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

Abstract

Background: Nonallergic vasomotor rhinitis (NAVMR) has been considered a diagnosis by exclusion due to unknown mechanisms or lack of diagnostic biomarkers. Methods: To determine clinical responses and biological pathways in NAVMR subjects challenged to cold dry air (CDA) in an environmental exposure chamber (EEC) pre- and posttreatment with azelastine/fluticasone (AzeFlu), 30 NAVMR subjects, prescreened for CDA-induced symptoms (approx. 14°C, <15% relative humidity, ×1 h) were randomized to treatment with AzeFlu (n = 20) or placebo (n = 10) for 2 weeks. Total nasal symptoms scores, minimum cross-sectional area, cough, and conjunctival redness were recorded at visit 1 (pretreatment) and visit 2 (posttreatment) before, during, and after CDA challenge. At both visits, nasal lavage fluid (NLF) and nasal scrapings (NS) were collected pre- and post-CDA challenge. Substance P, neurokinin-A, and calcitonin gene-related peptide concentrations in NLF were analyzed pre- and postchallenge at each visit. Their relationship with CDA-induced symptoms was determined by statistical analysis. MicroRNA sequencing from NS determined differentially expressed miRNA between the treatment groups post-CDA challenge at each visit. Results: The minimum cross-sectional area (p < 0.05), cough count (p < 0.05), and substance P (p < 0.01) improved posttreatment with AzeFlu versus placebo. Gene targets for differentially expressed miRNAs at visit 1 were enriched for biological pathways regulating epithelial ciliogenesis and cell integrity that were modified in the AzeFlu-treated group versus placebo posttreatment. Conclusions: This study demonstrated the feasibility of an EEC model to investigate CDA-induced clinical responses and pathobiology in NAVMR subjects pre- and posttreatment with AzeFlu. NAVMR disease mechanisms for other nonallergic triggers can be investigated similarly.

Rhinitis 2020: A practice parameter update

“…Cough is also a common component of VMR. 77 ''Idiopathic rhinitis'' is sometimes used as an alternative term to VMR and usually excludes NARES. 78 However, the term is confusing as some studies have found high levels of eosinophils and mast cells in some patients categorized as having idiopathic rhinitis.…”

“…Nasal challenge for VMR, to determine nasal hyperresponsiveness (eg, using cold dry air or hypertonic saline in a challenge chamber), may be used in research to assess drug efficacy but is rarely used for clinical diagnosis. 77,80 More recently, optical rhinometry with intranasal capsaicin challenge has been demonstrated to assist in the diagnosis of a subset of patients with VMR and nonallergic irritant rhinitis. 81 While the pathophysiology of VMR is not fully understood, there is evidence that it involves a neurogenic pathway with an increase in neural efferent traffic to the nasal mucosa with an imbalance between parasympathetic and sympathetic nasal innervation.…”

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023

“…The trigeminal nerve has nociceptive Aδ and C fibers that are stimulated by physical and chemical ligands as well as products of allergic reactions 562 . Inflammatory mediators (e.g., bradykinin, histamine, acetylcholine, and capsaicin) are capable of activating sensory neurons in the trigeminal nerve, largely through TRP ion channels 563–566 . Through repeated depolarization, lasting changes develop in TRP channels as demonstrated for the TRP cation channel subfamily V member 1 (TRPV1) and subfamily A member 1 (TRPA1).…”

“…Depolarization of these nociceptive channels on sensory nerves leads to the release of neuropeptides including substance P, CGRP, and neurokinin‐A 564 . Substance P receptors are located on nasal epithelium, glands, and arterial and venous vessels, and sinusoidal vessels, which leads to glandular secretion, increased vessel permeability, edema, vasodilation, and further activation of inflammatory cells 562,566,567 .…”

“…Substance P and CGRP also activate mast cells to release more inflammatory mediators, such as histamine, that further propagate the hypersensitivity reaction 565 . Neurokinin A, a tachykinin that acts similarly to substance P, causes increased vascular permeability, vasodilation, bronchial smooth muscle contraction, mucus secretion, mast cell degranulation, as well as leukocyte chemotaxis and activation 562,564,567 . Understanding these biologic pathways has led to investigation of novel therapies including bradykinin antagonists and TRP receptor calcium ion channel blockers 567 …”