The Plasma Proteome in Community-acquired Pneumonia: Pathophysiology, Outcome, and 10-Year Risk

Rationale: Community-acquired pneumonia (CAP) represents a significant health burden. Objectives: We aimed to map the plasma proteome in patients with CAP and associate protein abundance with pathophysiology, tissue source, and outcome. Methods: We measured the plasma proteome of patients with CAP upon admission to a general ward using Olink technology (derivation cohort). Additional Olink measurements were performed in patients with CAP admitted to the ICU and patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia across care settings (validation cohorts). Measurements and Main Results: Of 2,676 proteins analyzed in 93 ward patients with CAP and 21 healthy control subjects, 904 (33.8%) were higher in CAP, 396 (14.8%) lower, and 1,376 (51.4%) not different. More abundant proteins were associated with innate immune and mitosis pathways and mainly originated from lung and cardiac tissue. A total of 131 proteins associated with time to clinical stability (TCS), of which 124 (primarily related to monocyte and macrophage and RNA processing) were connected with a long TCS. Most TCS-associated proteins were differentially abundant in nonsurvivors versus survivors among 88 patients with ICU-CAP (1.4- to 3.5-fold higher) and 305 patients with SARS-CoV-2 pneumonia (1.16- to 1.35-fold lower or 1.14- to 2.65-fold higher; all P < 0.05). In the general population (UK Biobank), 115 of 124 (92.7%) proteins correlated with long TCS were associated with an increased risk of pneumonia during a 10-year follow-up, whereas 6 of 7 (85.7%) proteins correlated with shorter TCS were associated with a lower risk of pneumonia. Conclusions: This now publicly available CAP plasma proteome provides information on pathophysiological mechanisms and tissue involvement and may support development of personalized therapies.