Abstract Rationale Bronchiectasis is an increasingly recognized manifestation in alpha-1 antitrypsin deficiency (AATD), yet its airway inflammatory profile, microbiological environment, and relationship to structural and functional disease remain poorly characterized. While neutrophil elastase (NE) mediated injury is a hallmark of emphysema dominant AATD, its role in bronchiectasis-predominant and combined disease phenotypes is less clear. Objectives To investigate relationships between bronchoalveolar-lavage (BAL) inflammatory mediators including NE, interleukin-6 (IL-6), interleukin-1β (IL-1β) and disease severity indices (Bronchiectasis Severity Index BSI, BODE score). To explore BAL protease inhibitor balance, including proteinase-3 (PR3), cathepsin-G (Cat G), cathepsin-S (Cat S), secretory leukoprotease inhibitor (SLPI), and A1AT activity, and microbiology in distinct AATD radiologic phenotypes. Methods Thirteen participants (10 AATD, 3 non-AATD bronchiectasis controls) were enrolled. Each underwent comprehensive phenotyping with CT-based classification into four predefined groups: (1) AATD with bronchiectasis only, (2) AATD with emphysema only, (3) AATD with combined bronchiectasis + emphysema, and (4) non-AATD bronchiectasis controls. Clinical evaluation included BSI, BODE and comorbidity assessment; pulmonary function testing (FEV1, FVC, DLCO); and plasma cytokine analysis. Dual-lobe BAL (right-middle-lobe + lingula) was performed for total and differential cell counts, cytospins, quantitative microbiology, protease/antiprotease assays, and cytokine measurement. Paired BAL and plasma samples were analyzed in parallel to assess systemic airway inflammatory concordance. Shotgun metagenomic sequencing was performed for comprehensive airway microbiome characterization. Results NE activity was minimal overall (N = 10 ≈ 0), correlating with mild CT changes. Higher NE levels in three patients paralleled higher BSI scores. Right-left activity was strongly correlated (R² = 0.85, p = 0.025). Higher IL-6 and IL-1β concentrations correlated with elevated BSI and BODE scores (p-0.22, r2= 0.7) and occurred in patients with positive microbiology. Four AATD participants were culture-positive: one with MRSA (both lobes), one with Streptococcus pneumoniae (both lobes), and two with Stenotrophomonas maltophilia (both lobes). One control grew Streptococcus pneumoniae in a single lobe. Radiologically, bronchiectasis without emphysema remained generally mild, while combined disease cases exhibited greater functional impairment. Conclusions Early findings indicate a significant infection and cytokine driven inflammatory pattern in AATD bronchiectasis, but further research is ongoing. Continued recruitment will enable further comparative analyses across structural groups and correlation of BAL and plasma protease/cytokine profiles with lung function, radiologic severity, and microbial diversity. This will define mechanistic endotypes to inform biomarker-guided therapy and personalized management in AATD. This abstract is funded by: RCSI
Quigley et al. (Fri,) studied this question.