Review 2: "Brain-targeted Autoimmunity is Strongly Associated with Long COVID and Its Chronic Fatigue Syndrome as Well as Its Affective Symptoms"

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: 

Long Covid (LC) is an organic disease and researchers are still working to understand its causes of main mechanisms. This paper further reinforce the organic nature of the disease, and at least in a cohort of patients with more pronounced neurocognitve symptoms, autoimmunity (probably triggered by a viral infection, in this case SARS-CoV-2) to neuronal proteins may be a very important mechanisms. Theoretically, this can be targeted by medications, eg IVIG.

This is a very important, case controlled study. The methodology in terms of tests, autoimmunity, and analytic approach looks very solid, and interesting. My main issues is about the study selection of patients with Long Covid. The list of symptoms included as indicative of LC is a bit restrictive (eg pivotal symptoms like post exertional malaise or POTS are missing), and are mostly focused on psychiatric symptoms (including neurocognitive), which anyway are still linked with Long Covid. In fact, I see in the methodology that the assessments are done by psychiatrists and most tests assessed mental health, and not physical.

In fact, although very strong differences between cases and controls, there is still a large overlap between the two groups. It is possible that, in fact, LC cohort may be very variegate, and some inclusion bias can have been included, eg LC patients may have been just some patients with new psychiatric onset of conditions.

Also, it is unclear if these patients have NEW onset symptoms that were not present before covid, this should be clarified. Also, I would appreciate if the authors would show more persisting clinical symptoms, and link the main clusters of symptoms with a more specific signature. We have increasing evidence that LC is not just one disease, but may have more clusters and as a consequence linked with different signatures.

Last, I would appreciate to know if these patients are from pre omicron or also omicron included. In any case, extremely relevant paper that further confirm that LC is a real disease.