The Relationship Between Gas Transfer Measurements, Lung Volumes, and Spirometric Indices in Alpha-1 Antitrypsin Deficiency and Non-AATD COPD: A Systematic Review

Background: Alpha-1 Antitrypsin Deficiency (AATD) is associated with persistent airflow limitation with a predominant emphysema phenotype. While spirometry is the gold standard for diagnosis and staging of airflow obstruction, gas transfer is more specific for alveolar damage and may support early diagnosis. We performed a systematic review of the published evidence to support measurements of gas transfer in AATD, with comparison to non-AATD Chronic Obstructive Pulmonary Disease (COPD).

Methods: The systematic review was conducted using standardised methodology (protocol registration number: CRD42024516788). Electronic databases were searched and randomised controlled trials, observational studies, and case series of > 10 participants with AATD which compared gas transfer tests with spirometry were included. Non-AATD COPD studies were included only where they contained a separate AATD comparative cohort. Risk of bias was assessed using Newcastle-Ottawa Scale. The primary outcome was the relationship between gas transfer and airflow obstruction. Additional outcomes included gas transfer measurements with other lung function measures, respiratory symptom scores, exacerbation frequency, mortality, and imaging markers of emphysema.

Results: Twenty-two studies were included. Gas transfer impairment was common in patients with AATD and generally associated with worse airflow obstruction. Gas transfer impairment related strongly with imaging markers of emphysema and was consistently associated with worse health-related quality of life (HRQL), greater exacerbation frequency, and increased mortality, most strongly in AATD, but also in non-AATD COPD patients. In several studies, impaired gas transfer was present with normal spirometry and studies of never smokers identified through screening suggested that impairments in gas transfer were an early marker of disease. However, all studies highlighted the heterogeneity of lung function decline and presentation in AATD, which could only be partially explained by antitrypsin genotype.

Conclusion: Gas transfer measurements provide valuable, early information in assessing physiological impairment and risk of poor outcomes in both AATD and non-AATD COPD.