Abstract
BACKGROUND: Bronchoalveolar lavage (BAL) is essential in determining the efficacy of novel therapies in alpha-1 antitrypsin deficiency (AATD). These require initial proof-of-concept demonstration that treatment administration increases alpha-1 antitrypsin (AAT) levels and/or anti-neutrophil elastase inhibitory capacity (ANEC) in the lung. Early-phase studies often encounter high interindividual variability of BAL results, primarily stemming from the inherent dilution characteristics of returned BAL fluid. A BAL protocol that minimises this variability is needed for reliable comparison of biochemical endpoints in the lung. METHODS: The study population included 21 severe AATD (ZZ), 22 moderate AATD (MZ) and 23 non-AATD (MM) individuals, further categorised as healthy, unobstructed current smokers or patients with chronic obstructive pulmonary disease (COPD). An additional six ZZ individuals were receiving intravenous alpha-1 augmentation therapy. We compared common BAL correction methods-albumin, total protein and epithelial lining fluid (ELF) volume measured by urea-when reporting early-phase biochemical endpoints, AAT and ANEC. RESULTS: BAL performed with a paediatric bronchoscope (PB) improved alveolar sampling compared with a traditional adult bronchoscope. Both uncorrected and ELF-corrected BAL demonstrated high interindividual variability regardless of lung health status. BAL total protein correction minimised interindividual variability, producing significant differences in AAT and ANEC between all genotypes, the strongest relationship with plasma AAT levels (r(2)=0.83), greatest inter-lobar concordance in AAT levels (r(2)=0.76) and strong correlation between BAL AAT and ANEC (r(2)=0.88). CONCLUSIONS: By capitalising on the marked consistency in AAT levels between AAT genotypes, and the close relationship between plasma and lung AAT levels, we demonstrate reliable alveolar sampling that aligns closely with plasma.