Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome patients
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Abstract
Deep metabolomic, proteomic and immunologic phenotyping of patients suffering from an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have matched a wide diversity of clinical symptoms with potential biomarkers for coronavirus disease 2019 (COVID-19). Several studies have described the role of small as well as complex molecules such as metabolites, cytokines, chemokines and lipoproteins during infection and in recovered patients. In fact, after an acute SARS-CoV-2 viral infection almost 10-20% of patients experience persistent symptoms post 12 weeks of recovery defined as long-term COVID-19 syndrome (LTCS) or long post-acute COVID-19 syndrome (PACS). Emerging evidence revealed that a dysregulated immune system and persisting inflammation could be one of the key drivers of LTCS. However, how these biomolecules altogether govern pathophysiology is largely underexplored. Thus, a clear understanding of how these parameters within an integrated fashion could predict the disease course would help to stratify LTCS patients from acute COVID-19 or recovered patients. This could even allow to elucidation of a potential mechanistic role of these biomolecules during the disease course.
Methods
This study comprised subjects with acute COVID-19 (n=7; longitudinal), LTCS (n=33), Recov (n=12), and no history of positive testing (n=73). 1 H-NMR-based metabolomics with IVDr standard operating procedures verified and phenotyped all blood samples by quantifying 38 metabolites and 112 lipoprotein properties. Univariate and multivariate statistics identified NMR-based and cytokine changes.
Results
Here, we report on an integrated analysis of serum/plasma by NMR spectroscopy and flow cytometry-based cytokines/chemokines quantification in LTCS patients. We identified that in LTCS patients lactate and pyruvate were significantly different from either healthy controls (HC) or acute COVID-19 patients. Subsequently, correlation analysis in LTCS group only among cytokines and amino acids revealed that histidine and glutamine were uniquely attributed mainly with pro-inflammatory cytokines. Of note, triglycerides and several lipoproteins (apolipoproteins Apo-A1 and A2) in LTCS patients demonstrate COVID-19-like alterations compared with HC. Interestingly, LTCS and acute COVID-19 samples were distinguished mostly by their phenylalanine, 3-hydroxybutyrate (3-HB) and glucose concentrations, illustrating an imbalanced energy metabolism. Most of the cytokines and chemokines were present at low levels in LTCS patients compared with HC except for IL-18 chemokine, which tended to be higher in LTCS patients.
Conclusion
The identification of these persisting plasma metabolites, lipoprotein and inflammation alterations will help to better stratify LTCS patients from other diseases and could help to predict ongoing severity of LTCS patients.
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Peer review report
Title: Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients
version: 1
Referee: Christopher Gerner
Institution: University of Vienna
email: Christopher.gerner@univie.ac.at
ORCID iD: 0000-0003-4964-0642
General assessment
The manuscript of Berezhnoy et al. is a well written report regarding metabolomics and cytokines in long term COVID-19 syndrome patients. The applied methodology is of some interest and I cannot detect methodological errors. However, I have some concerns which need to be addressed before the manuscript should sent for journal publication.
Most importantly, the manuscript did not adhere to good scientific practice regarding literature research. There are papers about LTCS patients published more than a year ago …
Peer review report
Title: Maintained imbalance of triglycerides, apolipoproteins, energy metabolites and cytokines in long-term COVID-19 syndrome (LTCS) patients
version: 1
Referee: Christopher Gerner
Institution: University of Vienna
email: Christopher.gerner@univie.ac.at
ORCID iD: 0000-0003-4964-0642
General assessment
The manuscript of Berezhnoy et al. is a well written report regarding metabolomics and cytokines in long term COVID-19 syndrome patients. The applied methodology is of some interest and I cannot detect methodological errors. However, I have some concerns which need to be addressed before the manuscript should sent for journal publication.
Most importantly, the manuscript did not adhere to good scientific practice regarding literature research. There are papers about LTCS patients published more than a year ago following highly similar research strategies with quite similar results. It is not sufficient to cite them in subordinate clauses in the Discussion, they need to be cited in the Introduction accordingly, as well when discussing the results. Indeed, relevant similarities in the results would deserve some discussion, such as the dysregulation of cytokines in LTCS.
Another weakness is the structure of data interpretation. It is mentioned in the Introduction that several cell types were reported to show altered metabolism after a COVID-19 infection. I cannot see how plasma analysis should allow to verify such observations as it represents a mixture of all cell types in the body. This obvious challenge regarding data interpretation should be addressed.
This is in line with another weak aspect. The numerous findings a reported without a clear structure regarding potential pathomechanisms. As such, the manuscript is sometimes not easy to read.
To sum up, the manuscript reports interesting analysis results largely corroborating previous results, which deserved publication after some essential improvements.
Essential revisions that are required to verify the manuscript
An improved appreciation of existing literature is essential, as well as an improved data interpretation.
Other suggestions to improve the manuscript
A discussion of the pros and cons of NMR-based metabolomics in contrast to other techniques would be helpful.
Decision
Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.
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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
email: turano@cerm.unifi.it
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 …
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
email: turano@cerm.unifi.it
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.
Decision
Verified with reservations: The content is academically sound but has shortcomings that could be improved by further studies and/or minor revisions.
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