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Review
. 2017 May 2:12:1295-1308.
doi: 10.2147/COPD.S130440. eCollection 2017.

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

Affiliations
Review

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

Ross G Edgar et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Background: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.

Methods: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.

Results: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.

Conclusion: Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

Keywords: alpha-1 antitrypsin deficiency; emphysema; transplantation; treatment.

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Conflict of interest statement

Disclosure Mr Edgar reports grants from HEE and NIHR, during the conduct of the study. This article presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, HEE, or the Department of Health. Dr Patel, Mrs Bayliss, and Dr Crossley have nothing to disclose. Dr Sapey reports grants from NIHR, during the conduct of the study, and grants from Medical Research Council, Alpha-1 Foundation, and British Lung Foundation, outside the submitted work. Dr Turner reports grants from Grifols Biotherapeutics, Alpha-1 Foundation, outside the submitted work, and The Birmingham AATD Registry has received past funds from CSL Behring for work in AATD, although this was not held by any of the authors. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
PICO chart detailing inclusion in systematic review. Note: PICO assessed are shown. Abbreviations: AATD, alpha-1 antitrypsin deficiency; AAT, alpha-1 antitrypsin; Pi, protease inhibitor; COPD, chronic obstructive pulmonary disease; PICO, population, interventions, comparators, and outcomes.
Figure 2
Figure 2
PRISMA flow diagram. Notes: Adapted from Moher et al. Articles were excluded where there were insufficient data in the public domain for the study to be assessed against the inclusion criteria including data from ClinicalTrials.gov. Abbreviation: COPD, chronic obstructive pulmonary disease.
Figure 3
Figure 3
Forest plots of the objective results from meta-analysis of augmentation trials. Notes: (A) Mean annual change in lung density. (B) Mean FEV1 % predicted. (C) Standardized mean difference in DLCO. Differences in units used for DLCO (mmol/min/kPa and mL/mmHg/min) and the use of percentage change from baseline in RAPID, but annual change in the other studies required the use of a standardized mean difference plot. Abbreviations: FEV1, forced expiratory volume in one second (L); DLCO, diffusing capacity of the lungs for carbon monoxide; mmol/min/kPa, millimole per minute per kilopascal; mL/mmHg/min, milliliter per millimeter of mercury per minute; SD, standard deviation; CI, confidence interval; df, degrees of freedom; Std, standard; IV, inverse variance.
Figure 4
Figure 4
Forest plots for patient-reported outcomes. Notes: (A) Annual patient-reported exacerbation episodes. (B) Health status: SGRQ, measures recorded as change from baseline. Abbreviations: SGRQ, St Georges Respiratory Questionnaire; SD, standard deviation; CI, confidence interval; df, degrees of freedom; IV, inverse variance.
Figure 5
Figure 5
Risk of bias in included studies. Notes: (A) Risk of bias in augmentation RCTs. (B) In view of the large number of studies and the differing scales for assessment of risk based on the study design, a summary of the relative risk of bias is shown across all included studies, other than the RCTs of augmentation. This represents review authors’ judgments about each risk of bias item presented as the mean percentage across all included studies. Individual bias assessments are available in the Supplementary materials. Abbreviation: RCT, randomized controlled trial.

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