Review 2: "Symptom Persistence and Biomarkers in Post-COVID-19/Chronic Fatigue Syndrome – Results From a Prospective Observational Cohort"

RR:C19 Evidence Scale rating by reviewer:

• Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

A plethora of complaints can arise from COVID-19 infection for which natural recovery usually occurs. When a debilitating post-acute infective syndrome like ME/CFS is diagnosed following COVID-19 infection, natural recovery might not occur and rehabilitative/supportive therapy is usually recommended. Debilitating complaints following SARS-CoV-2 infection can last up to 20 months. Patients who experience fatigue and PEM following SARS-CoV-2 infection show poorer recovery when diagnosed with ME/CFS according to CCC diagnostic criteria. 

The results in this preprint describe a longitudinal analysis of PCS patients who experienced persistent fatigue and PEM following their SARS-CoV-2 infection. A distinction was made between those who met WHO criteria (selecting fatigue and PEM with possible additional symptoms, lasting > 3 months) and those who met CCC criteria (more stringent/specific and lasting > 6 months) at baseline (3 to 8 months following infection). Those who met CCC criteria recovered slowly or not at all compared to PCS. The distinction that is made here is between a diagnostic criterion that has relatively good sensitivity (PCS) and a criterion that has relatively good specificity (CCC) for diagnosing a post-acute infective syndrome (PAIS). With good relative sensitivity comes background noise, which is people recovering naturally from their infection with lingering symptoms that can last for quite some time. The authors have compared post infective ME/CFS with a less severely affected post infective group that is still recovering from their infection. This is important data for our understanding of SARS-CoV-2/PCS convalescence and strengthens the poor prognosis that ME/CFS diagnosis has following infection. 

This paper’s abstract is strong with a valid conclusion. The introduction could be widened further in ME/CFS pathophysiology. Is EBV further investigated in this paper as it plays a prominent role in the introduction? The authors state that they want to characterize PCS patients up to 20 months following infection, and identify predictors and subgroups. It provides a good description of the results, especially in table 2. Unfortunately, supplementary data were not available for me. I am missing a section on normal convalescence following infections and its range. Post infective complaints are very much on a spectrum in which the authors have measured one extreme side. I am also missing a section on EBV as was promised in the introduction? Perhaps this should be changed towards a section on recovery from post infective complaints and criteria to diagnose post-acute infective syndromes like ME/CFS.

Stating that PEM is a hallmark for ME/CFS, based on these findings, is a perhaps too strong of a conclusion. Fatigue and PEM were part of the inclusion criteria. With these data, one can look for symptoms that are discriminative for ME/CFS on the post infective spectrum. I believe there are other symptoms/findings that are as much or even more of a hallmark for ME/CFS (compared to PCS) based on these findings? I am however not able to view the supplementary material so I might miss something.
The conclusion on affective symptoms persisting in ME/CFS is a bit hasty. The authors state that this is due to burden of disease but provide no data on causality. They further state that psychological interventions could help PCS patients. I think they mean PCS-ME/CFS patients. The inflammatory marker conclusions are a bit of a stretch when you are not using a recovered control group.