Methylprednisolone Therapy Induces Differential Metabolic Trajectories in Severe COVID-19 Patients

Summary: Corticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. This study assessed the temporal metabolic profiles in the plasma of methylprednisolone (MP)-treated COVID-19 patients.Background: Corticosteroids have become a choice for managing severe COVID-19, but the molecular mechanisms behind the response after corticosteroid administration remain incompletely understood. This study assessed the temporal metabolic profiles in the plasma of methylprednisolone (MP)-treated COVID-19 patients.Methods: Patient plasma was obtained from a double blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe COVID-19 patients in the Brazilian Amazon. Patients received placebo or 0.5 mg/kg MP intravenously twice daily for five days. Plasma samples collected before treatment and longitudinally over 14 days were then analyzed using high-resolution untargeted metabolomics. Network analysis also included blood cell counts, inflammation and tissue damage markers, and cytokine data.Findings: MP treatment reduced the number of metabolites in the plasma of patients during follow-up and was associated with different metabolic pathways related to steroid hormones and eicosanoids. Direct comparison between the two groups revealed differences at baseline, which peaked five days after initiation of MP treatment. Metabolic pathways differing between the two groups over time included galactose metabolism, glucose and gluconeogenesis, N-glycan metabolism, and prostaglandin formation from arachidonate. Deoxy-galactose, prostaglandin H2, sphingosine, and sphinganine exhibited differential trajectories after 14 days of MP treatment. Survival of MP-treated COVID-19 patients was associated with modulation of tryptophan metabolism. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting eicosanoid metabolism, such as arachidonic acid and prostaglandins.Interpretation: Treatment of COVID-19 with methylprednisolone modulates metabolic activity associated with tryptophan and inflammatory lipids.Funding: This work was financially supported by the Fundação de Amparo à Pesquisa do Estado do Amazonas (under Resolutions # 002/2008, 007/2018, 005/2019, 005/2020, 006/2020 and 005/2022), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (403253/2020-9) and the Serrapilheira Institute (to LGG, grant number Serra – R-2011-37433).Declaration of Interest: VIM, RLAN and MGSB report they are recipients of doctorate scholarships from Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). MNY reports to be a doctorate scholarship recipient from CNPq. We also disclose that BGV, MGVL, WMM, AGC, LGG and GCM are CNPq productivity fellows. All other authors declare no competing interests. Ethical Approval: The Fundação de Medicina Tropical Doutor Heitor Vieira Dourado Research Ethics Committee approved this study (CAAE 46193821.5.0000.0005), which was a sub-study of a larger clinical trial study (30615920.2.0000.0005).