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* From the Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, Divisions of Clinical Pharmacology (Drs. Jenkins, Szefler, Covar, and Spahn), Allergy-Clinical Immunology (Dr. Gelfand), and Pediatric Pulmonology (Dr. Brugman), National Jewish Medical and Research Center, Denver; and the Department of Pathology (Dr. Cool), University of Colorado Health Sciences Center, Denver, CO.
Correspondence to: Joseph D. Spahn, MD, National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson St (K-926), Denver, CO 80206
Background: To date, little has been published describing the pathology of severe childhood asthma. The currently accepted model of asthma holds that persistent airway inflammation leads to various symptoms of asthma, airway hyperresponsiveness, and airway remodeling that ultimately results in permanent loss of lung function.
Methods: Evaluation of six children referred to the National Jewish Medical and Research Center with difficult-to-control asthma, despite aggressive anti-inflammatory therapy, who underwent bronchoscopy with endobronchial biopsy to better characterize their disease.
Results: In every case, endobronchial biopsies revealed changes consistent with airway remodeling characterized by thickening of the basement membrane, smooth-muscle hypertrophy, with varying degrees of goblet-cell and submucous gland hyperplasia. The degree of subbasement membrane thickening did not appear to correlate with baseline FEV1, ultimate FEV1 following aggressive therapy, or lability in lung function. In five of six cases, there was minimal to no histologic evidence for airway inflammation with mild and patchy submucosal lymphocytic infiltration noted; eosinophils and neutrophils were not present. Further, the majority of the patients achieved normal FEV1 values despite significant subbasement membrane thickening, counter to the current beliefs regarding airway remodeling and irreversible loss of lung function.
Conclusions: This case report highlights some of the shortcomings of the current inflammatory paradigm for severe asthma. Despite little evidence of ongoing airway inflammation, many of the subjects displayed significant lung function lability. The lack of inflammation argues against steroid resistance at a cellular level, although it could be argued that inflammation may have been distal to the site sampled. Additionally, normal to nearly normal lung function was achieved despite the presence of significant remodeling. These findings suggest the need to look beyond inflammation to fully treat severe asthma and ultimately alter its progression.
Key Words: airway inflammation • airway remodeling • glucocorticoids • severe asthma
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