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Indications for Active Case Searches and Intravenous Alpha-1 Antitrypsin Treatment for Patients With Alpha-1 Antitrypsin Deficiency Chronic Pulmonary Obstructive Disease: An UpdateActualización sobre indicaciones de búsqueda activa de casos y tratamiento con alfa-1 antitripsina por vía intravenosa en pacientes con enfermedad pulmonar obstructiva crónica asociada a déficit de alfa-1 antitripsina

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Abstract

The effect of hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD). AAT deficiency (AATD) is defined as a serum concentration lower than 35% of the expected mean value or 50 mg/dl (determined by nephelometry). It is associated in over 95% of cases with Pi*ZZ genotypes, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles. A systematic qualitative review was made of 107 articles, focusing mainly on an active search for AATD in COPD patients and intravenous (iv) treatment with AAT. On the basis of this review, the consultant committee of the Spanish Registry of Patients with AATD recommends that all COPD patients be screened for AATD with the determination of AAT serum concentrations, and when these are low, the evaluation must be completed with phenotyping and, on occasions, genotyping. Patients with severe AATD COPD should receive both the pharmacological and non-pharmacological treatments recommended in the COPD guidelines. There is enough evidence from large observational studies and randomized placebo-controlled clinical trials to show that the administration of iv AAT reduces mortality and slows the progression of emphysema, hence its indication in selected cases that meet the inclusion criteria stipulated in international guidelines.

The administration of periodic infusions of AAT is the only specific treatment for delaying the progression of emphysema associated with AATD.

Resumen

El déficit hereditario de la alfa-1 antitripsina (AAT) se puede manifestar clínicamente como una enfermedad pulmonar obstructiva crónica (EPOC). Se define por una concentración sérica por debajo del 35% del valor medio esperado, o 50 mg/dL (medida por nefelometría) y está relacionado en más del 95% de los casos, con genotipos Pi*ZZ, y muy infrecuentemente con otros genotipos resultantes de combinaciones entre alelos Z, S, raros y nulos. Se ha realizado una revisión sistemática cualitativa de 107 artículos, centrados principalmente en la búsqueda activa del déficit de AAT (DAAT) en pacientes con EPOC y en el tratamiento con AAT por vía intravenosa (iv). El comité asesor del Registro Español de pacientes con DAAT, sobre la base de esta revisión, considera que se debe descartar el DAAT, mediante la cuantificación de las concentraciones séricas de AAT, en todos los pacientes con EPOC y cuando sean bajas se debe completar el estudio mediante la determinación del fenotipo y, en ocasiones, del genotipo. El tratamiento de los individuos con EPOC asociado a DAAT grave debe incluir el tratamiento farmacológico y no farmacológico recomendado en las normativas de la EPOC. Existe suficiente evidencia, derivada de grandes estudios observacionales y de ensayos clínicos aleatorizados con placebo, que demuestran que el tratamiento con AAT iv disminuye la mortalidad y reduce la velocidad de progresión del enfisema, por lo que está indicado en casos seleccionados que cumplan los criterios de inclusión establecidos en las normativas internacionales.

La terapia con infusiones iv periódicas de AAT es el único tratamiento específico que existe para frenar la progresión del enfisema asociado al DAAT.

Introduction

Hereditary alpha-1 antitrypsin (AAT) deficiency can manifest clinically in the form of chronic obstructive pulmonary disease (COPD) (typically as panacinar pulmonary emphysema), liver cirrhosis at any age and, less commonly, as panniculitis, systemic vasculitis and other diseases.1 Severe AAT deficiency (AATD) is defined as a serum AAT level lower than 35% of the expected mean value or less than 50 mg/dl (determined by nephelometry). It is associated with Pi*ZZ genotypes in over 95% of cases, and much less frequently with other genotypes resulting from combinations of Z, S, rare and null alleles.2

Since the detection of severe AATD cases involves genetic counseling, the study of first-degree relatives and, in selected cases, the administration of regular intravenous (IV) AAT infusions, in 2006, the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), in collaboration with the Spanish Registry of Patients with AATD (REDAAT) advisory committee, published guidelines on the diagnosis and treatment of AATD, the basic concepts of which remain valid today.3 However, several subsequent studies4, 5, 6, 7 have provided new data supporting the importance of detecting AATD in individuals with COPD and the use of replacement therapy in patients with COPD and severe AATD,8, 9, 10, 11, 12, 13 all of which justify this update.

Section snippets

Methodology

The authors performed a literature search of articles published between 1985 and 2013 in the MEDLINE, EMBASE and Cochrane Library databases, using the keywords: “alpha-1 antitrypsin deficiency”, “COPD”, “asthma”, “bronchiectasis”, “augmentation therapy” and “replacement therapy”. Meta-analyses and systematic reviews by other authors, based on quality of scientific evidence, as well as some articles cited in those selected previously and not detected in the databases, were also included for

Results

The results of the qualitative systematic analysis are summarized in Table 1, Table 2. It should be noted that the REDAAT working group detected major shortcomings in the literature, which highlight the need for future high quality studies to address several of the issues raised. Even so, analysis of the 4 papers selected49, 54, 71, 93 and a recent high-quality meta-analysis13 focusing on research of AATD in COPD suggest that AATD should be ruled out by measuring serum AAT concentrations in all

Discussion

The results shown support the recommendation to rule out AATD in all patients with COPD. This was proposed by the World Health Organization as far back as 1997,35 and was subsequently included in various guidelines, including those of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and SEPAR.1, 3 Furthermore, although there are insufficient studies to precisely establish a strength of recommendation, the authors also advise ruling out AATD in first-degree relatives

Funding

The authors have not received any funding for this article.

Conflict of Interest

The Spanish Lung Foundation (Respira) received donations from Laboratorios Grifols for sponsoring activities by the Spanish Registry for Patients with Alpha-1 Antitrypsin Deficiency.

Ana Bustamante received honoraria for lecturing from Grifols, Astra, Boheringer-Ingelheim, Pfizer, Chiesi, and Almirall.

Francisco Casas received honoraria for scientific advice and/or for lecturing from Almirall, AstraZeneca, Boehringer Ingelheim, Grupo Ferrer, GlaxoSmithKline, Grifols, Laboratorios Esteve, Pfizer,

Acknowledgements

The REDAAT Committee would like to thank Doctors Rafael Vidal, Rosendo Jardí, Juan Carlos Barros-Tizón, Pedro Pablo España and Carlos Escudero for their contribution to the work of the Registry over the years.

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    Please cite this article as: Casas F, Blanco I, Martínez MT, Bustamante A, Miravitlles M, Cadenas S, et al. Actualización sobre indicaciones de búsqueda activa de casos y tratamiento con alfa-1 antitripsina por vía intravenosa en pacientes con enfermedad pulmonar obstructiva crónica asociada a déficit de alfa-1 antitripsina. Arch Bronconeumol. 2015;51:185–192.

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