ALPHA-1-ANTITRYPSIN DEFICIENCY

Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency

Dawn L DeMeo¹, Robert A Sandhaus², Alan F Barker³, Mark L Brantly⁴, Edward Eden⁵, N Gerard McElvaney⁶, Stephen Rennard⁷, Esteban Burchard⁸, James M Stocks⁹, James K Stoller¹⁰, Charlie Strange¹¹, Gerard M Turino⁵, Edward J Campbell¹², Edwin K Silverman¹

¹ Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA
² National Jewish Medical and Research Center, Denver, Colorado, USA
³ Oregon Health and Science University, Portland, Oregon, USA
⁴ University of Florida, Gainesville, Florida, USA
⁵ St. Luke’s/Roosevelt Hospital, New York, New York, USA
⁶ Beaumont Hospital, Dublin, Ireland
⁷ University of Nebraska, Omaha, Nebraska, USA
⁸ University of California, San Francisco, California, USA
⁹ University of Texas at Tyler, Tyler, Texas, USA
¹⁰ Cleveland Clinic, Cleveland, Ohio, USA
¹¹ Medical University of South Carolina, Charlottesville, South Carolina, USA
¹² University of Utah, Salt Lake City, Utah, USA

Correspondence to:
Dr Dawn L DeMeo
Channing Laboratory, 181 Longwood Avenue, Boston, Massachusetts 02115, USA; dawn.demeo{at}channing.harvard.edu

Background: Severe ₁-antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.

Methods: The AAT Genetic Modifier Study is a multicentre family-based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV₁) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV₁ <50% predicted).

Results: In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV₁ percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV₁ values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non-index cases (p<0.01). Men had lower pre- and post-bronchodilator FEV₁ percentage predicted than women (p<0.0001); the lowest FEV₁ values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with men representing the majority of non-index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician’s report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men but not women.

Conclusion: In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.

Abbreviations: AAT, ₁-antitrypsin; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity

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