Asthma, Rhinitis, Other Respiratory Diseases
Both inflammation and remodeling influence nitric oxide output in children with refractory asthma

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Abstract

Background

Exhaled nitric oxide can be used to monitor airway inflammation in asthma. We hypothesized that the strong link between nitric oxide and inflammation may obscure a weaker link with airway remodeling.

Objective

The aim of this study was to determine whether airway remodeling influenced exhaled nitric oxide in 28 asthmatic children (median age [25th-75th], 11 [10-14] years old) with refractory asthma defined as airflow limitation and/or exacerbations despite high-dose inhaled steroids.

Methods

Multiple-flow analysis of exhaled nitric oxide was used to correlate alveolar nitric oxide concentration and maximal conducting airway nitric oxide output to pulmonary function tests, bronchoalveolar lavage, and bronchial biopsy findings.

Results

Nitric oxide measurements were related to inflammation and TH1/TH2 balance, that is, subepithelial eosinophilic infiltration and eosinophilic cationic protein and IFN-γ/IL-4 ratio in bronchoalveolar lavage fluids. Nitric oxide measurements were also correlated with several parameters of airway remodeling: alveolar nitric oxide concentration with TGF-β in bronchoalveolar lavage fluid (r = 0.42, P = .03) and maximal conducting airway nitric oxide output with reticular basement membrane thickness (r = 0.61, P = .0007) and tissue inhibitor of matrix metalloproteinases 1/matrix metalloproteinase 9 ratio in bronchoalveolar lavage fluid (r = 0.43, P = .04). Moreover, alveolar nitric oxide concentration was correlated with MEF25-75 (r = 0.60, P = .02).

Conclusions

These findings suggest that both subacute inflammation and remodeling influence nitric oxide output in refractory asthma.

Section snippets

Patients

Children with refractory asthma were included prospectively and investigated by fiberoptic bronchoscopy. The diagnosis of asthma was based on clinical symptoms and history of reversible airflow limitation. In accordance with the recent ATS workshop, refractory asthma was defined as presence of the major criterion, for example, need for high-dose inhaled corticosteroids and at least 2 of the following 5 minor criteria: (1) requirement for daily long-acting β-agonist or leukotriene antagonist in

Patients, pulmonary function testing

Twenty-eight children (16 boys and 12 girls) were enrolled (median age, 11 years; range, 10 to 14 years). All had asthma since early childhood and were atopic, as defined by one or more positive skin tests. All were receiving beclomethasone (1000 μg/d) or equivalent (major inclusion criterion) and a long-acting β-agonist (22 children) or leukotriene antagonist (6 children) (first minor inclusion criterion). The second minor criteria were (1) persistent airway obstruction defined as FEV1 < 80%

Discussion

In children with asthma, bronchoscopy, and BB are appropriate only to clarify the diagnosis and to assist in treatment decisions for patients with poorly controlled disease. The patients in this study were children with refractory asthma, for example, with frequent symptoms and/or airflow obstruction despite maximal conventional therapy. We examined relations between multiple-flow measurements of exhaled NO and evidence of airway inflammation or remodeling obtained by bronchoscopy and BB. Our

Acknowledgments

The authors wish to thank SERES Industry for providing the NO analyzer.

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