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Determinants of Airflow Obstruction in Severe Alpha 1- Antitrypsin Deficiency
  1. Dawn L DeMeo (redld{at}
  1. Brigham & Women's Hospital/Harvard Medical School, United States
    1. Robert A Sandhaus
    1. National Jewish Medical and Research Center, United States
      1. Alan F Barker
      1. Oregon Health and Science University, United States
        1. Mark L Brantly
        1. University of Florida, Gainesville, United States
          1. Edward Eden
          1. St. Luke's-Roosevelt Hospital, United States
            1. N. Gerard McElvaney
            1. Beaumont Hospital, Republic of Ireland
              1. Stephen Rennard
              1. University of Nebraska, United States
                1. Esteban Burchard
                1. University of California, United States
                  1. James M Stocks
                  1. University of Texas at Tyler, United States
                    1. James K Stoller
                    1. Cleveland Clinic, United States
                      1. Charlie Strange
                      1. University of South Carolina, United States
                        1. Gerard M Turino
                        1. St. Luke's-Roosevelt Hospital, United States
                          1. Edward J Campbell
                          1. University of Utah, United States
                            1. Edwin K Silverman
                            1. Brigham & Women's Hospital, United States


                              Rationale: Severe alpha 1-antitrypsin deficiency is an autosomal recessive genetic condition associated with an increased, but variable, risk for chronic obstructive pulmonary disease (COPD).

                              Objective: To assess the impact of chronic bronchitis, pneumonia, asthma, and sex on the development of COPD in individuals with severe alpha 1- antitrypsin deficiency. Methods: The Alpha 1-Antitrypsin Genetic Modifier Study is a multi-center family-based cohort study designed to study the genetic and epidemiological determinants of COPD in alpha 1-antitrypsin deficiency. 378 individuals (age range: 33-80), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses.

                              Measurements and Main Results: The primary outcomes of interest were a quantitative outcome, forced expiratory volume in one second (FEV1) as a percent of predicted, and a qualitative outcome, severe airflow obstruction (FEV1 < 50% predicted). In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percent predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories, and more reports of asthma, pneumonia, and asthma before age 16 compared to non-index cases (p<0.01). Men had lower pre and post- bronchodilator FEV1 percent predicted measures than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9% +9.1). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with males representing the majority of non- index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI: 1.8-12.0) and a physician's report of asthma (OR 4.2, CI: 1.4-13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men not women.

                              Conclusion: In individuals with severe alpha 1- antitrypsin deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that amongst severely AAT deficient subjects, men, individuals with symptoms of asthma or chronic bronchitis, and/or a past diagnosis of pneumonia may benefit from closer monitoring and potentially earlier treatment.

                              • Alpha 1-Antitrypsin Deficiency
                              • COPD
                              • asthma
                              • epidemiology
                              • sex

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