Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

Large scale epidemiologic studies of lung function in asthma over time generally measure lung function annually, suggesting that there is an annual linear rate of decline in lung function. However, studies comparing asthmatics who have frequent acute asthma exacerbations versus those who do not have suggests that asthma exacerbations may trigger a step-wise decrease in lung function in asthma over time in a subset of genetically predisposed individuals. 3 For example, a cohort study of 93 non-smoking asthmatics followed for over 5 years, showed that asthmatics with frequent asthma exacerbations had a significantly larger annual decline in FEV1 compared to those with infrequent asthma exacerbations (median difference,16.9 mL/year; 95% CI, 1.5-32.2). 67 In addition, severe asthma exacerbations predicted an excess decline in FEV1, such that 1 severe asthma exacerbation per year was associated with a 30.2 mL greater annual decline in FEV1. 67 In another study of 128 nonsmoking well-controlled asthmatics followed up for 3-years, FEV1 also declined according to the number of asthma exacerbations (no exacerbation, 13.6 mL/year; 1 exacerbation, 41.3 mL/ year; 2 or more exacerbations, 58.3 mL/year). 68 The changes in bronchodilator reversibility were also significantly correlated with the annual rates of change in FEV1. 68 Using linear modeling analysis, a recent study of severe eosinophilic asthmatics estimated lung function decline per asthma exacerbation was 50mL in FEV1. 69 There is also some evidence that preventing acute exacerbations in asthma can reduce decline in lung function in asthma. For example, using inhaled corticosteroid treatment as a regular therapy in early asthma demonstrated that low doses of inhaled corticosteroid were associated with attenuation of decline in lung function. 70 In the placebo-treated group of asthmatics, decline in lung function was significantly greater in those who had a severe asthma exacerbation (−6.44% of FEV1%) than in those who did not (−2.43% of FEV1%). 70 In contrast, in the inhaled corticosteroid-treated group of asthmatics, decline in lung function was much less in those who had severe asthma exacerbation (−2.48% of FEV1%) or who did not (−1,72% of FEV1%) than in the placebo-treated group of asthmatics (−6.44% of FEV1%). 70 Therefore, adequate asthma treatment with inhaled corticosteroids may reduce not only the frequency of asthma exacerbations, but also decline in lung function associated with asthma exacerbations.