Esmaili Soha, Rodríguez Hermosa Juan Luis, Vargas Centanaro Gianna, Álvarez-Sala José Luis, Esmaili Iman, Calle Rubio Myriam
Pulmonology Department, Hospital Clínico San Carlos, 28040 Madrid, Spain.
Heart Lung Innovation Centre, Vancouver, BC V6Z 1Y6, Canada.
Biomolecules. 2025 Apr 17;15(4):599. doi: 10.3390/biom15040599.
Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with an increased risk of developing chronic obstructive pulmonary disease (COPD) with variable phenotypic expression among different genotypes. While the PiZZ genotype is well characterized, the clinical and structural progression of PiSZ individuals remains less defined. This study evaluates genotype-specific disease trajectories and the impact of augmentation therapy over a two-year follow-up.
A prospective observational cohort study was conducted, including 74 AATD patients (41 PiSZ, 33 PiZZ), stratified by augmentation therapy status. Disease progression was assessed through lung function decline (forced expiratory volume in one second [FEV1], diffusing capacity for carbon monoxide [DLCO], carbon monoxide transfer coefficient [KCO]) and densitometric changes (15th percentile lung density [PD-15], percentage of lung voxels below -950 Hounsfield units [HU-950]). Mixed-effects models and multivariable regression analyses were performed to evaluate genotype-specific progression patterns and treatment effects.
Results: PiZZ individuals exhibited significantly greater annual decline in lung function and densitometric parameters compared to PiSZ individuals, with more pronounced loss in basal lung regions and with greater decline in advanced stages, in contrast to the PiSZ genotype, which showed greater progression in earlier stages. Augmentation therapy was associated with a significant reduction in PD-15 decline in both genotypes, with the greatest benefit observed in PiZZ patients and in those diagnosed within five years of disease onset. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression.
PiZZ individuals experience a more aggressive disease trajectory than PiSZ individuals in the absence of treatment. Augmentation therapy effectively mitigates disease progression in both genotypes, with greater efficacy when initiated early. Smoking and frequent exacerbations were identified as independent risk factors for accelerated disease progression. These findings underscore the importance of genotype-specific monitoring and personalized therapeutic strategies in AATD to optimize clinical outcomes.
α-1抗胰蛋白酶缺乏症（AATD）是一种遗传性疾病，与慢性阻塞性肺疾病（COPD）的发病风险增加相关，在不同基因型中具有可变的表型表达。虽然PiZZ基因型已得到充分表征，但PiSZ个体的临床和结构进展仍不太明确。本研究评估了特定基因型的疾病轨迹以及强化治疗在两年随访中的影响。
进行了一项前瞻性观察队列研究，包括74例AATD患者（41例PiSZ，33例PiZZ），按强化治疗状态分层。通过肺功能下降（一秒用力呼气容积[FEV1]、一氧化碳弥散量[DLCO]、一氧化碳转移系数[KCO]）和密度测量变化（第15百分位肺密度[PD-15]、低于-950亨氏单位的肺像素百分比[HU-950]）评估疾病进展。进行混合效应模型和多变量回归分析以评估特定基因型的进展模式和治疗效果。
结果显示，与PiSZ个体相比，PiZZ个体的肺功能和密度测量参数的年下降幅度明显更大，基础肺区域的损失更明显，晚期下降幅度更大；而PiSZ基因型在早期阶段进展更大。强化治疗与两种基因型的PD-15下降显著减少相关，在PiZZ患者以及疾病发作五年内确诊的患者中观察到最大益处。吸烟和频繁加重被确定为疾病加速进展的独立危险因素。
在未接受治疗的情况下，PiZZ个体的疾病轨迹比PiSZ个体更具侵袭性。强化治疗可有效减轻两种基因型的疾病进展，早期启动时疗效更佳。吸烟和频繁加重被确定为疾病加速进展的独立危险因素。这些发现强调了在AATD中进行特定基因型监测和个性化治疗策略以优化临床结果的重要性。
