The persistence of [ME/CFS] after SARS-CoV-2 infection: A systematic review and meta-analysis, 2024, Dehlia et al

Objectives
Long COVID-19 (LC) patients experience a number of chronic idiopathic symptoms that are highly similar to those of post-viral Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We have therefore performed a systematic review and meta-analysis to determine the proportion of LC patients that satisfy ME/CFS diagnostic criteria.

Methods
Clinical studies published between January 2020 to May 2023 were identified using the PubMed, Web of Science, Embase and CINAHL databases. Publication inclusion/exclusion criteria were formulated using the global CoCoPop framework. Data were pooled using a random-effects model with a restricted maximum-likelihood estimator. Study quality was assessed using the Joanna Briggs Institute critical assessment tool.

Results
We identified 13 eligible studies that reported a total of 1,973 LC patients. Our meta-analysis indicated that 51% (95% CI, 42%-60%) of LC patients satisfied ME/CFS diagnostic criteria with fatigue, sleep disruption, and muscle/joint pain being the most common symptoms. Importantly, LC patients also experienced the ME/CFS hallmark symptom, post-exertional malaise.

Conclusions
Our study not only demonstrates that LC patients exhibit similar symptom clusters to ME/CFS, but that approximately half of LC patients satisfy a diagnosis of ME/CFS. Our findings suggest that current ME/CFS criteria could be adapted to the identification of a subset of LC patients that may facilitate the standardized diagnosis, management and the recruitment for clinical studies in the future.

Link | PDF (J Infection, September 2024, open access)

 

The corresponding author for a number of years was a quite active ME/CFS advocate perhaps particularly on Twitter
https://x.com/Dr_M_Guthridge
but he hasn't tweeted or even retweeted in over 3 years.

 

Looks like a misleading review, most of these studies are surveys or come from single-centre clinics so have a huge selection bias.

 

Indeed for example Scheibenbogen's studies by definition tend to focus on the ME/CFS subtype of LC and are as such of course not representative of LC (and yet she had shown in a different study that only 50% of ME/CFS like-LC looks like ME/CFS after one year). Interestingly they also didn't include the aforementioned Scheibenbogen study albeit it fulfilling all necessary criteria.

There however seem to be even more substantial problems in this study.

For instance they include Nehme et al and say that according to that study 48% of LC patients meet ME/CFS criteria (123 of 258). However, according to Nehme et al only 8.2% of LC patients had PEM (and only 1.1% actually meet criteria for chronic fatigue syndrome). So what happened here? Their restricted their analysis to a specific subset of LC patients in the paper (those that reported fatigue). But even then Nehme report that only 6.2% of those meet ME/CFS criteria.

I don't see them giving a reason for such a restriction in their paper.

If you use the numbers Nehme et al actually reports their 50% average over 13 studies will go down to somewhere around 30%. Nehme et al was the only citation I looked at and as such I would be very suprised if similar problems don't exist elsewhere as well.

 

Yes, I think there are other issues:

The 58.7% for the Twomey 2022 paper seems to refer to the proportion of LC cases that had post-exertional malaise, not ME/CFS.

Chronic Fatigue and Postexertional Malaise in People Living With Long COVID: An Observational Study - PubMed (nih.gov)

In the Gonzales 2022 paper, they studied 130 Long covid patients, and reported a prevalence of ME/CFS of somewhere between 13% to 19.2%. This review, however, only took the 61 Long Covid patients with fatigue as the denominator although 54 other Long Covid patients did have other symptoms (just not fatigue). That increased the estimate to 28%-41%.
Post-Acute COVID-19 Symptoms, a Potential Link with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A 6-Month Survey in a Mexican Cohort - PubMed (nih.gov)

In the Tokumaso 2022 paper, the reported prevalence of ME/CFS is 17.9% for both the CCC and IOM (50 patients out of 279). However this review reports a prevalence of 26% for this paper (25/96) in figure. I'm not sure where these numbers come from.
Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID - PubMed (nih.gov)

 

All three of the studies by Leonard Jason are just online questionnaires shared on social media. ME/CFS cases were determined by the (abbreviated) DePaul Symptom questionnaire without clinical examinations.

I also think that the Jason & Dori 2023 and Jason & Islam 2022 describe the same dataset because they both report a prevalence of 145/299 in Long Covid patients.
Predictors of impaired functioning among long COVID patients - PubMed (nih.gov)
A CLASSIFICATION SYSTEM FOR POST-ACUTE SEQUELAE OF SARS CoV-2 INFECTION | Central Asian Journal of Medical Hypotheses and Ethics (cajmhe.com)

 

In the 3 studies from the Charité Fatigue Center (Haffke 2022, Sotzny 2022, Kedor 2022), the included Long Covid patients already
suffered from persistent moderate to severe fatigue and exertion intolerance. So this was a highly selected sample, already quite similar to ME/CFS.

It's also possible that there is overlap between these 3 studies (the same data appearing in multiple papers) considering how similar their recruitment methods are and that they were all published in the same year.
Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity - PubMed (nih.gov)
A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity | Nature Communications
Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) - PubMed (nih.gov)

And then there is the study from the ME/CFS clinic of Visser & Van Campen where 100% of Long Covid patients had ME/CFS. That probably also gives an indication of how reliable these studies are.

 

Here are some reasons to think that the % of ME/CFS cases among Long Covid patients will be substantially lower than 50%:

In the ONS survey, only 19% of those with self-report Long Covid symptoms, said that their ability to undertake their day-to-day activities had been "limited a lot".
Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK - Office for National Statistics (ons.gov.uk)

Two recent epidemiological studies failed to find a clear increase of ME/CFS following SARS-CoV-2 Infection. There are probably multiple reasons for these findings including weaknesses in study design, but it's not exactly what one would expect if 50% of Long Covid patients had ME/CFS. To me it suggests that only a minority of Long Covid patients will have ME/CFS.

Unger et al. 2024:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection | Public Health | JAMA Network Open | JAMA Network

Wood et al. 2024:

Impact of COVID-19 on myalgic encephalomyelitis/chronic fatigue syndrome-like illness prevalence: A cross-sectional survey - PubMed (nih.gov)

 

Maybe there isn't a clear or large increase visibile in the data because the healthcare system is generally bad at diagnosing ME/CFS without several years of delay.

In the EU wide patient survey the average time to diagnosis was 7 years.

 

To be fair, if I didn't have to be on twitter because however lousy it has become, it's still a very important resource for all advocacy and basic awareness about most things chronic illnesses, I wouldn't be either. It has become such a cesspool, but the chronic illness community is one of the last valid uses for it.

 

He was very active for a few years. As I recall he used to go to some trouble to make awareness images. But then disappeared.

 

Another issue: based on the forst plot (figure 3), it seems that the authors inserted multiple estimates from the same study.These are based on the same data and participants but simply using different ME/CFS case definitions. So these estimates are not independent. It's like counting the same results twice or thrice.

They should probably separate these into different meta-analyses (one for each case-definition).

 

It might seem tempting to use such papers from an advocacy standpoint, ME/CFS is clearly occuring in LC patients and is a very significant manifestation of LC.

The problem however is that people can then run a CBT or GET trial on LC patients or simply do nothing and once most patients improve naturally over time you can justify that these things work for ME/CFS following from Covid because the rate of ME/CFS amongst said patients must have been high.

The solution is: Don't define LC as an exercise in symptom counting. If you look at the long-lasting and severely disabling proportions of LC, which is precisely what you anyways want to be doing, the rate of ME/CFS will be non-negligible.

 

Agree, I would avoid naming a proportion or percentage, but one could use these studies to argue that several researchers have noted a high percentage of ME/CFS cases among Long Covid patients or something like that, to get the message across.

It was not my intention to be too harsh on the authors of this review. This is an important subject and it's good to have an overview of what is known about it. My take however, would be that very little can be concluded from these poor quality studies.

It's really sad that we have no better estimates. The epidemiological community has failed. This was a major pandemic, all over the news, lots of people dying, lots of people with long-term symptoms and still they have managed to set up proper longitudinal studies. All that I have seen thus far are studies that count the number of people that say they have a symptom.

 

I've quickly tried to recreate their analysis in R using the meta package (random effects with Freeman-Tukey Double arcsine transformation)
but with some changes in the data:

• I've only used one estimate per study. I chose the CCC because that seemed to be used the most, otherwise the IOM criteria.
• Deleted the Twomey 2022 study because it only seemed to assess PEM instead of ME/CFS.
• Deleted the Jason & Islam 2022 study because its data seems the same as in Jason & Dorri 2023.
• For the Nehme 2022 et al. study I used the 6.2% out of 258 SARS-CoV-2-positive participants with fatigue. The total sample of 1497 had Sars-Cov-2 but may not have symptoms and thus no Long Covid.
• For the Gonzalez study I used 20 ME/CFS cases out of 119. The total sample was 130 but 11 were said to be asymptomatic at the 3 month-follow up.
• For the Tokumasu study I used 50 out of 279 Long Covid cases.

Overall, the results did not change very much. The estimate is 0.43 with wider confidence intervals [27%-59%]. the high I2 value indicates a problem with heterogeneity.

 

I think this Canadian survey shows similar results:

https://health-infobase.canada.ca/covid-19/post-covid-condition/summer-2024-report.html
ME/CFS case definitions usually require a substantial reduction in ability to to daily activities.