Kenneth R. Chapman

Extract Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by variants in the SERPINA1 gene, resulting in reduced circulating AAT levels [1]. Deficiency of functional AAT disrupts the protease antiprotease balance and predisposes individuals to early-onset pulmonary emphysema[2]. While liver disease is driven by intracellular accumulation of misfolded and polymerised Z-AAT within hepatocytes[1, 3].

The interindividual phenotypic heterogeneity in Alpha-1 Antitrypsin Deficiency (AATD), despite a shared genetic etiology (the Z-allele of SERPINA1), is explained by the interaction of dual pathogenic mechanisms (gain-of-function vs. loss-of-function), additional genetic modifiers, and environmental or metabolic factors. Building on recent evidence suggesting divergent disease trajectories, we investigated whether pulmonary and hepatic impairments represent coupled manifestations or independent clinical dimensions within a large European cohort. Methods: This international multicenter study utilized the European Alpha-1 Research Collaboration (EARCO) registry (n = 1217). Pulmonary and hepatic severities were quantified using concurrent 0.0–10.0 composite indices. Independence was evaluated via partial Spearman correlations, multivariable multinomial regression, and geometric mapping across a continuous phenotypic space. Results: Cross-domain correlations between respiratory metrics and liver stiffness were near zero (r = −0.03), demonstrating statistical independence. Phenotypic dominance classification isolated distinct profiles; the lung-dominant group exhibited a higher age (57.0 vs. 54.0 years; p < 0.001) and tobacco exposure, while the liver-dominant group registered a higher body mass index (25.8 vs. 24.4 kg/m²; p < 0.001). Multivariable models identified age (OR 1.03; 95% CI 1.02–1.05) and smoking as independent predictors of lung dominance, whereas body mass index was independently associated with liver dominance (OR 1.04; 95% CI 1.01–1.07). Geometric mapping revealed advanced disease clusters at orthogonal margins rather than forming a systemic continuum. Conclusions: Hepatic and pulmonary impairments in AATD operate as independent clinical dimensions modulated by distinct metabolic and environmental factors. Risk stratification must transition toward organ-specific prognostic models.

Alpha-1 antitrypsin deficiency (AATD) is a rare, monogenic disorder predisposing individuals to liver and lung diseases. Yet, even within the same genotype, AATD is very heterogeneous in clinical presentation. This heterogeneity suggests a complex interplay of environmental and (epi-)genetic factors, highlighting the need for a detection and study of clinical phenotypes. Here, we performed a cluster analysis using baseline data from the European Alpha-1 Research Collaboration (EARCO) to identify distinct clinical phenotypes in AATD. We identified six clusters of AATD clinical phenotypes using K-Prototypes with a cross-validated weighted F1 score of 0.926. Moreover, using a trained Random Forest classifier, we identified age at diagnosis, lung function and tobacco consumption as most important features in distinguishing these clusters, in addition to the AATD-associated genotype. Overall, these findings underscore that, beyond genotype, a multitude of other factors significantly influence AATD clinical phenotypes. Accordingly, this emphasizes the importance of integrating (epi-)genetic, environmental and behavioral data in future fundamental and translational research in order to unravel the complex mechanisms underlying patient heterogeneity. Moreover, longitudinal follow-up of individuals allocated to these clusters will help to better understand disease progression and to assess the potential benefits of specific therapies in different phenotypes.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that causes emphysema from lack of the alpha-1 antitrypsin (AAT) serpin antiprotease, leading to protease–antiprotease imbalance. Weekly intravenous AAT therapy (augmentation) is the only specific treatment available. Alvelestat is an oral inhibitor of neutrophil elastase (NE) in development as a novel approach to AATD therapy. Here, we tested the safety and mechanistic efficacy of alvelestat in severe AATD. Methods: We conducted two complementary, double-blind, randomised, placebo-controlled, 12-week trials, incorporating two doses of alvelestat in AATD. ATALANTa investigated 120 mg twice daily, including a subset of participants also receiving augmentation; ASTRAEUS tested 120 and 240 mg twice daily without augmentation. Primary and secondary end-points were the change in blood NE (the putative target) and its activity in AATD (Aα-Val ³⁶⁰ and desmosine/isodesmosine) as well as safety and tolerability. Results: We enrolled 161 participants (63 in ATALANTa and 98 in ASTRAEUS). Blood NE was significantly suppressed in both studies at both doses, with the greatest effect (>90% suppression) at alvelestat 240 mg twice daily. There was no effect of alvelestat 120 mg on disease activity biomarkers, while 240 mg demonstrated significant reduction in Aα-Val ³⁶⁰ and desmosine. The most common adverse event was headache, particularly at the 240 mg dose. No safety signals of concern were detected. Conclusions: Alvelestat effectively suppressed NE and its activity at both doses, but only the 240 mg twice-daily dose demonstrated relevant efficacy compared to placebo on disease activity biomarkers with a favourable safety profile. These findings support progression of the 240 mg twice-daily dose into a clinical end-point study.

Background: α-1 antitrypsin deficiency (AATD) is a rare genetic disorder caused by mutations in the SERPINA1 gene and associated with reduced levels of α-1 antitrypsin (AAT). It predisposes individuals to pulmonary diseases, including bronchiectasis, through protease–antiprotease imbalance and immune dysregulation. While the Pi*ZZ genotype has been extensively studied, the prevalence and characteristics of bronchiectasis in other genotypes remain unclear. Methods: This cross-sectional study analysed data from the European α-1 Research Collaboration (EARCO) registry, focusing on individuals with bronchiectasis on computed tomography (CT). Participants were stratified by AATD genotypes (Pi*ZZ , Pi*SZ, Pi*SS and rare variants) and data were compared. Disease severity was evaluated using FACED (forced expiratory volume in 1 s (FEV ₁ ), age, chronic colonisation, extension and dyspnoea) score and bronchiectasis severity index (BSI) scores. Results: 349 patients had bronchiectasis on a CT scan, of whom 70.5% had Pi*ZZ, 18.6% had Pi*SZ, 4.3% had Pi*SS and 6.6% had rare variants. Lower lobe involvement was predominant across genotypes, whereas Pi*SS exhibited distinct upper lobe patterns and Pi*SZ showed more frequent middle lobe involvement. People with rare genotypes and Pi*ZZ had worse lung function (FEV ₁ % of 65.3% and 71.4%, respectively) and higher disease severity scores. Emphysema co-occurrence was most frequent in Pi*ZZ (60.6%). No significant differences were observed in sputum microbiology or systemic inflammatory markers, except for lower platelet counts in Pi*ZZ subjects. Conclusion: Bronchiectasis in AATD is not limited to the Pi*ZZ genotype, with significant phenotypic variability across genotypes. Lower lobe involvement and mild disease predominate; however, severe forms are more frequent in rare genotypes and Pi*ZZ. These findings underscore the importance of systematic screening and genotype-specific management to improve patient outcomes.

Introduction: Clinically important deterioration (CID), a composite of exacerbation, declines in lung function and health status has been studied as an indicator of disease worsening in moderate–severe COPD clinical populations. We assessed whether CID is predictive of worsening over 18 months in a population-based mild–moderate COPD cohort. Methods: Canadian Cohort Obstructive Lung disease (CanCOLD) participants with COPD were assessed over 18 months for CID, and over the next 18 months for outcomes. Their association was then examined: 1) defined into threshold-based binary variables, the declines in forced expiratory volume in 1 s (FEV ₁ ), health status and dyspnoea, using logistic regression models; 2) time to moderate/severe exacerbation and rates of moderate/severe exacerbations using Cox proportional hazards and Poisson regression, respectively. Results: Out of 420 participants, 252 (60%) demonstrated CID (definition 1, St George's Respiratory Questionnaire (SGRQ)). Presence of CID at 18 months showed association with future moderate/severe exacerbation (not statistically significant), worsening health status (COPD Assessment Test (CAT) score), and dyspnoea. As a component, FEV ₁ was found to be less informative, compared with exacerbation for health status outcome (OR 4.31, 95% CI 1.29–14.41 for ≥8-unit increase in SGRQ) alongside future exacerbation, and SGRQ health status component, for future health status decline (OR 0.33, 95% CI 0.17–0.66 for ≥4-unit increase in SGRQ and OR 0.53, 95% CI 0.30–0.94 for ≥2-unit increase CAT score). Discussion: Our finding of informative CID components seems to support recommendations of emphasis on exacerbation history and health status, over severity of airway obstruction in clinical assessments to predict outcomes. Suitable adaptations of the current CID definition may be needed for mild–moderate COPD populations.