Molecular epidemiology and prognostic impact of lower respiratory tract infections during immune checkpoint inhibitor therapy in advanced non-small cell lung cancer: A retrospective cohort study

Patients with advanced non-small cell lung cancer (NSCLC) are prone to lower respiratory tract infection (LRTI) during immune checkpoint inhibitor (ICI) treatment, but the pathogen spectrum and clinical impact remain unclear. This study provides comprehensive microbiological characterization of pathogen spectrum, molecular resistance mechanisms, and prognostic significance of LRTI during ICI treatment in patients with advanced NSCLC. A single-center retrospective cohort design was adopted, and 903 patients with advanced NSCLC who first received PD-1 or PD-L1 inhibitor treatment between January 1, 2019 and November 30, 2023 were included. Molecular characterization of resistant isolates was performed using PCR and sequencing for ESBL genes (blaCTX-M, blaSHV, blaTEM), carbapenemase genes (blaKPC, blaNDM, blaVIM, blaIMP, blaOXA-48, blaOXA-23), and mecA, with multilocus sequence typing (MLST) for clonality analysis. Competing risk models estimated cumulative incidence of first LRTI; time-dependent Cox models evaluated associations with overall survival (OS) and progression-free survival (PFS). Among 903 patients, 176 (19.49%) developed LRTI during ICI treatment. Among 243 infection episodes, any phenotypic resistance was identified in 31 episodes (12.76%). Of 24 available resistant isolates, molecular characterization revealed blaCTX-M-15 as the predominant ESBL determinant (87.5%), blaKPC-2 and blaNDM-1 in CRE, blaVIM-2 and blaIMP-4 in CRPA, and blaOXA-23 in CRAB. MLST identified high-risk clones: K. pneumoniae ST11 (n = 3) and ST15 (n = 2), E. coli ST131 (n = 2), Pseudomonas aeruginosa ST235 (n = 3), A. baumannii ST2 (n = 6), and MRSA ST239 (n = 2). Older age, male sex, higher ECOG score, stage IV disease, COPD, ILD, baseline corticosteroid exposure, and higher NLR were associated with increased infection risk (all P < 0.05). First LRTI was independently associated with worse OS (HR = 1.78) and PFS (HR = 1.41). Fungal infection (HR = 2.48), mixed infection (HR = 2.34), resistance-associated infection (HR = 2.61), and severe infection (HR = 2.96) indicated worst prognosis. LRTI during ICI treatment in advanced NSCLC carries substantial burden and is associated with poor prognosis. Molecular characterization reveals that resistant infections are driven by established epidemic clones (ST2 CRAB, ST11 CRKP, ST235 CRPA, ST131 ESBL-EC), highlighting the need for enhanced infection control and targeted antimicrobial strategies in this vulnerable population.