Allergen inhalation challenge, refractoriness and the effects of ibuprofen

Shawn Nomani, Donald W Cockcroft, Beth E Davis, Shawn Nomani, Donald W Cockcroft, Beth E Davis

Abstract

Background: Bronchoprovocation challenges use direct or indirect acting stimuli to induce airflow obstruction. Indirect stimuli either non-allergic/non-IgE mediated (e.g. exercise, mannitol) or allergic/IgE mediated (i.e. allergen) trigger mast cells to release bronchoconstricting mediators (e.g. cysteinyl leukotrienes, histamine). Performing repeat challenges within a short timeframe (e.g. 3 h) with non-allergic indirect stimuli results in a diminished, refractory response to the second challenge that is inhibited by non-steroidal anti-inflammatory medications. Cross refractoriness occurs between indirect stimuli. It follows that repeat bronchoprovocation with allergen might exhibit refractoriness that might be altered by ibuprofen. We assessed the response to a second allergen challenge performed 24 h after an initial allergen challenge to determine if the response is refractory. If refractoriness developed, the study aimed to determine whether a single dose of ibuprofen would alter the refractory response to the second allergen challenge. In the absence of a refractory response, the study design allowed for the assessment of the effect of ibuprofen on allergen challenge outcomes, including indices of airway inflammation.

Methods: Thirteen mild atopic asthmatics were enrolled in a randomized, double-blind, placebo controlled, cross-over study. Ibuprofen (400 mg) or placebo was administered 1 h prior to the first of two allergen challenges, performed 24 h apart. Blood and sputum eosinophils, airway responsiveness to methacholine and levels of fractional exhaled nitric oxide were assessed before and 7 h after each allergen challenge. All data were log transformed and differences in geometric means were analyzed by paired t-tests.

Results: After placebo, early asthmatic responses for the two challenges were not significantly different (p = 0.82). A single 400 mg dose of ibuprofen decreased both the early (p = 0.03; n = 12) and late asthmatic responses (p = 0.03; n = 3).

Conclusion: Allergen challenges conducted 24 h apart do not exhibit refractoriness. Single dose ibuprofen inhibits early and late asthmatic responses to allergen bronchoprovocation. Ibuprofen should be withheld for at least 24 h prior to investigations utilizing allergen bronchoprovocation. Trial registration clinicaltrials.gov #NCT02327234.

Keywords: Allergen challenge; Ibuprofen; Refractoriness.

Figures

Fig. 1
Fig. 1
Early asthmatic responses to the four allergen challenges. The data on the left (Placebo AC1 and AC2) depicts the absence of refractoriness. The data on the right shows the inhibitory effect of ibuprofen (ibuprofen AC1 versus placebo AC1) and the duration of the inhibition (ibuprofen AC1 versus ibuprofen AC2). Data are presented as the geometric mean allergen PC20. Error bars represent the standard error of the mean SEM. The time interval between AC1 and AC2 for each treatment is 24 h
Fig. 2
Fig. 2
Inhibitory effect of ibuprofen on the late asthmatic response in 3 (a) and 5 (b) late responders. Data are presented as the geometric mean allergen PC15. Error bars represent the standard error of the mean SEM

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