Asthma and lower airway disease
Different patterns of exhaled nitric oxide response to β2-agonists in asthmatic patients according to the site of bronchodilation

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Background

In asthmatic patients undergoing airway challenge, fraction of exhaled nitric oxide (Feno) levels decrease after bronchoconstriction. In contrast, model simulations have predicted both decreased and increased Feno levels after bronchodilation, depending on the site of airway obstruction relief.

Objective

We sought to investigate whether β2-agonists might induce divergent effects on Feno values in asthmatic patients as a result of airway obstruction relief occurring at different lung depths.

Methods

Feno, FEV1, and the slope of phase III of the single-breath washout test (S) of He (SHe) and sulfur hexafluoride (SSF6) were measured in 68 asthmatic patients before and after salbutamol inhalation. SHe and SSF6 decreases reflected preacinar and intra-acinar obstruction relief, respectively. Changes (Δ) were expressed as a percentage from the baseline.

Results

No Feno change (|ΔFeno| ≤ 10%) was found in 16 patients (mean [SD]: 2.5% [5.2%]; ie, Feno= group); a ΔFeno value of greater than 10% was found in 23 patients (31.7% [20.3%]; ie, the Feno+ group); and a ΔFeno value of less than −10% was found in 29 patients (−31.5% [17.3%]; ie, the Feno− group). All groups had similar ΔFEV1 values. In the Feno= group neither SHe nor SSF6 changed, in the Feno+ group only SHe decreased significantly (−21.8% [SD 28.5%], P = .03), and in the Feno− group both SHe (−29.8% [24.0%], P < .001) and SSF6 (−27.2% [23.3%], P < .001) decreased.

Discussion

Three Feno behaviors were observed in response to β2-agonists: a decrease likely caused by relief of an intra-acinar airway obstruction that we propose reflects amplification of nitric oxide back-diffusion, an increase likely associated with a predominant dilation up to the preacinar airways, and Feno stability when obstruction relief involved predominantly the central airways. In combination, these results suggest a new role for Feno in identifying the site of airway obstruction in asthmatic patients.

Section snippets

Subjects

Asthmatic patients exhibiting airway obstruction defined according to Global Initiative for Asthma guidelines (FEV1/forced vital capacity ratio < 0.75)17 were recruited from the outpatient asthma clinic (CUB-Erasme University Hospital, Brussels, Belgium). Asthma was defined according to standard criteria.17 Asthma control level at the time of inclusion was evaluated through the Asthma Control Questionnaire.18 Subjects were requested to halt short- and long-acting β2-agonists for 6 and 24 hours,

Results

We recruited a total of 68 asthmatic patients, including 10 who had received a new diagnosis and were yet untreated. After bronchodilation, 16 (23%) patients had a change in Feno values of less than 10% of baseline (Feno= group), 23 (34%) patients had an increase of greater than 10% (Feno+ group), and 29 (43%) patients had a decrease of greater than 10% (Feno− group). Fig 2 shows Feno value changes in the 3 groups.

Discussion

This study documents 3 different patterns of Feno response to β2-agonist action in patients with uncontrolled asthma, and the responses most likely depend on the site of pre-existing airway obstruction. A large proportion of subjects exhibit a Feno value decrease that seems related to the relief of airway obstruction up to the lung periphery (ie, from the central up to the intra-acinar airways), as assessed by changes occurring in ventilation distribution indices. In contrast, a Feno value

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    Chiesi provided a grant for the Immunobiology of Asthma Unit.

    Disclosure of potential conflict of interest: A. Michils has received research support from and is a board member for Chiesi, Novartis, and AstraZeneca; has received lecture fees from AstraZeneca, GlaxoSmithKline, Stallergène, and Chiesi; and has received travel support from Chiesi, GlaxoSmithKline, and Novartis. A. Haccuria has received research support from and is a board member for Chiesi. A. Van Muylem has received research support and lecture fees from Chiesi. The rest of the authors declare that they have no relevant conflicts of interest.

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