Review 1: "Symptom Persistence and Biomarkers in Post-COVID-19/Chronic Fatigue Syndrome – Results From a Prospective Observational Cohort"

RR:C19 Evidence Scale rating by reviewer:

• Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

This manuscript describes the 20 month outcomes from an uncontrolled prospective observational study following 106 individuals with moderate to severe fatigue from six months post-acute COVID – approximately half met diagnostic criteria for ME/CFS and half did not (designated as post-COVID syndrome [PCS]). The details of the medical and psychiatric assessments, as well as the investigations for exclusionary conditions to allow the ME/CFS diagnosis are not provided.

The paper describes the clinical characteristics of the two sub-cohorts (ME/CFS and PCS) at 9-16 months and 17 -20 months. The rationale for this arbitrary split in follow-up time points is not provided. It is clear that both groups remain symptomatic and disabled, with the ME/CFS group being more so, but with a pattern of slow resolution. This data includes outcomes in a series of questionnaires describing “clinical signs of ongoing inflammation” but actually describing symptoms which may or may not have an association with inflammation. This data is largely consistent with the symptom profiling of many, many post-COVID studies previously published.

There are some more objective measures recorded including handgrip strength (HGS). It should be noted that this measure is heavily dependent on volition, and the negative impacts (voluntary and involuntary) of current musculo-skeletal pain. Given these caveats, the finding that HGS reflected more severe symptoms is unsurprising. The other objective parameters studied are an eclectic set of “inflammatory biomarkers” including red blood cell  IL-8, ANA, MBL and ferritin. The assay systems used are not described. It is reasonable to expect these so-called “inflammatory biomarkers” to be elevated in acute COVID and to slowly dissipate (regardless of clinical outcome) – hence it is surprising that they remain elevated over 1-2 years. Unfortunately, without a contemporaneous healthy control group (and given the uncertain assay systems) the findings are uninterpretable.

Overall, this paper suffers from a lack of novelty, over analysis of questionnaire-based symptom data, and lack of a control group to evaluate the significance of both biomarkers and symptom outcomes.