maybe the error is also that the ME/CFS-like form of LC is insufficiently included in studies because so much attention is on severe infections, hospitalizations, organ damage and death, rather than mild infections in younger people where the ME/CFS-like illness tends to appear.

 

Oh good. Statistics and semantics conjoined in a single piece highlighting two confusing and contested diseases. What could go wrong?

 

This doesn't seem to make any sense to me.
All they seem to be saying is that if Covid-19 causes ME then they haven't been able to find any clues as to what factors are critical in causation. Not that there is no causation.

 

See https://www.s4me.info/threads/long-covid-in-the-media-and-social-media-2023.31490/


post #91. Sorry no spoons.

edit: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9839201/
Conclusions
Long COVID is a multisystemic illness encompassing ME/CFS, dysautonomia, impacts on multiple organ systems, and vascular and clotting abnormalities. It has already debilitated millions of individuals worldwide, and that number is continuing to grow. On the basis of more than 2 years of research on long COVID and decades of research on conditions such as ME/CFS, a significant proportion of individuals with long COVID may have lifelong disabilities if no action is taken. Diagnostic and treatment options are currently insufficient, and many clinical trials are urgently needed to rigorously test treatments that address hypothesized underlying biological mechanisms, including viral persistence, neuroinflammation, excessive blood clotting and autoimmunity.

 

I'm not sure how the analysis they carried out actually works. Based on what the data they're using, my guess is that it involves checking if SNPs found to be associated with covid severity, hospitalization and susceptibility (respectively) are also appearing in the self-reported ME/CFS cases in the UK biobank.

 

The Covid-19 Host Genetics initiative is collecting the following phenotypes:

Critically ill covid19 patients vs population controls.
Hospitalized vs non-hospitalized patients.
Hospitalized vs population controls.
Reported infection vs population controls.

https://app.covid19hg.org/

From what I understood the ME/CFS-like subtype of long covid is almost entirely composed of patients with mild infections.

 

That's clearly something that should be accounted for by Wangzi Xu el al, but it is also pretty weird - with EBV which is often said to be implicated in ME/CFS onset it is precisely the most severe forms of infection i.e Mononucleosis that are suggested to be involved. If COVID 19 plays a role in the development of ME/CFS, is it really the case that having severe acute COVID is protective of developing ME/CFS ? Or is it that the status of being prone to severe acute COVID (i.e older, male, overweight etc) is itself protective of developing ME/CFS ?

To me the question of ME/CFS from COVID is too messy to understand, I think it will be years before there is clear enough data to be able to say anything useful.

 

Mild in the context of covid19 means staying at home during the infection, and not being hospitalized. Is that not how mononucleosis usually goes?

 

Until we can demonstrate conclusively that there are absolutely no Covid remnants in any patient who presents with persistent symptoms, "causal" studies such as this cannot rise above definitional white noise.

 

Honestly the entire profession needs to do serious work on how research results are presented. It's often forgotten when talking about how STEM fields badly need the humanities that the M stands for medicine. Terrible communication skills.

 

Categorisation of acute Covid has been largely imprecise - there's this: https://patient.info/news-and-features/coronavirus-what-are-asymptomatic-and-mild-covid-19

"Mild COVID-19

The virus affects mainly your upper respiratory tract, primarily the large airways. Mild symptoms of COVID are temperature, a new, continuous cough and/or a loss of your sense of smell or taste.

Patients with mild illness have flu-like symptoms. These may include dry cough and mild fever, but the fever may not reach 37.8°C, and there may sometimes be little or even no cough. Patients might notice a feeling of being a bit more breathless than normal on exercise, but they are not out of breath on normal household activity.

With mild COVID-19:

You may have a fever, including one that doesn't reach the 37.8°C mark.
You may lose your sense of smell or taste.
You may have tiredness, muscles aches or a headache.
You are not highly likely to have sore throat or runny nose, but they do occur in some cases.
You do not have marked breathlessness.
Your self-care, cooking, eating and drinking are not affected. Your appetite is normal or fairly normal.
You may feel sad or weepy.
The symptoms typically seem to last about 7-10 days."

compare that to:

https://www.cdc.gov/epstein-barr/about-mono.html

"Symptoms

Typical symptoms of infectious mononucleosis usually appear four to six weeks after you get infected with EBV. Symptoms may develop slowly and may not all occur at the same time.

These symptoms include:

extreme fatigue
fever
sore throat
head and body aches
swollen lymph nodes in the neck and armpits
swollen liver or spleen or both
rash

Enlarged spleen and a swollen liver are less common symptoms. For some people, their liver or spleen or both may remain enlarged even after their fatigue ends.

Most people get better in two to four weeks; however, some people may feel fatigued for several more weeks. Occasionally, the symptoms of infectious mononucleosis can last for six months or longer."

I've always understood mononucleosis to be a pretty challenging illness, substantially worse than annual flu, but that's based on anecdote and personal experience.

 

There has never been a correlation between severe illness and getting ME. I was no sicker than a usual summer flu, laid up in bed for a few days.

Not up to looking into it, but I felt no surprise that mild covid was more likely to lead to long covid, I just took it for granted that was the case for ME and I would have to try to find out why now.

 

Not disagreeing with your point, but the M is mathematics (although there seem to be some variants to retrofit).
https://en.wikipedia.org/wiki/Science,_technology,_engineering,_and_mathematics

 

The idea may have come from the Dubbo study by Andrew Lloyd.

"Severe acute infective illnesses predicted prolonged illness, prolonged mood disturbance and PIFS. These factors may facilitate early intervention to manage both PIFS and mood disturbances."

https://ammes.org/tag/dubbo-study/

 

In his large study of glandular fever, Peter White found that days of bedrest was a predictor of developing CFS. Bedrest is most obviously a marker of severity of illness, though Peter, White. chose to interpret it as a sign that excessive resting was a risk factor.

 

But why would more severe acute illness be less likely to be a precursor to ME/CFS ? If acute infection has a causal role in ME/CFS, yet neither symptom insignificant nor severe infections have the same propensity to lead to ME/CFS as mild acute illness, then some very specific processes have to be in play and I'm not clear what line of reasoning could begin to elucidate what those processes might be. How can mild illness be more damaging than severe illness ?

 

Can pwME get long covid? Anyone looking? I'd suspect Hanson or Levine, but don't really know if anyone has published anything. But I'd be curious to see that math.