Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma

doi:10.1016/j.jaci.2005.09.029

Journal of Allergy and Clinical Immunology

Volume 116, Issue 6, December 2005, Pages 1249-1255

https://doi.org/10.1016/j.jaci.2005.09.029 Get rights and content

Background

The fractional concentration of exhaled nitric oxide (FE_NO) is increased in asthma, correlates with eosinophilic inflammation, and decreases after steroid therapy.

Objective

We sought to examine whether persistent eosinophilia would be accompanied by an increased FE_NO level despite steroid therapy in patients with severe refractory asthma (SRA) as manifestations of steroid resistance.

Methods

Subjects with SRA, subjects with mild-moderate asthma, and healthy control subjects had FE_NO measured, followed by endobronchial biopsy and bronchoalveolar lavage. Tissue and bronchoalveolar lavage inflammatory cells were assessed for all subjects, and eosinophil status (EOS⁺/EOS⁻) was determined for subjects with SRA.

Results

Twenty-four subjects with SRA, 15 subjects with moderate-mild asthma, and 17 healthy control subjects were studied. Subjects with EOS⁺ SRA had significantly higher median FE_NO levels compared with levels in subjects with EOS⁻ SRA (P = .0084) and all other groups. In subjects with SRA, FE_NO levels correlated with tissue eosinophils (r_s = 0.54, P = .007), lymphocytes (r_s = 0.40, P = .003), and mast cells (r_s = 0.44, P = .05). FE_NO levels of greater than 72.9 ppb were associated with a sensitivity of 0.56 and a specificity of 1.0 for EOS⁺ status in subjects with SRA.

Conclusion

FE_NO measurement identified the subgroup of subjects with SRA with persistent eosinophilia despite steroid therapy. Further studies are needed on the use of FE_NO to monitor response to therapy over time in subjects with SRA.

Section snippets

Study design

This was a cross-sectional study at a single time point looking at the relationship between exhaled NO and bronchoscopic parameters of inflammation.

Subjects

Subjects with asthma of various severities who were referred to National Jewish Medical and Research Center for evaluation were recruited together with healthy control subjects. They underwent history and physical examination, lung function testing (short-acting bronchodilators and long-acting bronchodilators were held for 4 hours and 12 hours,

Subject characteristics

Twenty-four subjects with SRA, 4 subjects with moderate asthma, 11 subjects with mild asthma, and 17 healthy control subjects were studied. This article reports only subjects with both FE_NO measurement and a bronchoscopy: for EOS⁺ SRA, 8 of 10 underwent BAL, and 8 of 10 underwent EBBX (different missing subjects); for EOS⁻ SRA, 14 of 14 underwent BAL, and 12 of 14 underwent EBBX. All 14 subjects with mild-moderate asthma and all control subjects underwent both procedures. Eleven of 14 subjects

Discussion

In this study FE_NO measurement identified the persistent eosinophilic phenotype in subjects with SRA despite therapy with inhaled and systemic steroids. Correspondingly, FE_NO levels correlated with eosinophilic inflammation in the SRA group but not in the subjects with mild-moderate asthma, probably because of more significant suppression of both eosinophilia and exhaled NO by ICSs. Exhaled NO levels also correlated with tissue lymphocyte and mast cell counts in SRA, with no significant

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: Supported by National Heart, Lung, and Blood Institute grant no. HL64087A-400600RR-00051.

View full text

Mechanisms of asthma and allergic inflammationExhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma

Background

Objective

Methods

Results

Conclusion

Section snippets

Study design

Subjects

Subject characteristics

Discussion

J Allergy Clin Immunol

Chest

Immunol Today

Biochem Biophys Res Commun

J Allergy Clin Immunol

Lancet

Cytokine

Biochem Pharmacol

Blood

J Allergy Clin Immunol

Lancet

J Pediatr

Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society

Am J Respir Crit Care Med

NIH conference. Airway inflammation

Ann Intern Med

Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics

Am J Respir Crit Care Med

Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids

Am J Respir Crit Care Med

Increased amount of nitric oxide in exhaled air of asthmatics

Eur Respir J

Exhaled nitric oxide and bronchial reactivity during and after inhaled beclomethasone in mild asthma

J Asthma

Increased formation of the potent oxidant peroxynitrite in the airways of asthmatic patients is associated with induction of nitric oxide synthase: effect of inhaled glucocorticoid

FASEB J

Correlation between exhaled nitric oxide, sputum eosinophils, and methacholine responsiveness in patients with mild asthma

Thorax

Comparison of airway immunopathology of eosinophilic bronchitis and asthma

Thorax

Mechanisms of asthma and allergic inflammation
Exhaled nitric oxide identifies the persistent eosinophilic phenotype in severe refractory asthma