Airway hyperresponsiveness in asthma: mechanisms, clinical significance, and treatment

Abstract

Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either "direct" or "indirect," referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.

Keywords: airway hyperresponsiveness; asthma; bronchial provocation; diagnosis; pharmacotherapy.

Figure 1

A schematic demonstrating the mechanism of action of common bronchoconstricting stimuli delivered as standardized bronchial provocation tests in the research and clinical setting.

Figure 2

The relationship between the airway sensitivity to inhaled methacholine and mannitol compared to the percentage (%) of eosinophils in sputum in a selected group of steroid naïve asthmatic subjects. Airway hyperresponsiveness (AHR) to mannitol is defined as a 15% reduction in the forced expiratory volume in 1 s (FEV₁) to a cumulative dose of less than 635 mg (PD₁₅); for methacholine as a 20% reduction in FEV₁ to less than eight micromoles (PD₂₀). The relationship of % eosinophils with those who had a positive AHR (closed circles) was significant for mannitol (r_p = −0.52, p < 0.05) compared to methacholine (r_p = −0.28, p = ns). Those who had no AHR to either mannitol or methacholine (open squares) in this group of subjects had significantly less sputum eosinophils (adapted from Porsbjerg et al., 2008).

Figure 3

The relationship between the airway sensitivity to inhaled methacholine and mannitol compared to the fraction of exhaled nitric oxide (FeNO) in parts per billion (ppb) in a selected group of steroid naïve asthmatic subjects. Airway hyperresponsiveness (AHR) to mannitol is defined as a 15% reduction in the forced expiratory volume in 1 s (FEV₁) to a cumulative dose of less than 635 mg (PD₁₅); for methacholine as a 20% reduction in FEV₁ to less than eight micromoles (PD₂₀). The relationship of FeNO with those who had a positive AHR (closed circles) was more significant for mannitol (r_p = −0.63, p < 0.001) compared to methacholine (r_p = −0.43, p < 0.05). There were a proportion of subjects with AHR that had normal FeNO values (adapted from Porsbjerg et al., 2008).

Figure 4

A summary of the improvement in AHR following treatment with inhaled corticosteroids (ICS) expressed as a provoking dose (PD20) or provoking concentration (PC20) to cause a 20% fall in FEV1 from six studies using either histamine or methacholine (du Toit et al., ; Lim et al., ; Sont et al., ; Reddel et al., ; Foresi et al., ; Jenkins et al., 2005). Significant AHR to direct stimuli remains in the presence of high doses of ICS over short- and long-term treatment periods.

Figure 5

The provoking dose of mannitol to cause a 15% fall in FEV₁ (PD₁₅) following short-term (6–9 weeks) and long-term (6 months) treatment with inhaled corticosteroids (ICS; Brannan et al., ; Koskela et al., 2003). Following 6–9 weeks 7/18 subjects had no PD₁₅. Following 6 months treatment 10/17 subjects had no PD₁₅ and the airway reactivity was within the non-asthmatic range, however four subjects with a PD₁₅ at 6 months had no PD₁₅ at 3 months. AHR in individuals on ICS who were once negative to mannitol can result following a decrease in ICS dose (Leuppi et al., 2001) and suggest these subjects may have decreased ICS adherence.