Alpha 1 antitrypsin augmentation therapy for alpha 1 antitrypsin deficiency-associated lung disease

Alpha-1 antitrypsin (AAT) is a protein produced by the liver that stops certain enzymes from harming body tissues, especially in the lungs. AAT deficiency (AATD) is a genetic condition that can manifest clinically as chronic obstructive pulmonary disease (COPD), causing cough and breathlessness. AAT augmentation therapy could help prevent or slow the progression of COPD in people with AATD. Whilst correcting the protein deficit seems a logical approach to treating a condition caused by a protein deficiency, this intervention is only worthwhile if it leads to improvements in clinically important outcomes. The evidence synthesised in a previous Cochrane review (last updated in 2016) was insufficient to conclude whether AAT augmentation therapy influenced any clinical outcomes. However, no inhaled AAT augmentation therapy studies were available for inclusion in that review, only studies on intravenous AAT augmentation therapy.

To assess the effects of alpha 1 antitrypsin (AAT) augmentation therapy on respiratory disease in people with alpha 1 antitrypsin deficiency (AATD).

We searched CENTRAL, MEDLINE, Embase, and two trials registries to August 2025. We checked the reference lists of included articles and other related papers for any additional studies.

We included randomised controlled trials (RCTs). Cluster-RCTs were also eligible if the data had been, or could be, adjusted for clustering. We included studies comparing AAT augmentation by any route (inhaled, intravenous, or subcutaneous) with AAT augmentation by a different route, placebo, or no treatment. We excluded studies that compared different doses of AAT via the same route, without a placebo or no treatment group.

Our critical outcomes were annual airway disease exacerbation rate, all-cause mortality, and participants experiencing one or more serious adverse events.

We used the Cochrane risk of bias tool (RoB 2).

Two review authors independently extracted data and assessed the risk of bias. We conducted meta-analyses to calculate odds ratios (ORs) for dichotomous outcomes, and mean differences (MDs) or standardised mean differences (SMDs) for continuous outcomes, all with corresponding 95% confidence intervals (CIs). We used GRADE to assess the certainty of evidence for our critical outcomes.

Six multicentre studies randomised a total of 526 people with AATD and analysed the results for 524 participants. The studies were conducted in Europe, North America, and Australia and were published between 1997 and 2025. The route of AAT administration was intravenous in four studies and inhaled in two studies. This review has three new studies compared to the 2016 Cochrane review.

Intravenous AAT augmentation therapy versus placebo Intravenous AAT augmentation therapy may increase the annual airway disease exacerbation rate slightly compared with placebo (MD 0.29 exacerbations, 95% CI 0.04 to 0.54; P = 0.02, I² = 0%; 2 studies, 257 participants; low-certainty evidence, downgraded for serious imprecision and indirectness). It may make little or no difference to all-cause mortality (OR 0.30, 95% CI 0.03 to 2.98; P = 0.31; 2 studies, 187 participants; low-certainty evidence, downgraded for very serious imprecision). We are uncertain whether intravenous AAT augmentation therapy has an impact on the risk of experiencing one or more serious adverse events (OR 0.67, 95% CI 0.32 to 1.41; P = 0.29, I² = 43%; 2 studies, 257 participants; very low-certainty evidence, downgraded for serious inconsistency and indirectness and very serious imprecision). Inhaled AAT augmentation therapy versus placebo We are uncertain if inhaled AAT augmentation therapy has an impact on the annual airway disease exacerbation rate compared with placebo (MD 0.45 exacerbations, 95% CI -0.42 to 1.32; P = 0.31; 1 study, 168 participants; very low-certainty evidence, downgraded for serious indirectness and very serious imprecision). It may make little or no difference to the risk of experiencing one or more serious adverse events (OR 5.33, 95% CI 0.61 to 46.54; P = 0.13, I² = 0%; 2 studies, 204 participants; low-certainty evidence, downgraded for very serious imprecision). No studies reported all-cause mortality.

Compared with placebo, intravenous AAT augmentation therapy may have little or no effect on all-cause mortality but may increase the annual airway disease exacerbation rate slightly. We are uncertain if intravenous AAT augmentation therapy has any effect on the risk of serious adverse events. Inhaled AAT augmentation therapy may have little or no effect on the annual airway disease exacerbation rate or the risk of serious adverse events.

This Cochrane review had no dedicated funding.

Protocol (2024) DOI: 10.1002/14651858.CD015930.