DENVER—Our current understanding of asthma assumes that most of its features—dyspnea, wheezing, bronchial hyperresponsiveness, and ultimately, structural changes—stem from airway inflammation. Yet, not all patients with asthma respond to corticosteroids and other anti-inflammatory agents. Further evidence that additional pathways must be involved in the disease’s pathogenesis comes from a recent case series of six children, five of whom had severe, difficult-to-control asthma despite having minimal or no airway inflammation.[1] Yet, all six children had evidence of airway remodeling.

Changes in airway architecture are generally believed to progress gradually in patients with poorly controlled asthma, becoming prominent only in adulthood. The study demonstrates, however, that airway remodeling can occur in young children with severe asthma, noted principal researcher Joseph D. Spahn, MD, an Associate Professor of Pediatrics at National Jewish Center for Immunology and Respiratory Medicine in Denver. He and his colleagues found significant remodeling in children as young as 6 years despite the fact that all of the children had been treated with both high-dose inhaled and oral corticosteroids for much of their lives. “This suggests,” said Dr. Spahn, “that steroid-independent mechanisms occur with repair.” Nevertheless, the children had close-to-normal lung function, he pointed out. “That argues against a clear structure/function relationship” between airway architecture and airflow.

The six children were between the ages of 6 and 17. All of the children had difficult-to-control asthma despite aggressive anti-inflammatory therapy; their inhaled corticosteroid doses ranged from 1,000 to 3,750 µg/d. Four of the children had had at least one previous severe exacerbation requiring intubation. On admission, mean FEV1 was 69.5% of predicted.

The researchers performed bronchoscopy and endobronchial biopsy in each child. In only one was the airway mucosa markedly inflamed and friable. In the other five children, only mild and patchy lymphocytic infiltration in the tissues immediately below the subbasement membrane was seen. There were few or no eosinophils or neutrophils.

Nevertheless, moderate to severe thickening of the basement membrane was evident in all patients. Goblet-cell hyperplasia was observed in four of six samples. Although biopsy depths were not always adequate to sample all layers, hyperplasia was evident in smooth muscle in four of five samples and in submucosal glands in four of four samples. Despite these findings, all of the children achieved normal FEV1 measurements after treatment.

“In five of six cases, there was no evidence for inflammation,” Dr. Spahn emphasized. He added, “Steroids do a lot of good things for asthma, but they didn’t prevent the development of significant airway remodeling in these six kids.” As Dr. Spahn also noted, “In this small group of children with severe asthma, … there wasn’t a good relationship between loss of lung function and thickness of the basement membrane.” Thus, the functional significance of airway remodeling remains unclear.

—Mimi Zucker, PhD