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  1. Peer review report

    Title: Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients

    version: 1

    Referee: Paola Turano

    Institution: University of Florence


    ORCID iD: 0000-0002-7683-8614

    General assessment

    This is an integrated study reporting NMR-based metabolomics data and flow cytometry-based cytokine in the blood of 125 individuals (healthy controls (HC; n=73), COVID-19-recovered (n=12), COVID-19 acute (n=7) and LTCS (n=33)).

    The main goal appears to be that of demonstrating alterations in the metabolome and immune markers of patients with long COVID. This condition is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation.

    As admitted by the authors, the 4 groups are very unbalanced in terms of numbers of enrolled subjects; moreover, all numbers are low but those in the recovered groups and even more in the acute phase are extremely low. Therefore, the only reliable comparison appears to be that between HC and LTCS. And this is a pity because the most important comparison to define the signature associated with long-COVID symptoms would have been the one between recovered and LTCS subjects.

    Another problem is that there is no information on the status of the LTCS before infection nor during the acute phase. This, combined with the low number of individuals, does not allow to draw a real trajectory of the alterations during the observed time line. It is therefore difficult to be 100% sure that alterations in certain metabolites of lipoproteins are a consequence of LTCS or instead intrinsic characteristics of a group of individual that make them more prone to develop LTCS.

    These critical aspects have nothing to do with the experimental approach, which is powerful and carefully performed. Unfortunately, the available cohort is not the best to achieve the goal of a molecular characterization of LTCS.

    In any case the present manuscript provides useful hints to be further investigated in future studies and therefore might deserve publication.

    Essential revisions that are required to verify the manuscript

    If it were possible to enlarge the cohort of patients, confirming the observed trends, this would lead to a significant improvement in the impact of the work. But I understand the practical difficulties in achieving this goal.


    Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.