Disease trajectories in hospitalized COVID-19 patients are predicted by clinical and peripheral blood signatures representing distinct lung pathologies

Linking clinical biomarkers and lung pathology still is necessary to understand COVID-19 pathogenesis and the basis of progression to lethal outcomes. Resolving these knowledge gaps enables optimal treatment approaches of severe COVID-19. We present an integrated analysis of longitudinal clinical parameters, blood biomarkers and lung pathology in COVID-19 patients from the Brazilian Amazon. We identified core signatures differentiating severe recovered patients and fatal cases with distinct disease trajectories. Progression to early death was characterized by rapid and intense endothelial and myeloid activation, presence of thrombi, mostly driven by SARS-CoV-2+ macrophages. Progression to late death was associated with systemic cytotoxicity, interferon and Th17 signatures and fibrosis, apoptosis, and abundant SARS-CoV-2 + epithelial cells in the lung. Progression to recovery was associated with pro-lymphogenic and Th2-mediated responses. Integration of ante-mortem clinical and blood biomarkers with post-mortem lung-specific signatures defined predictors of disease progression, identifying potential targets for more precise and effective treatments. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement M.M. is supported by Wellcome Trust Center award (number 104111) and Global Challenges Research Fund (GCRF 2020/21). J.LS.F. was supported by the Sao Paulo Research Foundation (FAPESP grant 2019/01578-2 and 2016/12855-9) and it is currently supported by the UK Medical Research Council (MRC) (MR/W018802/1). F.T.M.C is supported by the Sao Paulo Research Foundation (FAPESP grants 2020/05369-6 and 2017/18611-7). W.M.M. is supported by the Amazonas Research Foundation (FAPEAM N. 005/2020 - PCTI-EMERGESAUDE AM). M.V.G.L., G.C.M., W.M.M. and F.T.M.C. are CNPq research fellows. M.P. is supported by the Wellcome Trust grant (206369/Z/17/Z) and UK Medical Research Council grant (MC\_UU\_00034/9). C.A.M. is a UKRI MRC Future Leaders Fellow (MR/V025856/1). K.N.C. was supported by the MRC (MR/R010099/1). MR/R010099/1 was jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concord at agreement and was also part of the EDCTP2 program supported by the European Union. ### Author Declarations 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: Research Ethics Committee of the Tropical Medicine Foundation Dr Heitor Vieira Dourado gave ethical approval for this work (#CAAE: 30152620.1.0000.0005 and #CAAE: 32077020.6.0000.0005). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.