Circulating alpha-1 antitrypsin and its c-terminal peptides differentiate bacterial from viral community-acquired pneumonia

Journal of Translational Medicine, Page 10.1186/s12967-026-08651-8

BACKGROUND: Distinguishing bacterial from viral community-acquired pneumonia (CAP) remains a major clinical challenge, often leading to inappropriate antimicrobial use. Alpha-1 antitrypsin (AAT) is an acute-phase protein that regulates neutrophil protease activity and is cleaved during inflammation, generating bioactive peptides. We investigated whether circulating AAT and its peptides could discriminate bacterial from viral CAP. METHODS: Serum samples were obtained from 81 prospectively enrolled adults with CAP (bacterial, n = 36; viral, n = 45) at hospital admission (day 0) and day 3. AAT concentrations were measured by ELISA, and nine AAT-derived C-terminal peptides were quantified by LC-MS/MS. Associations with CAP etiology were assessed using multivariable logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: AAT concentrations were significantly higher in bacterial than viral CAP at both admission (p = 0.006) and day 3 (p < 0.001) and remained independently associated with bacterial etiology after adjustment for clinical covariates, whereas C-reactive protein (CRP) did not. A predictive model combining AAT, age, and leukocyte count demonstrated the highest discriminatory performance (AUC = 0.803). Four of nine analyzed peptides (C36, C37, C40, and C42) were consistently detectable. C37 levels were higher in bacterial CAP at admission (p = 0.010). C36 showed a similar trend but declined from day 0 to day 3 (p = 0.006). In contrast, C40 levels increased in viral CAP (p = 0.017), resulting in a higher C40/AAT ratio at admission compared with bacterial CAP (p = 0.014). Correlations between AAT, peptides, and inflammatory markers were observed in bacterial but not in viral CAP, indicating distinct patterns of AAT processing. CONCLUSIONS: Circulating AAT independently discriminates bacterial from viral CAP and, when combined with age and leukocyte count, show improved discriminatory performance compared with CRP-based models. Distinct patterns of AAT-derived peptides suggest etiology-specific proteolytic processing and merit further evaluation as markers for differentiating bacterial and viral CAP.

DOI: 10.1186/s12967-026-08651-8