Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection, 2024, Unger et al

Wyva

Wyva

Senior Member (Voting Rights)
Key Points

Question Does prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)–like illness differ between individuals with an acute infection–like index illness who are COVID-19 positive or negative?

Findings In this cohort study of 4378 participants, the weighted prevalence of ME/CFS-like illness was 4.5% or less at 3 to 12 months after the index illness in the COVID-19–positive and COVID-19–negative groups, with no significant differences in odds of ME/CFS-like illness.

Meaning The findings suggest that ME/CFS-like illness following an acute infection–like index illness does not vary by COVID-19 test result.


Abstract

Importance Chronic symptoms reported following an infection with SARS-CoV-2, such as cognitive problems, overlap with symptoms included in the definition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective To evaluate the prevalence of ME/CFS-like illness subsequent to acute SARS-CoV-2 infection, changes in ME/CFS symptoms through 12 months of follow-up, and the association of ME/CFS symptoms with SARS-CoV-2 test results at the acute infection–like index illness.

Design, Setting, and Participants This prospective, multisite, longitudinal cohort study (Innovative Support for Patients with SARS-CoV-2 Infections Registry [INSPIRE]) enrolled participants from December 11, 2020, to August 29, 2022. Participants were adults aged 18 to 64 years with acute symptoms suggestive of SARS-CoV-2 infection who received a US Food and Drug Administration–approved SARS-CoV-2 test at the time of illness and did not die or withdraw from the study by 3 months. Follow-up surveys were collected through February 28, 2023.

Exposure COVID-19 status (positive vs negative) at enrollment.

Main Outcome and Measures The main outcome was the weighted proportion of participants with ME/CFS-like illness based on the 2015 Institute of Medicine clinical case definition using self-reported symptoms.

Results A total of 4378 participants were included in the study. Most were female (3226 [68.1%]). Mean (SD) age was 37.8 (11.8) years. The survey completion rates ranged from 38.7% (3613 of 4738 participants) to 76.3% (1835 of 4738) and decreased over time. The weighted proportion of participants identified with ME/CFS-like illness did not change significantly at 3 through 12 months of follow-up and was similar in the COVID-19–positive (range, 2.8%-3.7%) and COVID-19–negative (range, 3.1%-4.5%) groups. Adjusted analyses revealed no significant difference in the odds of ME/CFS-like illness at any time point between COVID-19–positive and COVID-19–negative individuals (marginal odds ratio range, 0.84 [95% CI, 0.42-1.67] to 1.18 [95% CI, 0.55-2.51]).

Conclusions and Relevance In this prospective cohort study, there was no evidence that the proportion of participants with ME/CFS-like illness differed between those infected with SARS-CoV-2 vs those without SARS-CoV-2 infection up to 12 months after infection. A 3% to 4% prevalence of ME/CFS-like illness after an acute infection–like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.

Open access: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2821459
 
Surprising result.

The controls had an infectious disease as well ('Our study design required an acute infection prompting COVID-19 testing') so that may explain the lack of difference between the groups. Nonetheless, the prevalence of ME/CFS-like illness was quite low, as the authors note:
The prevalence of ME/CFS-like illness in the present study sample (4.5%) was lower than that in several previous studies of ME/CFS following a specific infection or syndrome (ie, 27% in a 4-year follow-up study of 223 patients who experienced severe acute respiratory syndrome,23 13% in a 6-month follow-up study of 301 adolescents diagnosed with acute Epstein-Barr virus infection24)
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Study took place from 2020-2022 (ending August 2022).

What are the odds that a lot of the people who didn’t test positive for covid were false negatives? (Based on time range). I know I had to get tested three times when I first got COVID before the test came out positive.

It’s not exactly like there was a high rate of other illnesses going around pre-2023.

Additionally given the suprisingly low rate in both groups, I’d note a rather high non-response rate. Is it possible people who’s lives were derailed by developing ME were much less likely to respond?
 
Wyva said:
Findings In this cohort study of 4378 participants, the weighted prevalence of ME/CFS-like illness was 4.5% or less at 3 to 12 months after the index illness in the COVID-19–positive and COVID-19–negative groups, with no significant differences in odds of ME/CFS-like illness.
ME/CFS Outcomes of Interest
We used the 2015 Institute of Medicine (IOM) criteria 15 for binary classification of the primary ME/CFS outcome, operationalized using participants’ responses to symptoms from the CDC ME/CFS Symptom Screener–Short Form, version 1.2 (eAppendix 1 in Supplement 1) and the Physical Function subscale of the PROMIS-29, version 2.118 profile (algorithm in eTable 1 in Supplement 1). In brief, the criteria include activity limitations associated with fatigue, postexertional malaise, and sleep problems as well as either cognitive impairment or orthostatic intolerance. Because ME/CFS diagnosis requires a full clinical evaluation to identify treatable conditions contributing to symptoms used in diagnosis, the self-reported information in this study only allowed determination of ME/CFS-like illness, hereafter referred to as ME/CFS.
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The weighted percentage of participants meeting the ME/CFS criteria at 3 months was 3.4% in the COVID-19–positive group and 3.7% in the COVID-19–negative group, and there was no statistically significant difference between the COVID-19–positive and COVID-19–negative groups in the prevalence of ME/CFS at any time point through 12 months of follow-up (range, 2.8%-3.7% in the COVID-19–positive group and 3.1%-4.5% in the COVID-19–negative group) (Table 3). At each follow-up survey, approximately one-third of the COVID-19–positive group and one-third of the COVID-19–negative group (range, 31.0%-37.6%) reported 1 or more of the 5 ME/CFS symptoms assessed. In both the COVID-19–positive group and the COVID-19–negative group, unrefreshing sleep was the most frequently reported ME/CFS symptom (range, 20.2%-26.3%), followed by postexertional malaise (range, 16.9%-22.4%) and orthostatic intolerance (range, 9.0%-13.1%).
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Corresponding Author: Elizabeth R. Unger, MD, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30329 (eru0@cdc.gov).
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:banghead:
 
“Our findings suggest that ME/CFS may follow several precipitating events (acute COVID-19 illness, other acute infections, or life disruptions due to the COVID-19 pandemic) but that regardless of reason or exact percentages, there will be millions affected who will seek care.”

Frustrating. I wonder whether the originally submitted manuscript had this or whether it was suggested in the review process.
 
I think peer review should have led to emphasis of the following, in limitations —

In both groups, symptoms suggestive of ME/CFS were reported prior to the index illness, but information was not complete enough to identify preexisting ME/CFS-like illness. This could have led to misclassification of ME/CFS-like illness in that we may have attributed symptoms to the index illness when those symptoms may have predated the illness.
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False-positive and false-negative COVID-19 test results at enrollment may have led to misclassification in the cohorts. Although we adjusted for reports of subsequent COVID-19 illness in our main model, it is possible that not everyone with a subsequent illness was symptomatic or was tested for COVID-19; thus, we may have underreported the frequency of these events. Additionally, we did not collect histories of other infection or diagnostic tests and thus could not characterize the specific infection that might account for ME/CFS in the COVID-19–negative group. The requirement for access to a verifiable COVID-19 test and internet-enabled device to complete surveys may have biased the sample to a more engaged and technologically savvy population. Furthermore, we did not include vaccination status in our analysis.
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But now everyone is picking up that likelihood of ME/CFS is the same following any infection, which is simply unsupportable.

In fact there have been data to suggest that a negative Covid PCR test at the time someone has Covid is associated with increased risk of LC. We need studies to use advanced techniques to more reliably demonstrate viral history.

Eg SARS-CoV-2–Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19 (2023, Neurology - Neuroimmunology Neuroinflammation) —

Antibody and T-cell assays showed evidence of prior SARS-CoV-2 exposure in approximately 40% of the PVS [symptomatic but no positive Covid test group].
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And Divergent adaptive immune responses define two types of long COVID (2023, Frontiers in Immunology) —

this analysis showed that a majority of seronegative long COVID patients were likely to have been infected by SARS-CoV-2
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The amount of bad studies in medicine is absurd. And as usual they get a lot more press. The CDC continues to be inept and the profession generally appears incapable of learning much about issues that doesn't interest them.
 
On further review, I think I got sidetracked by how it's being reported. This is actually pretty much expected, COVID is creating far more cases because it became so prevalent and ran through the population like a wildfire several times, but there's nothing special about it and that all points to the immune reaction as being the problem, at least for ME/CFS.

So this finds that about 3% of people with an acute infection-like illness meet case definition for ME/CFS at 12 months. It's actually huge. Infections are common and this result is holding up solidly. There are now multiple corroborations that as a general statement of fact, it is true that following an acute infection, there is a small but significant percentage, 3-4%, who will develop a highly disabling chronic illness that meets case definition for ME/CFS, of which 3/4 are too ill to work and function normally.

The reporting and how the paper is written is atrocious and generally blatant propaganda, but it does include the important takeaway:
A 3% to 4% prevalence of ME/CFS-like illness after an acute infection–like index illness would impose a high societal burden given the millions of persons infected with SARS-CoV-2.
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The press is reporting it under the same framing as the abstract: COVID likely doesn't cause Long Covid. This is how the paper is written to be interpreted, and it hides the major takeaway that this isn't a potential "high societal burden", it's already there in many studies. I've seen several headlines like this, all different ways of saying roughly this.

The pattern where significant findings from major institutions continue to be hidden in plain sight is disturbing. The NIH intramural study did find interesting leads, but it got entirely sidetracked by the awful effort preference thing. Here the conclusion is disturbing, but it's instead presented in just the right way that sounds like minimizing, but actually confirms the overall picture of ME/CFS and how it relates to Long Covid and infections in general.

This has to take into account that many long haulers don't have ME/CFS, but do have significant symptoms, so the overall burden of illness is immense. It becomes clear that reigning in infections will have major societal and economic benefits, including higher government revenue and lower taxes. The investment is worth it, and there's almost zero chance that it happens. Instead we'd rather do nothing about it, even though it's more expensive and worse in every way. What a weird people we are.
 
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