Development of Predictive Models for Airflow Obstruction in Alpha-1-Antitrypsin Deficiency

Abstract

Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002-2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV(1)) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV(1) and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV(1) explained 50% of the variance in FEV(1), and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).

PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD

“…Consistent with this, we have shown in a relatively small cohort (n=63), matched for smoking status, that PiSZ patients exhibit less severe lung disease than PiZZ 8. Even low levels of smoke exposure may be deleterious to lung function in PiZZ patients; however, an important threshold may occur at 20 pack-years, above which associations between FEV1 and pack-years are less apparent 9. Whether this differs in PiSZ patients is unknown, and little is known about their prognosis.…”

“…A direct relationship between FEV1 and smoke exposure occurred below 30 pack-years in PiSZ and 20 pack-years in PiZZ patients. The reasons for this are discussed elsewhere,9 one of which is a ‘floor effect’, in which lung function has dropped sufficiently by the threshold that in many patients either no further decline occurs or they die. A smaller amount of ‘resistant’ smokers is also seen, adding to the lack of correlation at higher smoke exposures.…”

Alpha-1-Antitrypsin Deficiency in Children: Case Series

“…При мутации М-субтипов произошли остальные аллели. Среди них выделяют нормальные (Christschurch, B, F, Х, M4, PSt.albans) и редкие аномальные (S и Z) аллели [3,20,21]. Плазменная концентрация А1АТ у носителей Z-мутации составляет 10-20% от нормы за счет полимеризации низкомолекулярного гликопротеида.…”

“…По данным L. Fregonese, у курящих пациентов эмфизема развива-ется в возрасте 30-40 лет, у некурящих -в 50-70 лет [33]. При наличии хронической обструктивной болезни легких и бронхиальной астмы необходимо исследование гена PI на наличие носительства дефицитных аллеей [21]. Дефицит А1АТ при наличии патологии бронхолегочной системы диагностируется крайне редко по причине низ-кой осведомленности практикующих врачей различных специальностей о распространенности дефицита А1АТ, ложных представлений взаимоисключающих диагнозов бронхиальной астмы и дефицита А1АТ, а также изолиро-ванных проявлений каждого из заболеваний [26].…”

Genes and Chronic Obstructive Pulmonary Disease

“…In subjects with severe AAT deficiency, the development of airflow obstruction is associated with age, male sex, bronchodilator responsiveness and chronic bronchitis, and -most strongly- cigarette smoke 45–47 .…”