The Divergent Metabolomic Landscape of COVID-19 and Community-Acquired Pneumonia.

OBJECTIVES: To map and compare the serum metabolome of hospitalized patients with COVID-19 or community-acquired pneumonia (CAP). DESIGN: Observational matched cohort study using an untargeted metabolomics approach. SETTING: Serum samples were obtained at the time of hospital admission as part of two clinical trials conducted in hospitalized patients. PATIENTS: A matched cohort design was applied, including patients with COVID-19 and CAP, matched according to age, sex, and Charlson Comorbidity Index. The patient samples were obtained from two clinical studies, namely the suPAR-guided Anakinra Treatment for Validation of the Risk and Management of Respiratory Failure by COVID-19 (SAVE) trial (ClinicalTrials.gov identifier: NCT04357366; European Union Drug Regulating Authorities (EudraCT) number: 2020-001466-11) and the A randomized clinical trial of oral Clarithromycin in Community-acquired pneumonia to attenuatE inflammatory responseS and improve outcomeS (ACCESS trial) (ClinicalTrials.gov identifier: NCT04724044; EudraCT number: 2020-004452-15). The total study population comprised 92 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 3555 metabolites were detected, and differential analysis recovered more than 70% of the metabolome as altered between conditions. Metabolite pathway analysis highlighted pathways related to the citric acid cycle and arachidonic metabolism as activated in CAP, while COVID-19 was mainly driven by alterations in amino acid metabolism and metabolites related to mitochondrial function. CONCLUSIONS: Extensive divergence was observed in the metabolomic landscape of patients with COVID-19 or CAP, underscoring the disease-specific metabolic adaptations and providing potential targets for diagnostic and therapeutic development.