Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature

Figures & data

Table 1 Relationship between the commonest genotypes and AAT serum concentration

Genotypes	AAT serum concentration
	mg/dL	μM
MM	103–200	20–39
MS	100–180	19–35
SS	70–105	14–20
MZ	66–120	13–23
SZ	45–80	9–15
ZZ	10–40	2–8
Null–null	<10	<2

Note: Adapted with permission from Elsevier. Vidal R, Blanco I, Casas F, Jardí R, Miravitlles M. Diagnoses and treatment of alpha-1 antitrypsin deficiency. Arch Bronconeumol. 2006;42(12):645–659.⁸

Abbreviation: AAT, alpha-1 antitrypsin.

Table 2 Purified AAT products currently licensed for intravenous administration

Product name	Year of approval	Manufacturer	Regulatory approval
Prolastin^®	1987	Bayer	Austria, Belgium, Denmark, Finland, Germany, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, USA, Canada, Argentina and Colombia
Aralast^®	2002	Baxter	USA
Zemaira^®	2003	CSL Behring	USA and Brazil
Trypsone^®	2004	Grifols	Argentina, Brazil, Chile, México and Spain
Alfalastin^®	2005	LFB	France
Glassia^®	2010	Kamada	USA and Brazil
Respreeza^®	2015	CLS Behring	Recently approved by the European Medicaments Agency

Note: Reproduced with permission from the European Respiratory Society © European Respiratory Journal, Jul 2009, 34(1)17–41; DOI: 10.1183/09031936.00184308.³¹

Abbreviation: AAT, alpha-1 antitrypsin.

Table 3 Summary of studies to assess efficacy of AAT augmentation therapy

Authors	Dosing regime	Study design	Primary outcome	Principal results
Seersholm et al^Citation44	60 mg/kg weekly	Observational with control group (n=295)	FEV1 decline	Lower FEV1 decline in treatment group (56 vs 75 mL/year; P=0.02); treatment of apparent benefit in patients with FEV1 31%–65% predicted
American AAT Deficiency Registry Study Group^Citation45	33% weekly, 43% fortnightly, 24% monthly	Observational with control group (n=1,129)	FEV1 decline, mortality	Mortality reduction (OR 0.64; P=0.02); lower FEV1 decline in patients receiving IV AAT treatment and FEV1 35%–49% predicted (66 vs 93 mL/year; P=0.03)
Dirksen et al^Citation46	250 mg/kg/28 days	Randomized, double-blind, placebo controlled	FEV1 decline, CT lung density decline	Lower CT lung density decline (2.6 g/L/year vs 1.5 g/L/year, P=0.07).
Lieberman^Citation47	55% weekly, 37% fortnightly, 8% monthly	Observational (on-line questionnaire) (n=89)	Exacerbation frequency	Reduction in exacerbation frequency (3–5 exacerbations/year vs 0–1/year during AAT IV treatment)
Wencker et al^Citation48	60 mg/kg weekly	Observational cohort without control group (n=96)	FEV1 decline	Lower FEV1 decline rate during treatment (49.2 vs 34.2 mL/year, P=0.019); patients with FEV1 >65% (256 vs 53 mL/year, P=0.001)
Stockley et al^Citation42	60 mg/kg weekly	Descriptive/mechanistic (n=12)	Inflammatory markers (sputum)	Significant reduction in sputum LTB4
Tonelli et al^Citation49		Observational with control group (n=164)	FEV1 decline, mortality	Increase in FEV1 (10.6±21.4 mL/year) vs decline (36.96±12.1 mL/year; P=0.05); no difference in mortality
Dirksen et al^Citation50	60 mg/kg weekly	Double–blind, randomized, placebo-controlled study (FEV1 =25%–80% predicted) (n=77)	Lung function, quality of life, exacerbations and lung density measured by CT	Reduced rate of CT lung density decline in treated individuals (P=0.049); no difference in FEV1 and DLCO; no difference in exacerbation rate but less severe in patients on active treatment
Chapman et al^Citation51		Meta-analysis of studies including patients treated with IV AAT compared with controls from Canadian Registry (n=1,509)	FEV1 decline	Reduction in FEV1 decline in patients with AAT IV treatment in 26% (17.9 mL/year); limited to subjects with FEV1 30%–65% predicted
Cochrane review Gøtzsche and Johansen^Citation52	60 mg/kg weekly	Meta-analysis of 2 randomized studies, controlled with placebo (n=140)	FEV1 decline, DLCO decline, lung density (CT), exacerbations	Lung density decrease is lower in patients under IV treatment (P=0.03); no differences in lung function; no differences in exacerbations; augmentation therapy not recommended
Stockley et al^Citation53	60 mg/kg weekly	Integrated analysis of lung density (n=119)	Density decline, FEV1 decline	Lower lung density decline in treated patients (1.73 vs 2.74 g/L, P=0.006); no differences in FEV1 decline
Barros-Tizón et al^Citation54	180 mg/kg/21 days	Retrospective study (pre–post AAT IV treatment) (n=127)	Frequency and severity of exacerbations and hospitalization costs	Decrease in number and severity of exacerbations and costs related with hospitalizations
Ma et al^Citation43	60 mg/kg weekly	Observational cohort with control group (n=100)	Plasmatic desmosine and isodesmosine	Significant decrease in desmosine and isodesmosine levels in the treated cohort against non-treated cohort (P<0.0001), with similar values to normal population
Ma et al^Citation43	60 mg/kg weekly	Observational study without control group (n=10)	Desmosine and isodesmosine in bronchoalveolar lavage and plasma	Significant reduction of desmosine and isodesmosine levels in BAL (P=0.0273) and plasma at 12 (P=0.0038) and 24 weeks (P=0.0038) under treatment
Chapman et al^Citation55	60 mg/kg weekly	Multicenter study, double-blind, randomized, control with placebo (Pi*ZZ, null or rare genotype with AAT <11 μM, emphysema confirmed by CT and FEV1 35%–70% predicted) (n=180)	Lung function, quality of life, exacerbations, pulmonary density by CT	Reduction in decrease of lung density in treated patients (P=0.03); no differences in FEV1 or DLCO; no differences in exacerbations; no differences in quality of life; AAT IV treatment is safe
Cochrane review Gøtzsche and Johansen^Citation56	IV AAT compared with placebo or no treatment	Review of randomized trials; 3 trials (n=283)	Benefits and harms of augmentation therapy	No conclusion about impact of augmentation therapy on mortality, exacerbations, lung infections, hospital admission and quality of life; uncertainty about potential harms; lung density measured by CT deteriorated significantly less in the treatment group compared with placebo; augmentation therapy not recommended
McElvaney et al^Citation57	60 mg/kg weekly	Open label extension for RAPID patients who had received active (early start group) or placebo (delayed start group)	CT lung density decline, FEV1 decline, DLCO decline	Reduced and comparable lung density decline for both groups on active treatment No difference in FEV1 or DLCO decline

Notes: Adapted from Casas F. Hernandez JM. General treatment and intravenous treatment with alpha-1 antitrypsin. Chapter 12. Déficit de alfa-1 anitripsina: fisiopatología, enfermedades relacionadas, diagnóstico y tratamiento. Editorial Respira. ISBN 978-84-944876-8-2. Copyright 2016, Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).⁵⁸

Abbreviations: AAT, alpha-1 antitrypsin; OR, odds ratio; IV, intravenous; CT, computed tomography; FEV₁, forced expiratory volume in 1 second; DLCO, carbon monoxide diffusion capacity.

Figure 1 Voxel frequency distribution histogram showing the appearance of normal lung (black line) and emphysema (gray line) and the derivation of the commonest densitometric indices.

Notes: The 15th percentile point (PD15) is defined as the cutoff value, in HU, below which 15% of voxels with the lowest density are distributed. This index becomes more negative with emphysema progression. The voxel index at a threshold of −950 HU (VI-950), defined as the percentage of voxels with a value less than −950 HU, increases with emphysema progression.
Abbreviation: HU, Hounsfield unit.

Figure 2 Change from baseline in 15th percentile lung density (PD15), over the course of the RAPID study (RAPID-RCT and RAPID-OLE).

Notes: Data are from the mixed-effect regression model applied to each trial separately (RAPID-OLE ITT population). Adjusted PD15, lung volume-adjusted 15th percentile of the lung density. Reprinted from The Lancet Respiratory, 5(1), McElvaney et al, Long-term efficacy and safety of alpha-1 proteinase inhibitor treatment for emphysema cause by severe alpha-1 antitrypsin: an open label extension trial (RAPID-OLE).^51–60, Copyright 2016, with permission from Elsevier.⁵⁷
Abbreviations: ITT, intention to treat; TLC, total lung capacity; RCT, randomized controlled trial; OLE, open-label extension.

Table 4 Summary of key points from different AATD guidelines

	ATS/ERS^Citation9	SEPAR^Citation8	CTS^Citation93	Sociedad Argentina^Citation94	SEPAR^Citation95
Authors	AATD international expert group	Spanish registry of patients with AATD advisory board	COPD and AATD expert group	AATD international expert group	Spanish registry of patients with AATD advisory board
Document scope	International	National	National	National	National
Year	2003	2006	2012	2014	2015
Methodology	Evidence-based systematic review (since 1963)	Expert consensus	Evidence-based systematic review from 1980 to 2011 (AGREE II, GRADE and “PICO” questions)	Narrative review limited to treatment (GRADE)	Qualitative systematic review
Objectives	Diagnoses, clinical presentation, treatment, ethics, legal and social implications among others	Diagnoses, clinical presentation, treatment	Screening and augmentation therapy indications (COPD: FEV1/FVC <0.7 and AATD <11 μM/L)	Diagnoses, clinical presentations, physiopathology, epidemiology, genetic among others	Diagnoses and indications for augmentation therapy
Augmentation therapy recommendations	– Serum concentration <11 μM – FEV1 30%–65%	– Serum concentrations <11 μM/L – Airflow obstruction or evidence of rapid decline of FEV1 (>120 mL/year) – Treatment should not be withdrawn if FEV1 <30%	– Former or never smokers with COPD (FEV1 between 80% and 25%) – Serum concentration ≤11 μM/L – Optimized pharmacological and non-pharmacological COPD treatment	Adapted from Spanish guidelines. Treatment should not be withdrawn if FEV1 <30%	– Former or never smokers – >18 years – Serum concentration <35% of normal range Proven lung disease (airflow obstruction demonstrated by PFT and HRCT) (FEV1/FVC <70% and FEV1 <80% or rapid decline) – Absence of IgA deficiency

Notes: Adapted from Lara B, Miravitlles M, Casas F. Review of national and international guidelines about diagnoses and treatment of alpha-1 antitrypsin deficiency. Déficit de alfa-1 anitripsina: fisiopatología, enfermedades relacionadas, diagnóstico y tratamiento. Editorial Respira. ISBN 978-84-944876-8-2. Copyright 2016, Spanish Society of Pulmonology and Thoracic Surgery (SEPAR).⁹⁶

Abbreviations: AATD, alpha-1 antitrypsin deficiency; ATS, American Thoracic Society; ERS, European Respiratory Society; SEPAR, Sociedad Española de Neumología y Cirugía Torácica; CTS, Canadian Thoracic Society; COPD, chronic obstructive pulmonary disease; FVC, forced vital capacity; PFT, pulmonary function tests.

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