Provocation of nonallergic rhinitis subjects in response to simulated weather conditions using an environmental exposure chamber model

Abstract

Nonallergic rhinitis (NAR) subjects present clinically with similar symptoms to subjects with allergic rhinitis, but which mechanistically are not IgE- mediated. NAR is difficult to study because of multiple, as yet unknown, disease mechanisms and lack of biomarkers and diagnostic tests. The purpose of this proof of concept pilot study was to develop an environmental exposure chamber (EEC) model to simulate weather conditions in a controlled setting to objectively diagnose NAR subjects and ultimately to investigate novel NAR therapies. Thirty-seven subjects with a history of NAR confirmed by negative skin-prick test to a panel of aeroallergens were tested with cold dry air (CDA) and temperature change challenges. Objective (acoustic rhinometry [AcR] and nasal secretions) and subjective measures (total nasal symptom scores [TNSSs]: congestion, rhinorrhea, and postnasal drip [0-3]) were collected. Data was presented as mean ± SEM and statistical significance was assessed by paired t-test. The NAR EEC AcR responders to CDA had a significant decrease in mean minimal cross-sectional area (MCA; a measure of nasal patency) of 22.2 ± 2.43% (p < 0.0001) and 6.7 ± 7.22% (not statistically significant) at 30 and 60 minutes, respectively, with a concomitant increase in TNSS of 1.0 ± 0.24 U and 1.4 ± 0.30 U, respectively. AcR responders to temperature change showed a significant decrease in mean MCA to warm air of 16.0 ± 3.82% (p < 0.001) and 19.4 ± 3.88% (p < 0.0001) at 30 and 60 minutes, respectively, with an increase of TNSS of 0.4 ± 0.25 U and 0.4 ± 0.27 U, respectively. With rapid conversion to cold air, further decrease in mean MCA accompanied by an increase in TNSS was observed at 30 and 60 minutes. Increase in rhinorrhea was highest for CDA and the cold air phase of the temperature change challenge. Using the NAR EEC model, significant symptoms were induced in response to simulated weather changes in NAR patient responders. This proof of concept pilot study shows that the EEC model provides a consistent and reliable method to phenotype weather-induced NAR subjects that could be used to investigate disease mechanisms and novel therapies for NAR.

Correlation between a pollen challenge chamber and a natural allergen exposure study design for eliciting ocular and nasal symptoms: Early evidence supporting a paradigm shift in drug investigation?

“…Studies have been conducted for cat-and dust mite-induced perennial allergic rhinitis, and more recently, the feasibility of using an EEU to characterize more complex disorders, such as nonallergic rhinitis, subjectively by using symptom scores and objectively by using changes in nasal resistance with acoustic rhinometry in response to cold dry air and a temperature change (warm air / cold dry air) has been demonstrated. 11,13,15 Similar to the PCC study by Jacobs et al, 10 which identified distinct endotypes, supporting the need to include provocation as a criteria for patient selection, the nonallergic rhinitis chamber study found that a significant number of subjects who self-reported symptoms in response to cold dry air or temperature change did not elicit a response to cold dry air/ temperature change provocation, as predicted. 10,15 The study by Jacobs et al 10 represents the first important step in validating the utility of EEUs for multicenter clinical drug trials.…”

“…11,13,15 Similar to the PCC study by Jacobs et al, 10 which identified distinct endotypes, supporting the need to include provocation as a criteria for patient selection, the nonallergic rhinitis chamber study found that a significant number of subjects who self-reported symptoms in response to cold dry air or temperature change did not elicit a response to cold dry air/ temperature change provocation, as predicted. 10,15 The study by Jacobs et al 10 represents the first important step in validating the utility of EEUs for multicenter clinical drug trials.…”

Chemical-induced asthma and the role of clinical, toxicological, exposure and epidemiological research in regulatory and hazard characterization approaches

“…In fact, a recent study that reclassified chronic rhinitis patients with a physician diagnosis of allergic, mixed (allergic and non-allergic triggers) or non-allergic rhinitis using an irritant index scale found that a significant percentage of patients previously diagnosed with allergic rhinitis actually had mixed rhinitis. Furthermore, these mixed rhinitis patients with a high irritant index score had a greater prevalence of physician diagnosed asthma suggesting that chemical irritants in conjunction with allergen triggers compared to allergen triggers alone may contribute to disease severity (Bernstein et al, 2012). …”

“…Environmental exposure chambers can be used to expose patients to allergic and non-allergic asthma triggers (e.g., cold air; Bernstein et al, 2012). Responses are generally heterogeneous but these challenges can confirm what is learned from the patient’s history (Pfaar et al, 2017).…”

A Pilot Study Investigating Clinical Responses and Biological Pathways of Azelastine/Fluticasone in Nonallergic Vasomotor Rhinitis before and after Cold Dry Air Provocation

“…Bilateral ocular conjunctival redness was also assessed by trained staff before challenge based on a validated descriptive and photographic scale ranging from 0 to 4 in increments of 0.5 [23]. Subjects then entered the EEC and underwent CDA provocation (14 ± 5°C, <15% relative humidity, ×1 h) as described by Bernstein et al [24]. Four randomized NAVMR subjects were challenged simultaneously with CDA, which was directed into their face using air velocity tubes at a rate of 5 ± 3 ft/s, simulating a natural exposure similar to cold windy days.…”