Use of a vibrating mesh nebulizer for allergen challenge.

BACKGROUND: Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges. METHODS: Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (µg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks. RESULTS: All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 µg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003). CONCLUSION: The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.Trial registration clinicaltrials.gov: NCT03491358.

Methacholine Challenge Testing: A Novel Method for Measuring PD20.

BACKGROUND: New guidelines for methacholine challenge testing recommend reporting the test outcome as dose rather than concentration. Jet nebulizers have historically been used for methacholine challenge testing, but much of the weight loss, often (incorrectly) referred to as aerosol output, is actually evaporation. The Wright nebulizer is well characterized and still widely used, but its availability is unclear, and it is nondisposable. We developed a novel method using a vibrating mesh nebulizer (Solo). This method was compared with the standard 2-min tidal breathing method using the Wright nebulizer. Repeatability within and between nebulizers was also tested. METHODS: Fifteen patients with mild asthma completed four methacholine challenges (two with the Solo vibrating mesh nebulizer and two with the Wright jet nebulizer). Challenges with the same nebulizer were 24 h apart, and challenges between nebulizers were separated by 1 week. Standard 2-min tidal breathing methods were used with the Wright nebulizer. For the Solo nebulizer, the tidal breathing method was modified by nebulizing to completion 0.5 mL of doubling concentrations of methacholine at 5-min intervals. RESULTS: Geometric mean methacholine doses required to cause a 20% fall in FEV1 were similar (96 vs 110 µg; P > .05); methacholine concentrations that caused a 20% fall in FEV1 were significantly lower with the vibrating mesh nebulizer (0.48 vs 4.4 mg/mL; P < .001). Repeatability of methacholine doses required to cause a 20% fall in FEV1 within and between nebulizers was excellent (intraclass correlation coefficient > 0.92). CONCLUSIONS: We have developed a novel, simple, repeatable method for conducting methacholine challenges using new nebulizer technology. Importantly, the method meets recommendations set out in the new guidelines. TRIAL REGISTRY: ClinicalTrials.gov; No.: 02965482; URL: www.clinicaltrials.gov.

Allergen inhalation challenge, refractoriness and the effects of ibuprofen.

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.

Past, present and future uses of methacholine testing.

Methacholine challenge testing is a valuable diagnostic and research tool used by clinicians to assist in the diagnosis of asthma, and by researchers to understand disease pathophysiology and assess novel therapeutic efficacy. The use of methacholine challenge in asthma relates to its direct effect on airway smooth muscle (i.e., bronchoconstriction) as a measure of airway hyperresponsiveness, a cardinal feature of asthma. Airway hyperresponsiveness has been documented in other airway disorders, including chronic obstructive pulmonary disease, cystic fibrosis and allergic rhinitis; however, there is little clinical application of methacholine challenge in these conditions as a diagnostic or disease management tool. The authors will review the aspects of methacholine challenge testing, as they relate to asthma, and point out its usefulness in clinical research. A brief review of past (historical) uses and speculation as to the future uses of methacholine challenge will also be discussed.

Diagnostic and therapeutic value of airway challenges in asthma.

Airway challenges are of value in the assessment of asthma. Direct challenges (histamine and methacholine) are highly sensitive for clinically current symptomatic asthma and particularly useful to exclude current asthma when they are negative. Indirect challenges (exercise, eucapnic voluntary hyperventilation, adenosine monophosphate, hypertonic saline, mannitol) are more specific but very insensitive for clinical asthma. They are of particular value to confirm asthma and to differentiate asthma from other airway diseases, such as chronic airflow limitation. The indirect stimuli are the challenges of choice for evaluating exercise-induced bronchoconstriction.