Herron Malcolm, Roche Suzanne, Fraughen Daniel D, Heeney Ronan C, Kanchi Lasya, Leacy Emma J, Casey Michelle, Gunaratnam Cedric, Carroll Tomás P, Murphy Mark P, McElvaney Noel G
Royal College of Surgeons in Ireland School of Medicine, Dublin, Ireland
Beaumont Hospital, Dublin, Ireland.
Thorax. 2024 Dec 23;80(1):24-31. doi: 10.1136/thorax-2024-221797.
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.
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.
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=0.83), greatest inter-lobar concordance in AAT levels (r=0.76) and strong correlation between BAL AAT and ANEC (r=0.88).
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.
支气管肺泡灌洗（BAL）对于确定新型疗法治疗α-1抗胰蛋白酶缺乏症（AATD）的疗效至关重要。这些疗法需要初步的概念验证，即治疗给药可提高肺内α-1抗胰蛋白酶（AAT）水平和/或抗中性粒细胞弹性蛋白酶抑制能力（ANEC）。早期研究经常遇到BAL结果的个体间高度变异性，这主要源于回收的BAL液固有的稀释特性。需要一种能将这种变异性降至最低的BAL方案，以便可靠地比较肺内生化终点。
研究人群包括21名重度AATD（ZZ型）、22名中度AATD（MZ型）和23名非AATD（MM型）个体，进一步分为健康个体、无阻塞的现吸烟者或慢性阻塞性肺疾病（COPD）患者。另外6名ZZ型个体正在接受静脉注射α-1补充疗法。在报告早期生化终点AAT和ANEC时，我们比较了常用的BAL校正方法——白蛋白、总蛋白以及通过尿素测量的上皮衬液（ELF）体积。
与传统成人支气管镜相比，使用儿科支气管镜（PB）进行BAL可改善肺泡采样。无论肺部健康状况如何，未校正和ELF校正的BAL均显示出高度的个体间变异性。BAL总蛋白校正使个体间变异性最小化，在所有基因型之间的AAT和ANEC产生了显著差异，与血浆AAT水平的关系最强（r = 0.83），AAT水平的叶间一致性最高（r = 0.76），且BAL AAT与ANEC之间具有强相关性（r = 0.88）。
通过利用AAT基因型之间AAT水平的显著一致性以及血浆和肺AAT水平之间的密切关系，我们证明了与血浆密切相关的可靠肺泡采样。
