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 (r2=0.83), greatest inter-lobar concordance in AAT levels (r2=0.76) and strong correlation between BAL AAT and ANEC (r2=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. Data are available upon reasonable request.

中文翻译：

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优化支气管肺泡灌洗：α-1 抗胰蛋白酶缺乏症的经验教训


背景 支气管肺泡灌洗 （BAL） 对于确定 α-1 抗胰蛋白酶缺乏症 （AATD） 新疗法的疗效至关重要。这些需要初步的概念验证证明，治疗给药会增加肺部的 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 结果的高度个体间差异，这主要源于返回的 BAL 液固有的稀释特性。需要一种能够最大限度地减少这种变异性的 BAL 方案来可靠地比较肺部的生化终点。方法 研究人群包括 21 名重度 AATD （ZZ）、22 名中度 AATD （MZ） 和 23 名非 AATD （MM） 个体，进一步归类为健康、畅通无阻的当前吸烟者或慢性阻塞性肺病 （COPD） 患者。另有 6 名 ZZ 个体正在接受静脉注射 α-1 增强治疗。在报告早期生化终点、AAT 和 ANEC 时，我们比较了常见的 BAL 校正方法——尿素测量的白蛋白、总蛋白和上皮衬里液 （ELF） 体积。结果 与传统成人支气管镜相比，使用儿科支气管镜 （PB） 进行的 BAL 改善了肺泡取样。无论肺部健康状况如何，未校正和 ELF 校正的 BAL 都表现出很高的个体间变异性。BAL 总蛋白校正最大限度地减少了个体间变异性，在所有基因型之间产生 AAT 和 ANEC 的显著差异，与血浆 AAT 水平的关系最强 （r2=0.83），AAT 水平的肺叶间一致性最高 （r2=0.76） 以及 BAL AAT 和 ANEC 之间的强相关性 （r2=0.88）。 结论 通过利用 AAT 基因型之间 AAT 水平的显着一致性，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。数据可根据合理要求提供。