Defining the molecular mechanisms of novel emerging diseases like COVID-19 is crucial to identify treatable traits to improve patient care. To circumvent a priori bias and the lack of in-depth knowledge of a new disease, we opted for an unsupervised approach, using the detailed circulating proteome, as measured by 4985 aptamers (SOMAmers), of 731 SARS-CoV-2 PCR-positive hospitalized participants to Biobanque québécoise de la COVID-19 (BQC19). The consensus clustering identified six endophenotypes (EPs) present in this cohort, with varying degrees of disease severity. One endophenotype, EP6, was associated with a greater proportion of ICU admission, mechanical ventilation, acute respiratory distress syndrome (ARDS) and death. Clinical features of this endophenotype, showed increased levels of C-reactive protein, D-dimers, elevated neutrophils, and depleted lymphocytes. Moreover, metabolomic analysis supported a role for immunothrombosis in severe COVID-19 ARDS. Furthermore, the approach enabled the identification of Fibroblast Growth Factor Receptor (FGFR) and SH2-containing transforming protein 4 (SHC4) signaling as features of the molecular pathways associated with severe COVID-19. Finally, this information was sufficient to train an accurate predictive model solely based on clinical laboratory measurements, suggesting the use of blood markers as surrogates for generalizing these EPs to new patients and automating identification of high-risk groups in the clinic.

The authors have declared no competing interest.

This work was made possible through open sharing of data and samples from the Biobanque québécoise de la COVID-19, funded by the Fonds de recherche du Québec - Santé, Génome Québec, the Public Health Agency of Canada and, as of March 2022, the Ministère de la Santé et des Services Sociaux du Québec. We thank all participants to BQC19 for their contribution. This study was supported by the Fonds de recherche du Québec - Santé (FRQS)- Cardiometabolic Health, Diabetes and Obesity Research Network (CMDO)- Initiative. This work was also supported by Natural Sciences and Engineering Research Council of Canada (NSERC) grant RGPIN-2019-04460 (AE).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was approved by the Institutional Ethics Review Board of the Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean (CIUSSS-SLSJ) affiliated to Université de Sherbrooke [protocol #2021-369, 2021-014 CMDO - COVID19].

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Input data corresponding to the cohort can be obtained form BQC19 (www.quebeccovidbiobank.ca). The data generated as a result of the analyses are provided as tables and supplementary tables.

https://www.quebeccovidbiobank.ca