© 2005 American Thoracic Society doi: 10.1164/rccm.2501001
Airway RemodelingTherapeutic Target or Not?National Jewish Medical and Research Center Denver, Colorado The concern that asthma is associated with airway remodeling and loss of pulmonary function prompts clinicians to consider early recognition and early intervention (1). However, there are many unanswered questions around airway remodeling, including the following: What are the early indicators? Does it occur suddenly or evolve over time? Is it preventable or possibly reversible with current therapy? Saglani and coworkers (pp. 722–727) address some, but not all, of these questions in an accompanying article by measuring epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation as indicators of airway remodeling and ongoing airway inflammation (2). They conclude that RBM thickening and eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction. Important contributions are being made in areas related to the natural history of asthma, viral infection and asthma, the impact of allergic inflammation, and the genetics of asthma (3). Asthma in young children is no longer considered a benign disease, since it often presents with acute exacerbations. Current guidelines recommend that treatment with antiinflammatory therapy—namely, inhaled corticosteroids—should be considered if an infant meets one of the following criteria: frequent exacerbations together with a positive Asthma Predictive Index, significant exacerbations that occur fewer than 6 weeks apart, or fitting the definition of persistent asthma (1). Although inhaled corticosteroids reduce asthma morbidity, prevention or reversal of airway remodeling may not be affected (1, 4). The features of airway remodeling include subepithelial fibrosis, elevated numbers and volume of mucous cells in the epithelium, increased amounts of airway smooth muscle, and increased vascularization of the airway wall (5). Clearly, it is important to understand the etiology of airway remodeling in asthma to develop therapies that arrest or reverse it (6). Saglani and coworkers (2) evaluated biopsies in young children with a history consistent with asthma, specifically a population of infants who received a clinical bronchoscopy for severe wheeze and/or cough together with a research biopsy. Although the ethics of research biopsies in this age group can be argued, the information obtained could be helpful in understanding early asthma. The limitations of this study are from the subject selection, limited sample analysis, and the questionable diagnosis of asthma. The group of 53 infants with severe wheeze and/or cough was divided into three subgroups: those with decreased specific airways conductance (sGaw) and bronchodilator reversibility, those with decreased sGaw but without bronchodilator reversibility, and those with normal sGaw. Comparisons were made with a group of children with difficult asthma (median age, 10.3 years), children without asthma (median, 10 years), and a group of healthy adult control subjects (median, 27 years). RBM thickness and inflammatory cell number were comparable for the three infant groups with severe wheezing and/or cough. The thickest RBM occurred in the older children with difficult asthma (2, 7). The missing control group would consist of normal infants to provide specific measures of RBM thickness related to the normal aging process. One could argue that there was thickening of RBM in all three groups. Although RBM is a hallmark of asthma, it is not the only feature of airway remodeling. Furthermore, the infants included may not all have had asthma. There is no doubt that airway remodeling can occur in some children, especially those with severe asthma, as indicated by thickened RBM, hypertrophied airway smooth muscle, damaged airway epithelium, and elastin deposition (8). In addition, loss of pulmonary function over time occurs in a subgroup of mild to moderate patients with asthma, consistent with evolving airway pathology (9). Although Saglani and colleagues (2) reported the absence of airway inflammation in the three subgroups of infants, they did not comment on other features of pathology consistent with asthma. This information, together with bronchoalveolar lavage measures of inflammation, would have been useful in differentiating the subgroups from normal children (10–12). It is admittedly difficult to define asthma in young children. However, the Tucson Respiratory Study Group continues to make important observations related to the reduction of pulmonary function and characteristics of infants who go on to develop asthma (13). Whether this reduction in pulmonary function occurs abruptly or gradually between birth and 6 years is not known. Several other long-term studies also show significant reductions in pulmonary function by age 9 years in children with asthma (14, 15). These studies suggest some aspect of airway remodeling is present. A recent study by Pauwels and colleagues (16) indicated that early intervention with inhaled corticosteroids reduces morbidity, but only attenuates ongoing loss of pulmonary function, especially in children aged 5 to 10 years. Saglani and coworkers (2) indicate there is little evidence of airway inflammation or airway remodeling in this young study population, Thus, antiinflammatory therapy is not likely to be successful in early-onset asthma, if prevention of airway remodeling is the target. In Saglani and coworkers' (2) study, one patient with decreased sGaw and bronchodilator reversibility had thickened RBM and airway inflammation. Perhaps this is the type of patient that should be identified and aggressively treated to prevent future severe asthma. Until such predisposing features are established and firm guidelines developed for obtaining bronchoscopy and biopsy with associated treatment recommendations, there is currently no indication for obtaining clinical biopsy solely for asthma evaluation in young children, especially those younger than 2 years. The likelihood of finding features consistent with asthma, at least thickened RBM and inflammation, in the wheezing child who is younger than 2 years with suspected asthma is evidently very low. The observations from this limited cohort prompt the continuous investigation of the natural history of childhood asthma. The advances in imaging, markers of inflammation, and genetics combined with careful follow-up of such patients should help to identify infants destined to develop asthma and, most importantly, severe asthma. As indicated by Sagnali and coworkers (2), it is now important to follow the natural history of possible asthma in this cohort of infants. That will help clarify the current observations. FOOTNOTES Conflict of Interest Statement: S.J.S. has served as a consultant and member of an Advisory Board for GlaxoSmithKline, AstraZeneca (AZ), and Aventis for the last three years and received approximately $6,000 per year from each company, and from Merck for two years at $5,000 per year. He has received research funds for clinical trial performance from AZ for $90,000 for 2002–2004 and from Ross Pharmaceuticals for $1,200,000 for 2003–2005. He has no stock ownership or commercial royalties in any of these companies. REFERENCES
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