Alpha-1-Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Meta-Analysis...

Alpha-1-antitrypsin (A1AT) deficiency is a common hereditary disorder associated with increased risk of developing chronic obstructive pulmonary disease (COPD). Many individuals with severe A1AT deficiency go undiagnosed, or are diagnosed late, and fail to benefit from disease-specific counseling and modifying care. Since the 2012 Canadian Thoracic Society (CTS) A1AT deficiency clinical practice guideline, new approaches to optimal diagnosis using modern genetic testing and studies of A1AT augmentation therapy have been published. We performed a systematic review and meta-analysis, which along with expert clinical input, informed recommendations. We conditionally recommend testing for A1AT deficiency in all individuals with COPD at the time of diagnosis, individuals with adult-onset asthma with persistent airway obstruction, and individuals with unexplained bronchiectasis. We suggest genetic testing with DNA sequencing of SERPINA1 gene as the initial test for individuals with high clinical suspicion for A1AT deficiency, and initial measurement of serum A1AT levels in individuals with moderate clinical suspicion of A1AT deficiency, followed by genetic testing with DNA sequencing of SERPINA1 gene if A1AT level is <23 μmol/L (<1.2 g/L). Following identification of an abnormal gene for A1AT in individuals, whether heterozygote or homozygote, we suggest first-degree relatives be provided genetic counseling and offered testing for A1AT deficiency. The panel conditionally recommends A1AT augmentation therapy to patients who do not smoke or who formerly smoked with COPD (forced expiratory volume in 1 s [FEV₁] < 80% predicted; associated with emphysema), with documented deficiency genotypes and severely reduced A1AT level (< 11 μmol/L or < 0.57 g/L) in addition to receiving optimal pharmacological and nonpharmacological therapies for COPD.