xRead - Nonallergic Rhinitis (September 2025)

BAROODY ET AL

1439

J ALLERGY CLIN IMMUNOL PRACT VOLUME 12, NUMBER 6

FIGURE 2. Histamine activates its G-coupled protein receptor (GPCR) to activate phospholipase C b (PLC b ), causing hydrolysis of the phospholipid bilayer to release phosphatidylinositol 4,5-bisphosphate (PIP2) producing diacylglycerol (DAG) and inositol triphosphate (IP3). Phospholipase A 2 (PLA 2 ) enzymes produce arachidonic acid (AA) and a range of secondary lipid metabolites. The IP3 rises and induces calcium release from the endoplasmic reticulum. Intracellular calcium activates protein kinase C (PKC) and calmodulin-dependent protein kinase (CaM KII). The AA metabolites and PKC prime TRPV1 so that the threshold for activation and opening of the channel between the fifth and the sixth transmembrane pore allows anion influx. In sensory C fibers, this may generate an action potential and itch. Neuromediators, including substance P (SP) and CGRP, are released to cause vasodilation and excite nerves and some inflammatory cells including mast cells. HETE, Hydroxyeicosatetraenoic acid; HR1, haptad repeat 1; LTB4, leukotriene B4; PI3K, phosphoinositide 3-kinase; SNARE, soluble N -ethylmaleimide-sensitive factor attachment protein receptors.

suggest that combined IgE-mediated and neuropathic pathways may be associated with greater disease burden, although further investigation is required to con fi rm this theory. 7 Patients with NAR are usually older, most commonly pre senting between 30 and 60 years of age. 15,16 They are also more likely female with estimates of female-to-male ratios varying from 2:1 to 3:1. Information about the prevalence of NAR is limited because we lack a uniform de fi nition of the disease as well as consensus on diagnostic criteria leading to a wide variation in prevalence rates. The prevalence has been observed to be one third that of AR, affecting approximately 7% of the U.S. pop ulation or approximately 22 million people. 17 Reports from around the world vary from a prevalence of 8% at the age of 4 years to 6.3% at the age of 8 years in a Swedish cohort, to 24.9% in children in Singapore (mean age 7.8 y), to 9.6% in a popu lation older than 15 years from Belgium. 18-20 In the Singapore study, prevalence was more common in children younger than 6 years of age compared with the prevalence of AR and decreased in older children to a prevalence of 10% to 15%. 19 In a comprehensive review of the worldwide literature, Savoure and colleagues 21 reported that rhinitis prevalence ranged from 1% to 63% with the overall median prevalences of unspeci fi ed rhinitis, AR, and NAR at 29.4%, 18.1%, and 12.0% respectively. There was wide variation according to geographic locations. Based on

these data, it is reasonable to estimate that more than 200 million people suffer from NAR worldwide.

PATHOPHYSIOLOGY Evidence of vascular reactivity with underactivity of the sympathetic nervous system has been described in NAR; how ever, vascular changes can also be readily explained by the release of neuropeptides that have also been linked to NAR. 22-24 Gerth Van Wijk and colleagues 25 linked NAR with hyperreactivity to a spectrum of nonspeci fi c irritants, osmotic, and mechanical stimuli. The mechanism of NAR has best been characterized by sensitivity to cold dry air; however, symptoms are aggravated by multiple irritants including fragrances, components of smoke, and volatile organic compounds for which heterogeneous mul tiple triggers can induce symptoms in different patients as summarized in the Cincinnati Irritant index and con fi rmed in an NAR environmental exposure chamber (Table VI). 7,26-30 The main breakthrough in understanding the mechanism underlying NAR was the identi fi cation of increased expression of the transient receptor potential vanilloid 1 (TRPV1), which are polymodal ion channels expressed in the trigeminal nerve 31 (Figure 2). Treatment with capsaicin has been demonstrated to downregulate these receptors, which correlates with reduction in