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Derivation and External Validation of Community-Acquired Pneumonia Subphenotypes in Southeast Asia
39 Pages Posted: 10 Mar 2025
More...Abstract
Background: Identifying pneumonia subphenotypes in an understudied population can advance equitable personalized medicine for pneumonia care. We aimed to derive and validate clinically and biologically distinct subphenotypes of community-acquired pneumonia (CAP) in Southeast Asia.
Methods: We performed latent class analysis to identify subphenotypes using clinical and laboratory variables in a prospective cohort of adults hospitalized with CAP in northeastern Thailand. We compared clinical, cytokine, and metabolomic features between the subphenotypes and then developed a parsimonious classifier model (PCM) to assign subphenotypes. We tested the PCM in an internal validation cohort and then validated the subphenotypes in an external, multinational prospective cohort of patients hospitalized with CAP in Southeast Asia. Finally, we used the PCM to assign pneumonia subphenotypes in a U.S. COVID-19 cohort and evaluated heterogeneity of treatment effect with corticosteroids.
Findings: Among 955 CAP patients, we identified two subphenotypes: CAP1 (141, 14%) and CAP2 (814, 85%). We observed greater respiratory failure, 28-day mortality, inflammatory cytokines and metabolic derangements among CAP1 patients. A four-variable PCM discriminated subphenotype assignment in an internal validation subset (C-statistic 0.98). When defined in the external validation cohort using the PCM, these subphenotypes had similarly differential clinical features and outcomes. The subphenotypes were reproduced in a cohort of patients with COVID-19 pneumonia where subphenotype assignment revealed an interaction between corticosteroid treatment and mortality (P=0.003).
Interpretation: In Southeast Asia, CAP subphenotypes are associated with distinct outcomes, inflammatory profiles, and metabolomic signatures. These subphenotypes may represent unique targets for future CAP interventional trials.
Keywords: Pneumonia, Precision Medicine, Metabolomics, Low- and Middle-Income Countries, Subphenotypes
Suggested Citation: Suggested Citation