Corticosteroids have become a choice for managing severe
COVID-19, but the molecular mechanisms behind the response after
corticosteroid administration remain incompletely understood. In order to unravel this, comparisons between temporal metabolic profiles in the plasma samples of
methylprednisolone (MP)- and placebo-treated
COVID-19 patients were performed at different time points. The patient plasma samples used were obtained from a double-blind, randomized, placebo-controlled Phase IIb clinical trial performed on severe
COVID-19 patients in the Brazilian Amazon, where the patients received placebo or 0.5 mg/kg MP intravenously twice daily for 5 days. The MP treatment reduced the number of metabolites in the plasma of patients during follow-up. The longitudinal changes in the MP group were in eight metabolic pathways related to
steroid hormones and
eicosanoids. Direct comparison between the two groups, revealed differences at baseline, which peaked 5 days after initiation of MP treatment. The 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 by day 14 after initiating the MP treatment. Survival of MP-treated
COVID-19 patients was associated with modulation of
tryptophan metabolism and diminished levels of
oxidized glutathione. Network analysis revealed that MP treatment is highly associated with alterations in pathways reflecting
eicosanoid metabolism, such as
arachidonic acid and
prostaglandins. Curiously, there is a crosstalk between metabolomics, biochemistry, and
cytokine components. Treatment of systemic and inflammatory conditions induced by SARS-CoV-2
viral infections with
methylprednisolone modulates metabolic activity associated with
tryptophan and inflammatory
lipids.IMPORTANCEThe SARS-CoV-2 virus
infection in humans induces significant inflammatory and systemic reactions and complications of which
corticosteroids like
methylprednisolone have been recommended as treatment. Our understanding of the metabolic and metabolomic pathway dysregulations while using intravenous
corticosteroids in
COVID-19 is limited. This study will help enlighten the metabolic and metabolomic pathway dysregulations underlying high daily doses of intravenous
methylprednisolone in
COVID-19 patients compared to those receiving placebo. The information on key metabolites and pathways identified in this study together with the crosstalk with the
inflammation and biochemistry components may be used, in the future, to leverage the use of
methylprednisolone in any future pandemics from the coronavirus family.