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

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Abstract 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.

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