Bronchiectasis as a phenotype of Alpha-1 Antitrypsin Deficiency

De Soyza, Joshua Luke ORCID: 0000-0003-1311-9775 (2025). Bronchiectasis as a phenotype of Alpha-1 Antitrypsin Deficiency. University of Birmingham. M.D.

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Abstract

Alpha-1 Antitrypsin Deficiency (AATD) is a rare, inherited condition characterized by reduced or dysfunctional alpha-1 antitrypsin (AAT), a protease inhibitor that protects lung tissue from inflammation-mediated damage. AATD is a recognised genetic cause of chronic obstructive pulmonary disease (COPD), but its relationship with bronchiectasis, a condition involving permanent bronchial dilatation, recurrent infections, and impaired mucociliary clearance, is less well defined. This thesis investigates the hypothesis that bronchiectasis in AATD represents a distinct clinical phenotype, rather than a secondary complication of COPD, and examines its implications for diagnosis, prognosis, and management.
Using the Birmingham AATD registry, this research systematically examines radiological, microbiological, biochemical, and clinical data to characterise the prevalence, progression, and severity of bronchiectasis in AATD. Throughout the thesis, clinical outcomes of exacerbation rate, baseline FEV\(_1\), lung function decline, symptoms, and mortality are used. A systematic review highlights the scarcity of high-quality data addressing the characteristics of AATD-bronchiectasis. The analysis of registry data demonstrates that unclassified bronchiectasis is not associated with COPD diagnosis, and is associated with serum AAT level, suggesting a direct link between bronchiectasis and AATD, though bronchiectasis without further subclassification has no impact on clinical outcomes.
Sputum samples were obtained and combined with historic data to reveal the association of Pseudomonas aeruginosa with higher exacerbation rate and accelerated lung function decline, in common with other causes of bronchiectasis. Biomarker studies highlight the role of systemic inflammation in disease pathogenesis, with abnormal eosinophils and CRP correlating with poorer clinical outcomes in AATD-bronchiectasis, as did platelets when the whole cohort of AATD was included. Further study of a greater number of inflammatory biomarkers in a proteomics context could reveal therapeutic targets.
Analyses of CT scans assess severity of bronchiectasis using established visual and algorithmic markers, and revealed that bronchiectasis is usually mild, though with a subset of patients with more extensive disease, despite efforts to exclude those with alternative causes. Visual and algorithmic analyses correlated well with each other. In common with other causes of bronchiectasis, cystic bronchiectasis was the only subtype found to associate with clinical outcomes, in this case exacerbation rate and gas transfer decline. This assessment also allowed validation of the bronchiectasis severity index (BSI) in AATD for the first time, demonstrating increasing mortality risk between mild, moderate and severe scores.
In conclusion, this thesis establishes bronchiectasis as a distinct phenotype in AATD, being unrelated to COPD. However, being mostly mild, it is of limited clinical significance unless cystic morphology, P. aeruginosa colonisation, or eosinophilia develops, in common with other bronchiectasis aetiologies. This thesis therefore does not demonstrate a sufficiently strong or causal link to suggest widespread screening for AATD in idiopathic bronchiectasis. Avenues for future research include comparison of this data with other causes of bronchiectasis, study of proteomics to assess a broader range of inflammatory biomarkers, and the study of whether a combined prognostic tool can be developed for the bronchiectasis-COPD overlap syndrome, as frequently occurs in AATD. Ultimately, this work advances our understanding of AATD and reinforces the need for personalised approaches to care in this complex patient population.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):