Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype

R H Dougherty, J V Fahy, R H Dougherty, J V Fahy

Abstract

Asthma is a highly prevalent chronic respiratory disease affecting 300 million people world-wide. A significant fraction of the cost and morbidity of asthma derives from acute care for asthma exacerbations. In the United States alone, there are approximately 15 million outpatient visits, 2 million emergency room visits, and 500,000 hospitalizations each year for management of acute asthma. Common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults. Infection of airway epithelial cells with rhinovirus causes the release of pro-inflammatory cytokines and chemokines, as well as recruitment of inflammatory cells, particularly neutrophils, lymphocytes, and eosinophils. The host response to viral infection is likely to influence susceptibility to asthma exacerbation. Having had at least one exacerbation is an important risk factor for recurrent exacerbations suggesting an 'exacerbation-prone' subset of asthmatics. Factors underlying the 'exacerbation-prone' phenotype are incompletely understood but include extrinsic factors: cigarette smoking, medication non-compliance, psychosocial factors, and co-morbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to non-steroidal anti-inflammatory medications; as well as intrinsic factors such as deficient epithelial cell production of the anti-viral type I interferons (IFN-alpha and IFN-beta). A better understanding of the biologic mechanisms of host susceptibility to recurrent exacerbations will be important for developing more effective preventions and treatments aimed at reducing the significant cost and morbidity associated with this important global health problem.

Figures

Figure 1
Figure 1
A cycle of exacerbations and accelerated loss of lung function in asthma: Acute severe exacerbations in susceptible asthmatics activate pathways of inflammation and remodelling resulting in deterioration of lung function. Accelerated loss of lung function in turn puts these patients at increased risk of recurrent exacerbation resulting in a vicious cycle that may promote the exacerbation‐prone phenotype.
Figure 2
Figure 2
Chest radiograph from a 20‐year‐old woman admitted to the intensive care unit for management of acute severe asthma. The chest radiograph shows collapse of the right upper lobe secondary to mucus impaction. The abnormality resolved completely within 24 h of treatment with mechanical ventilation, corticosteroids, and bronchodilators. Reproduced, with permission, from Fahy [102].
Figure 3
Figure 3
Airway casts recovered from bronchoalveolar lavage from an asthmatic subject in acute exacerbation. Reproduced, with permission, from Lang et al. [47].
Figure 4
Figure 4
Model for asthma exacerbation. Viral infection of the epithelium is an important trigger for exacerbation, resulting in the production of pro‐inflammatory cytokines and chemokines, and the recruitment of inflammatory cells to the airway. This inflammatory process may be amplified by extrinsic or intrinsic host factors, such as cigarette smoking, epithelial cell deficiency of IFN‐β or IFN‐λ, or exposure to allergen.

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