xRead - Nonallergic Rhinitis (September 2025)

Clinical Reviews in Allergy & Immunology (2024) 67:40–46 https://doi.org/10.1007/s12016-024-09005-2

REVIEW

Efficacy of Capsaicin for Non‑allergic Rhinitis: An Updated Systematic Review and Meta‑analysis

Jiatong Wang 1 · Leilani Zhang 1,2 · Kangyang Zheng 1

Accepted: 12 October 2024 / Published online: 18 October 2024 © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024

Abstract Non-allergic rhinitis (NAR) is a prevalent condition with limited effective treatments. Capsaicin, an agonist of the transient receptor potential vanilloid subfamily 1 (TRPV1) receptor, has emerged as a potential therapeutic option for NAR by targeting heightened nasal reactivity. This systematic review and meta-analysis, conducted in accordance with PRISMA guidelines and registered on PROSPERO, evaluated the efficacy of capsaicin for NAR treatment. Nine studies with placebo-controlled group were included, with primary outcomes assessed as total nasal symptom scores (TNSS), visual analog scale (VAS) scores, and the proportion of therapeutic responders. Meta-analysis revealed significant improvements in TNSS and VAS scores, along with a higher proportion of therapeutic responders in patients receiving capsaicin treatment compared to pla cebo. While some studies demonstrated reductions in substance P levels and TRPV1 expression after capsaicin treatment, further investigation is warranted. This meta-analysis provides preliminary evidence suggesting that capsaicin treatment holds promise for alleviating symptoms in patients with NAR. However, the limited number of studies and methodological heterogeneity necessitate larger and more rigorously designed clinical trials with standardized methodologies and advanced diagnostic techniques to establish their definitive roles in clinical practice. Graphical Abstract

Keywords Non-allergic rhinitis · Capsaicin · TRPV1 · Meta-analysis · Systematic review · Nasal symptom · Efficacy

Abbreviations NAR

* Jiatong Wang

Non-allergic rhinitis Allergic rhinitis Idiopathic rhinitis

16622356879@163.com

AR IR IgE

1 Southern Medical University, Guangzhou, China 2 Imperial College London, London, Great Britain

Immunoglobulin E TRPV1 T ransient receptor potential vanilloid subfamily 1

Vol:.(1234567890)

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SP

Substance P

nasal blockage, and increased tear production. This is attributed to its ability to activate TRPV1 receptors, resulting in an influx of cations into nerve terminals and an increase in intracellular Ca 2+ concentration, which in turn stimulates the release of neu ropeptides and potentially triggers an inflammatory response. The therapeutic effect of intranasal capsaicin is believed to be due to the permanent degeneration of nerve terminals due to the overwhelming influx of Ca 2+4 . Recent clinical trials, employ ing more biochemical approaches, have further elucidated cap saicin’s mechanism. Treatment with capsaicin has been shown to reduce the expression of TRPV1, TRPM8, and PGP 9.5 in patients with idiopathic rhinitis. Importantly, capsaicin does not appear to alter mast cell marker c-KIT or nasal epithelial mor phology, nor does it induce apoptosis or necrosis in cultured human nasal epithelial cells and mast cells [3]. These findings suggest that capsaicin may offer a novel therapeutic approach for NAR, specifically targeting the TRPV1-SP nociceptive signal ing pathway without affecting mast cell function or nasal epi thelial integrity. Rhinitis, encompassing both allergic rhinitis (AR) and non-allergic rhinitis (NAR), is a prevalent condition glob ally, with a median global prevalence of 29.4%, 18.1%, and 12.0% respectively [4]. While geographic variations exist, studies consistently indicate a rising prevalence of rhinitis in recent decades [2]. The significant socio-economic impact of rhinitis, stemming from untreated or inadequately treated cases, includes absenteeism and presenteeism, leading to decreased productivity and increased healthcare costs [4]. Effective treatments and guideline-based care hold the potential for substantial cost savings. In recent years, clinical trials investigating capsaicin solu tions for NAR have shown promising results. However, despite a previous review with only four studies included [5], a com prehensive analysis and systematic review of the literature are still lacking, highlighting the need for evidence-based medicine methodologies and a sufficient number of published clinical tri als. The absence of approved mass-produced medications spe cifically for clinical application underscores the urgent need for a meta-analysis and systematic review to address these gaps and pave the way for effective treatment options for NAR. Methods This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement. In addition, this review has been registered on PROSPERO as CRD42023481563.

TNSS VAS OD PCR

T otal nasal symptom scores V isual analog scale

Optical density

P olymerase chain reaction PGP 9.5 P rotein gene product 9.5 TRE T rigeminal reflex test NGF N erve growth factor

Introduction Rhinitis, an inflammatory condition affecting the nasal pas sages, includes two distinct categories: allergic rhinitis (AR) and non-allergic rhinitis (NAR). While AR is readily diag nosed through IgE-mediated testing [1], the diagnosis of NAR, also known as idiopathic rhinitis (IR), relies on exclud ing other potential causes, thereby posing a significant diag nostic challenge. NAR is characterized by nasal symptoms such as congestion, sneezing, and postnasal drip, without an identifiable allergen or structural abnormality. Although the exact cause remains unclear, it is believed that heightened nasal mucosa reactivity is involved in the pathology, poten tially linked to dysregulation of the autonomic nervous system in response to non-immunological stimuli, such as variations in temperature, potent odors, and airborne irritants. This dif fers from AR, which is initiated by an immunoglobulin E (IgE)-mediated reaction [1]. Clinically, distinguishing AR and NAR requires a combination of specific IgE levels or skin prick tests and a comprehensive medical history [2]. However, managing NAR is significantly challenging. While intranasal antihistamines and corticosteroids offer temporary relief, their efficacy is limited and raises concerns regarding potential side effects, particularly in children and pregnant women. The per sistent nature of NAR symptoms and the limitations of current therapies have necessitated the exploration of novel treatment strategies. Capsaicin, known for its efficacy in managing other conditions including neuropathic pain, osteoarthritis, and obe sity, has emerged as a potential therapeutic option for NAR. Its mechanism of action, including activation of transient receptor potential vanilloid subfamily 1 (TRPV1), suggests the potential for addressing the heightened nasal reactivity associated with this condition. Clinical trials investigating capsaicin for NAR treatment are ongoing, offering hope for patients with this troubling condition by potentially a more effective and lasting solution. Capsaicin (C 18 H 27 NO 3 ), a naturally occurring alkaloid extracted from chili peppers, holds promise as a treatment for non-allergic rhinitis (NAR). As an agonist of the transient recep tor potential vanilloid subfamily 1 (TRPV1) receptor, capsaicin exerts its therapeutic effect by ablating the TRPV1-SP nocic eptive signaling pathway in the nasal mucosa [3]. Upon nasal application, capsaicin elicits burning sensations, nasal discharge,

Criteria for Considering Studies for this Review

This study included both randomized controlled trials and quasi-randomized controlled trials, acknowledging the

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were addressed through discussion, with a designated third author available for arbitration. Data analysis was conducted using a two-pronged approach. Numerical data from images was extracted using OriginPro software and used to supplement missing infor mation from the articles. Review Manager 5.4 was then employed to analyze the extracted data. The primary outcome measure focused on the overall treatment effects of NAR, evaluated by comparing scores or the number of patients showing improvement at the end of the study. All treatment groups were combined regardless of capsaicin application method for this analysis. Subgroup analysis was explored to investigate the effects of different dosages, decongestion medicine, and topical lidocaine use. Due to insufficient similar trials, this analysis was conducted narratively. Additionally, the study examined the potential for advanced diagnostic approaches to suggest alternative superior clinical approaches or more precise treatment recommendations. The process of comprehensive article identification is illus trated in Fig. 1. A total of 141 articles including two stud ies from a previous review were initially identified through searching various databases. Subsequently, 29 duplicate records were removed from the dataset. After considering the quality of the remaining articles, 52 articles that lacked relevance or did not correspond to the intended study type were excluded. Additionally, ten articles were eliminated due to insufficient available results. One more article was deemed ineligible upon assessment, owing to the incom parable nature of the outcomes. Consequently, these nine studies were consolidated and included in the meta-analysis and systematic review. Results Results of the Search

limited available clinical data in this field. Studies reporting unavailable results or deemed irrelevant were excluded. The intervention focus was on capsaicin solutions and medications related to capsaicin, including ICX72, a propri etary homeopathic preparation of capsaicin, but excluding clinical trials involving SB705498 due to its distinct mecha nism as a TRPV1 antagonist. Outcome measures were categorized as continuous or binary. Continuous variables, such as total nasal symptom scores (TNSS) and visual analog scale (VAS) scores, were analyzed using standardized mean difference to account for variations in scoring standards. Binary variables, reporting therapeutic responders, were analyzed using odds ratios. The primary outcomes of this study included TNSS, VAS scores, and the proportion of therapeutic responders. Sec ondary outcomes encompassed a broader range, including substance P (SP) levels, gene expression analysis (TRPV1, PGP9.5, TRPA1, TRPV4, TRPM8, and c-KIT), nasal hyper reactivity, nasal mucosal potential, and time to first relief. PubMed, ClinicalTrials, MedlinePlus, and the Cochrane Library were consulted for related articles published in English. For instance, a search query (rhinitis[Title]) AND (capsaicin[Title/Abstract]) was employed on PubMed. Key words like “capsaicin for rhinitis” were used on websites lacking advanced search functionalities. Additional relevant articles were discovered in reviews within this field to pro vide a more thorough description of the disease. The selection process involved a two-stage approach: initial manual screening by the primary author followed by fur ther refinement using Endnote software. Two authors inde pendently evaluated studies based on criteria such as study type, relevance, and data type. Discrepancies were resolved through discussion, with a third author designated as an arbi trator if necessary, although this was not required. Data extraction was performed independently by both authors, who meticulously reviewed each included article and extracted relevant information. This data was organized into tables outlining study characteristics, including meth ods, participants, interventions, and outcomes. Discrepan cies in data extraction were resolved through discussion, with a third author serving as an arbitrator if required. The risk of bias in included studies was assessed using the Cochrane collaboration’s tool for randomized controlled tri als. Authors independently appraised studies across various domains, including random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential bias sources. Disagreements Search Methods for Identification of Studies Data Collection and Analysis

Risk of Bias in Included Studies

All the included studies were evaluated using Review Man ager, and their biases are depicted in Fig. 2. Additionally, risk of bias summary illustrates the authors' evaluations of each bias item for each individual study.

Effects of Capsaicin Treatment at the End of Studies

VAS or TNSS of each study at the end of the trials were used for analysis for overall effects of capsaicin in analysis and showed the results in Fig. 3 which using standardized mean difference and showed 95% confidence interval. Due to different measure methods of nasal symptoms, random

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Fig. 1 Study flow gram of the review following PRISMA guidelines

between the intervention and the outcome. This suggests that capsaicin exhibits superior efficacy when compared to placebo.

effects model was utilized to cope with the heterogeneity. The funnel plot (Fig. 4) of this analysis suggests that the included studies exhibit an acceptable level of bias. For tri als reporting therapeutic responders, we conducted a sec ond analysis using odds ratio and showing 95% confidence interval in Fig. 3.

Description of Other Outcomes

The efficacy of capsaicin treatment for nasal inflammatory disorders has been assessed using various methods, includ ing clinical symptom scores, nasal airway resistance (NAR), and molecular markers. In 2021, Zebda observed a signifi cant decrease in median change in optical density (OD) from baseline at 4 and 12 weeks in the intervention group, indicat ing a reduction in nasal airway obstruction. While 100% of patients initially met criteria for NAR diagnosis, only 55% and 40% met the criteria at 4 and 12 weeks, respectively, sug gesting a potential improvement in NAR [1]. In 2014, Van Gerven observed a borderline significant correlation between decreased TRPV1 expression and reduced VAS scores for

Discussion

Description of Primary Outcomes

Through figures presenting results of analyses which are both considered statistically significant ( p < 0.05), it’s obvi ous that capsaicin does well in enhancing TNSS or VAS of NAR patients at the end of studies. Studies reporting on the number of therapeutic responders have demonstrated an odds ratio greater than 1, indicating a positive correlation

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Fig. 2 Risks and biases graph of included studies. Green for low risk of bias, yellow for unclear risk of bias, red for high risk of bias

model, 95% CI. Lower part is the forest plot for capsaicin versus pla cebo in numbers of therapeutic responders at the end of each study, odds ratio, M-H, fixed-effect model, 95% CI

Fig. 3 Forest plots of effects of capsaicin versus placebo for NAR. Upper part is the forest plot for capsaicin versus placebo in TNSS or VAS at the end of each study, std. mean difference, IV, random-effect

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Conclusions and Limitations This systematic review and meta-analysis, encompassing eight studies, demonstrate that capsaicin treatment holds potential for alleviating symptoms in patients with non allergic rhinitis (NAR). The observed improvements in total nasal symptom scores (TNSS) and visual analog scale (VAS) scores, coupled with a higher proportion of thera peutic respondersin capsaicin–treated patients, support its efficacy. The mechanism underlying capsaicin’s thera peutic effect is likely attributed to its interaction with the TRPV1 receptor, which effectively modulates the TRPV1 SP nociceptive signaling pathway in the nasal mucosa. However, it is crucial to acknowledge the limitations inherent in this meta-analysis. The findings are based on a relatively small number of studies, characterized by methodological heterogeneity and potential biases, which warrant further investigation. Furthermore, the lack of standardization in outcome rating methods across studies limits the ability to draw definitive conclusions regarding the efficacy of different capsaicin doses. Several studies also suggest alterations in other nasal symptoms and biochemical markers, such as reduced sub stance P levels and decreased TRPV1 expression, high lighting the complexity of capsaicin’s effects on nasal physiology. However, these findings require further explo ration and validation through larger and more rigorously designed studies. To solidify the role of capsaicin in NAR management, future research should prioritize larger scale clinical tri als with standardized methodologies and robust outcome measures. Employing advanced diagnostic techniques to accurately classify NAR subtypes will also improve the validity of future studies. The exploration of capsaicin’s efficacy and safety across a wider patient population, encompassing diverse demographics and clinical presen tations, is crucial for establishing its clinical utility and deepening our understanding of its molecular mechanisms in alleviating nasal symptoms. In conclusion, while this meta-analysis provides encour aging preliminary evidence for the efficacy of capsaicin in treating NAR, further research is needed to establish its definitive role in clinical practice. Author Contribution Jiatong Wang: Methodology, Formal analysis, Investigation, Data Curation, Writing—Original Draft, Writing— Review & Editing, Visualization, Supervision, Project administration Leilani Zhang: Methodology, Validation, Investigation, Data Cura tion Kangyang Zheng: Methodology, Validation, Investigation, Data Curation. Data Availability No datasets were generated or analyzed during the current study.

Fig. 4 Funnel plot of comparison capsaicin versus placebo for NAR in VAS or TNSS at the ends of studies. Vertical axis, standard error of std. mean difference. Horizontal axis, std. mean difference

major symptoms, indicating a possible role of TRPV1 in symptom severity. Substance P levels, elevated in patients with NAR compared to healthy controls, were reduced to control levels after capsaicin treatment [3]. However, in a later study, Van Gerven found no reduction in PGP9.5, TRPV1, TRPV4, TRPM8, and nerve growth factor (NGF) expression in patients with idiopathic rhinitis 4 and 26 weeks after capsaicin treatment using polymerase chain reaction (PCR) tests. Interestingly, baseline human TRPV1 expres sion is correlated with the results of the trigeminal reflex test (TRE) 12 weeks after capsaicin treatment [6]. Van Gerven further reported a positive correlation between substance P concentration and major nasal symptoms, suggesting its potential as a biomarker to predict therapeutic response [7]. While we cannot definitively compare the effectiveness of different doses due to inconsistent outcome measurement methods across studies, we can still draw upon the accumu lated clinical experience to offer practical, albeit tentative, suggestions for dosage. There are four records mentioning the concentration of capsaicin used in studies, all of which utilized a 0.1 mmol/L capsaicin solution. Among them, one study tested both a 0.1-mmol/L and a 0.01-mmol/L solution [1, 6–8]. In Van Gerven’s 2021 study, low doses of capsaicin were considered as eligible as the 0.1-mmol/L solution, but we cannot compare the superiority of the 0.1-mmol/L and 0.01-mmol/L solutions. However, the 0.1-mmol/L solution is more commonly employed in clinical trials [7]. Different Doses of Capsaicin Applied in the Studies

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5. Gevorgyan A, Segboer C, Gorissen R, van Drunen CM, Fokkens W (2015) Capsaicin for non-allergic rhinitis. Cochrane Database Syst Rev 2015:CD010591 6. Van Gerven L, Alpizar YA, Steelant B, Callebaut I, KortekaasK rohn I, Wouters M et al (2017) Enhanced chemosensory sensitiv ity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment. J Allergy Clin Immunol 140:437–46 e2 7. Van Gerven L, Steelant B, Cools L, Callebaut I, Backaert W, de Hoon J et al (2021) Low-dose capsaicin (0.01 mM) nasal spray is equally effective as the current standard treatment for idiopathic rhinitis: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 147:397-400 e4 8. Van Rijswijk JB, Boeke EL, Keizer JM, Mulder PG, Blom HM, Fokkens WJ (2003) Intranasal capsaicin reduces nasal hyperreac tivity in idiopathic rhinitis: a double-blind randomized application regimen study. Allergy 58(8):754–761 Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Declarations Competing Interests The authors declare no competing interests.

References 1. Zebda D, Jiang ZY, Gibson MM, Pham C, Ahmadi S, Floren S et al (2021) Double-blinded randomized prospective trial of intranasal capsaicin treatment for nonallergic rhinitis. Int Forum Allergy Rhinol 11:24–30 2. Hellings PW, Klimek L, Cingi C, Agache I, Akdis C, Bachert C et al (2017) Non-allergic rhinitis: position paper of the Euro pean Academy of Allergy and Clinical Immunology. Allergy 72:1657–1665 3. Van Gerven L, Alpizar YA, Wouters MM, Hox V, Hauben E, Jorissen M et al (2014) Capsaicin treatment reduces nasal hyperre activity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis. J Allergy Clin Immunol 133:1332–9 9 e1-3 4. Savouré M, Bousquet J, Jaakkola JJK, Jaakkola MS, Jacquemin B, Nadif R (2022) Worldwide prevalence of rhinitis in adults: a review of definitions and temporal evolution. Clin Transl Allergy 12:e12130

Clinical Management Review

Nonallergic Rhinopathy: A Comprehensive Review of Classification, Diagnosis, and Treatment

Fuad M. Baroody, MD a , Philippe Gevaert, MD, PhD b , Peter K. Smith, MD c , Navid Ziaie, MD d , and Jonathan A. Bernstein, MD d Chicago, Ill; Ghent, Belgium; Southport, Australia; and Cincinnati, Ohio

AMA PRA Category 1 Credit . Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Fuad M. Baroody, MD, Philippe Gevaert, MD, PhD, Peter K. Smith, MD, Navid Ziaie, MD, and Jona than A. Bernstein, MD (authors); David A. Khan, MD (editor) Learning objectives : 1. Describe the pathogenesis of non-allergic rhinopathy. 2. De fi ne clinical and diagnostic criteria for non-allergic rhinopathy. 3. Discuss the most effective treatment options for non-allergic rhinopathy. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Relevant Financial Relationships with Commercial Interests: F. M. Baroody is a consultant for Bayer. P. Gevaert has served as an advisor or speaker and received grant/research support from ALK, Argenx, AstraZeneca, Genentech, GSK, Hall Allergy, Novartis, Regen eron, Roche, Sano fi -Genzyme, and Stallergenes-Greer. P. K. Smith is a principal investigator/consultant for GSK, Sano fi Regeneron, and Viatris. J. A. Bernstein is a principal investigator/consultant for Astra Zeneca, GlaxoSmithKline (GSK), Novartis, Genentech, Sano fi Regeneron, Optinose, ALK, and Allergy Therapeutics. N. Ziaie and the editor declares that they have no relevant con fl icts of interest. symptoms triggered by chemical irritants and weather changes through chemosensors, mechanosensors, thermosensors, and/or osmosensors activated through different transient receptor potential calcium ion channels. Elucidating the speci fi c role of transient receptor potential vanilloid 1, triggered by capsaicin, has been an important advancement in better understanding the pathophysiology of NAR because it has now been shown that investigator/consultant for Astra Zeneca, GlaxoSmithKline (GSK), Novartis, Genentech, Sano fi Regeneron, Optinose, ALK, and Allergy Therapeutics. N. Ziaie declares that he has no relevant con fl icts of interest. Received for publication January 25, 2024; revised February 29, 2024; accepted for publication March 4, 2024. Available online March 11, 2024. Corresponding author: Jonathan A. Bernstein, MD, Department of Internal Medi cine, Division of Immunology/Allergy Section, University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML#563, Cincinnati, OH 45267-0563. E-mail: Bernstja@ucmailuc.edu. 2213-2198 2024 American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2024.03.009

INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaci inpractice.org/. Fax or other copies will not be accepted. Date of Original Release: June 1, 2024. Credit may be obtained for these courses until May 31, 2025. Copyright Statement: Copyright 2024-2026. All rights are reserved, including those for text and data mining, AI training, and similar technologies. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the fi eld of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Edu cation (ACCME) to provide continuing medical education for physi cians. The AAAAI designates this journal-based CME activity for 1.00 Chronic nonallergic rhinitis syndromes encompass various conditions, of which vasomotor rhinitis is the most common form, representing approximately 80% of patients, also referred to as nonallergic rhinopathy (NAR), nasal hyperreactivity, neurogenic rhinitis, or idiopathic rhinitis. Expert panels have recommended replacing vasomotor rhinitis terminology because it is more descriptive of this condition that is characterized by a Section of Otolaryngology e Head and Neck Surgery, University of Chicago Med icine, Chicago, Ill b Upper Airways Research Laboratory, Department of Head and Skin, Ghent Uni versity, Ghent, Belgium c Department of Surgery-Otolaryngology-Head and Neck, School of Medicine, Grif fi th University, Southport, Queensland, Australia d Department of Internal Medicine, Division of Rheumatology, Allergy and Immu nology, University of Cincinnati College of Medicine, Cincinnati, Ohio No funding has been received for this study. Con fl icts of interest: F. M. Baroody is a consultant for Bayer. P. Gevaert has served as an advisor or speaker and received grant/research support from ALK, Argenx, AstraZeneca, Genentech, GSK, Hall Allergy, Novartis, Regeneron, Roche, Sano fi Genzyme, and Stallergenes-Greer. P. K. Smith is a principal investigator/ consultant for GSK, Sano fi Regeneron, and Viatris. J. A. Bernstein is a principal

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treatments used to treat rhinitis. 2 The most common chronic nonallergic rhinitis condition is VMR comprising up to 80% of cases, which has also been referred to as nonallergic rhinopathy (NAR), idiopathic rhinitis, neurogenic rhinitis, or nasal hyper reactivity (NHR). 2-6 It has been challenging to develop consensus terminology for VMR because the diagnosis is solely made based on symptoms induced by nonallergic triggers and negative speci fi c IgE testing. 2-6 Expert panels have recommended replacing the term VMR with NAR because it is more descriptive of this condition that is characterized by symptoms triggered by chemical irritants and weather changes through chemosensors, mechanosensors, thermosensors, and/or osmosensors activated through different transient receptor potential (TRP) calcium ion channels. Therefore, the term NAR is used in this review in lieu of VMR that is associated with non e type 2 neuroin fl ammation and nasal hyperreactivity secondary to irritant triggers through neurogenic pathways. 7 It is also important to note that up to 50% of NAR sufferers may have a mixed rhinitis (MR) charac terized as having an IgE-mediated component based on sensiti zation to environmental allergens that correlates with symptoms when exposed in conjunction with symptoms induced by nonallergic triggers such as perfumes, fragrances, chemicals, and solvents. 8 Nonallergic rhinopathy is often an incorrectly diagnosed condition associated with signi fi cant patient morbidity because it can aggravate or impede management of many comorbid illnesses. 1 Thus, if not diagnosed or managed properly, this condition can result in unnecessary or inappropriate therapies causing unnecessary economic and health care burdens to the patient leading to signi fi cant impairment of their quality of life. This review provides a comprehensive overview of the classi fi cation, differential diagnosis, approach to diagnosis and treat ment, as well as controversies surrounding NAR and current needs for future investigations that could lead to more effective therapy tailored for this condition. CASE REPORT Joanne is a 42-year-old woman who presents to the allergy clinic with persistent nasal symptoms for the past 2 years con sisting of postnasal drainage and nasal congestion. She previously dismissed her symptoms as viral upper respiratory infections or owing to weather changes. She reports clear nasal discharge and embarrassing postnasal drip, leading to frequent coronavirus disease 2019 (COVID-19) testing. Joanne also describes pressure and pain behind her eyes, intensifying by evening, causing “ brain-fog. ” She also experiences throat and ear itchiness with intermittent ear plugging and pain. Her symptoms do not worsen during pollen seasons while outdoor gardening but are worsened during windy days and temperature drops. Indoors, she notices worsening symptoms after dusting her home and avoids strong fragrances, potpourris, and cleaning agents because they also aggravate her symptoms. Clinical examination by anterior rhinoscopy revealed swollen, erythematous nasal mucosa but no other abnormalities. Serological testing from her primary care doctor were negative for speci fi c IgE allergy to seasonal or perennial aeroallergens. Given the lack of allergen-speci fi c trig gers and her symptom pro fi le, Joanne was diagnosed with NAR, likely triggered by fragrances, volatile chemicals, and temperature changes. She had used intranasal corticosteroids (INCS) in the past with minimal improvement in symptoms. Treatment with

Abbreviations used

AR- Allergic rhinitis CGRP- Calcitonin gene e related peptide COPD- Chronic obstructive pulmonary disease COVID-19- Coronavirus disease 2019 CR- Chronic rhinitis CRS- Chronic rhinosinusitis FDA- U.S. Food and Drug Administration

IgE- Immunoglobulin E IIS- Irritant index score

INAH- Intranasal antihistamine INCS- Intranasal corticosteroids LAR- Localized entopic allergic rhinitis MR- Mixed rhinitis NAR- Nonallergic rhinopathy NARES- Nonallergic rhinitis with eosinophilia syndrome NHR- Nasal hyperreactivity

PAR- Perennial allergic rhinitis SAR- Seasonal allergic rhinitis TRP- Transient receptor potential

TRPA1- Transient receptor potential ankyrin 1 TRPV1- Transient receptor potential vanilloid 1 VMR- Vasomotor rhinitis

downregulation of transient receptor potential vanilloid 1 receptors by several therapeutic compounds provides symp tomatic relief for this condition. The classi fi cation of NAR is further complicated by its association with allergic rhinitis referred to as mixed rhinitis, which involves both immuno globulin E e mediated and neurogenic mechanistic pathways. Comorbidities associated with NAR, including rhinosinusitis, headaches, asthma, chronic cough, and sleep disturbances, underscore the need for comprehensive management. Treat ment options for NAR include environmental interventions, pharmacotherapy, and in refractory cases, surgical options, emphasizing the need for a tailored approach for each pa tient. Thus, it is extremely important to accurately diagnose NAR because inappropriate therapies lead to poor clinical outcomes and unnecessary health care and economic burdens for these patients. This review provides a comprehensive overview of NAR subtypes, focusing on classi fi cation, diag nosis, and treatment approaches for NAR. 2024 Amer ican Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2024;12:1436-47) Key words: Nonallergic rhinitis; Nonallergic rhinopathy INTRODUCTION Chronic nonallergic rhinitis syndromes comprise at least 8 non e immunoglobulin E (IgE) e mediated conditions including vasomotor rhinitis (VMR), nonallergic rhinitis with eosinophilia syndrome (NARES), senile rhinitis, atrophic rhinitis, gustatory rhinitis, drug-induced rhinitis, hormone-induced rhinitis, and occupational nonallergic rhinitis induced by low molecular weight chemicals that affect approximately 25% of patients presenting with chronic rhinitis (CR) symptoms. 1-6 Some have included cerebrospinal fl uid leak in this classi fi cation but this structural problem is more appropriately considered in the dif ferential diagnosis of clear rhinorrhea not responsive to

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ClassificaƟon of Chronic RhiniƟs

Mixed RhiniƟs (AR and NAR)

NAR (Non–IgE-mediated)

AR (IgE-mediated)

Nonallergic rhinopathy (vasomotor rhiniƟs)

NARES Senile rhiniƟs

PAR

SAR

Atrophic rhiniƟs Gustatory rhiniƟs Hormonal rhiniƟs

Entopic rhiniƟs

Drug-induced rhiniƟs OccupaƟonal rhiniƟs (low molecular weight irritant-induced rhiniƟs)

Symptoms year-round

Symptoms seasonal

FIGURE 1. Classification of chronic rhinitis subtypes.

TABLE I. Classification of AR and NAR by physician diagnosis based on history and specific IgE testing to aeroallergens vs using a quantitative IIS with specific IgE testing to aeroallergens 3

Physician diagnosis (number of patients in each group at baseline)

IIS reclassification (number of patients in each group after reclassification)

Clinical characteristic pre- and post-reclassification*

Rhinitis subtype

AR total MR total

404 129

254 low IIS 279 high IIS

Increased number of patients with more rhinitis symptoms. Increased number of patients with a diagnosis of asthma

NAR total

123

79 low IIS 44 high IIS

Increased number of patients with more rhinitis symptoms. Increased number of patients with a diagnosis of asthma

*Signi fi cant differences in clinical characteristics after reclassi fi cation using the IIS that were not discernable at baseline ( P < .01).

an intranasal antihistamine (INAH) was initiated. She was seen back in the of fi ce a month later, at which time she reported improvement of nasal symptoms but had persistence of anterior clear nasal drainage. Ipratropium bromide 0.03% nasal spray was added to her regimen 2 to 3 times a day as needed for rhinorrhea, which resulted in signi fi cant improvement of her symptoms. CLASSIFICATION AND EPIDEMIOLOGY The classi fi cation of CR conditions includes allergic rhinitis (AR) conditions (seasonal, perennial and entopic) and nonal lergic rhinitis conditions including NAR, NARES, senile rhinitis, atrophic rhinitis, gustatory rhinitis, drug-induced rhinitis, hor monal rhinitis, and occupational rhinitis induced by low mo lecular weight chemical irritants (Figure 1). 9-11 Nonallergic rhinopathy can be acute or chronic and, as mentioned, up to 50% of cases involve both allergic and neurogenic pathways referred to as MR. 9 Many have considered MR to represent AR with allergic in fl ammation causing secondary nasal airway hy perreactivity, making patients more reactive to irritant and me chanical triggers. However, there is now suf fi cient evidence to support parallel neuropathic mechanisms that can elicit

symptoms concomitantly because MR patients are not completely responsive to treatments commonly used for AR such as INCS and second-generation H1-antihistamines. 9,10,12 Differentiation of the nonallergic rhinitis conditions, NAR and NARES, is limited to the presence or absence of eosinophils in the nasal passages. 13 In retrospect, NARES may represent localized (entopic) AR, which would need to be excluded by speci fi c allergen nasal provocation to con fi rm this diagnosis. 14 Therefore, NAR is a non e Type 2 neuroin fl ammatory condi tion whereas NARES is a Type 2 in fl ammatory condition. It should be emphasized that symptoms and physical fi ndings are not pathognomonic for AR because patients with NAR often manifest similar features. Bernstein and colleagues 7 used an irritant index score (IIS) to further characterize patients with a physician diagnosis of AR and found that many of these patients had a high IIS consistent with MR (also referred to as AR with a high IIS burden) (Table I). Similarly, patients with NAR were also reclassi fi ed based on their IIS as having a high versus a low IIS burden. Interestingly, AR and NAR patients with a high IIS burden were found to have more frequent rhinitis symptoms and were more likely to have a physician diagnosis of asthma than those patients with a low IIS burden (Table I). 7 These results

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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

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TABLE II. Differential diagnosis of NAR AR (PAR, SAR) MR NARES LAR Gustatory rhinitis Hormonal rhinitis (pregnancy, exogenous estrogen) Drug-induced rhinitis (see Table III) Occupational rhinitis Atrophic rhinitis Senile rhinitis (rhinitis of the elderly) Infectious rhinitis Structural problems (see Table IV)

for NAR revealed 87% concordance before speci fi c IgE testing was performed to assess for atopy. 15 These are useful questions to ask any patient presenting with symptom suggestive of CR to ascertain the likelihood of whether they have NAR or a component of NAR characteristic of MR. On physical examination, the nasal mucosa usually may appear normal or red and beefy. 1,10 Serum IgE is usually normal and often very low, and aeroallergen skin testing or serological tests for speci fi c IgE are negative. 1 Peripheral eosino philia is absent, and nasal eosinophilia is usually absent except with NARES or entopic rhinitis. Patients with NAR typically report a poor or incomplete response to medications approved for the treatment of AR, 1 in contrast to entopic rhinitis (localized allergic rhinitis [LAR]) pa tients who respond well to second-generation H1-antihistamines and INCS and NARES patients who also respond well to INCS. 14 DIFFERENTIAL DIAGNOSIS The differential diagnosis of NAR is summarized in Table II. It is important to carefully differentiate nonallergic rhinitis condi tions including NAR from perennial allergic rhinitis (PAR), sea sonal allergic rhinitis (SAR), or MR because treatment will be less effective if not tailored to the patient ’ s clinical condition. 1,8,30 The majority of NAR patients suffer from NHR with symptoms triggered by changes in temperature, humidity, or barometric pressure and/or exposure to strong odors or perfumes. 30 Alcohol hyperresponsiveness is frequently a trigger for NAR patients; however, 1 study reported it was more common in patients with chronic rhinosinusitis (CRS) with nasal polyps. 37 Gustatory rhinitis is characteristically seen in older patients that experience clear rhinorrhea after eating. It is most often triggered by hot or spicy foods but may be triggered by nonspicy foods as well. 10 Hormonal rhinitis is most commonly diagnosed in pregnant women in the later trimesters of pregnancy and resolves within 2 weeks of delivery but can also be seen in women using estrogen containing oral contraceptives or exogenous estrogen therapy that causes vascular engorgement of the nasal mucosa with subse quent nasal obstruction and/or excessive mucus production. 38 In addition to estrogen, various drugs that can induce rhinitis manifesting as nasal congestion are listed in Table III. TABLE III. Pharmacological agents that induce rhinitis symptoms Centrally acting sympatholytics (eg, clonidine, guanfacine, methyldopa, reserpine) Ganglion-blocking sympatholytics (mecamylamine, trimethaphan) Peripherally acting sympatholytics (eg, prazosin, guanethidine, indoramin, phentolamine) Phosphodiesterase inhibitors for erectile dysfunction (sildena fi l, tadala fi l, vardena fi l) b -Blockers (oral or intraocular) Angiotensin-converting enzyme inhibitors Calcium channel blockers Diuretics (amiloride, chlorothiazide, hydrochlorothiazide) Other antihypertensives (hydralazine) Hormones (oral contraceptives, exogenous estrogens) Psychotropics (chlorpromazine, risperidone, thioridazine) Intranasal decongestants (prolonged use: rhinitis medicamentosa)

Miscellaneous (sarcoid, midline granuloma, chronic granulomatous polyangiitis, relapsing polychondritis, hypothyroidism, Horner syndrome, Sjögren)

symptoms. 32,33 Thus, the major ligand for the TRPV1 receptor is capsaicin and it has been synonymously referred to as the capsaicin receptor by David Julius who was awarded the 2012 Nobel Prize in Physiology for its cloning. 31 Moreover, activation of G coupled proteins by speci fi c ligands such as capsaicin or histamine lowers the activation threshold of this ion channel, which causes release of neuropeptides such as neurokinin A, calcitonin gene e related peptide (CGRP) and substance P, responsible for symptoms of NAR and AR. This potentially helps explain the overlapping pathways observed in MR, which as discussed, accounts for up to 50% of CR patients (Figure 2). 34 Many of the known irritants that cause NAR symptoms acti vate another ion channel called the transient receptor potential ankyrin 1 (TRPA1). 35 Both TRPV1 and TRPA1 are heavily coexpressed on trigeminal sensory nerves and highly coexpress the neuropeptides substance P and CGRP. These ion channels cofunction by forming tetradimers. 36 DIAGNOSIS The diagnosis of NAR requires exclusion of other known causes of rhinitis. Thus, a comprehensive history, physical ex amination, and appropriate diagnostic testing are important to exclude sensitization to aeroallergens and to assess for diseases mimicking rhinitis that can lead to substantial morbidity and even mortality. As mentioned, most patients with NAR endorse 1 or more irritant triggers, such as tobacco smoke, perfumes/ fragrances, and temperature or barometric pressure changes, causing their symptoms. 1 Unlike AR, there is no speci fi c test or biomarker that can establish a diagnosis of NAR. 7 Similar to AR, NAR can be persistent or intermittent, especially if patients are ef fi cient at avoiding nonallergic triggers. Using data derived from logistic regression analysis, the likely probability of diagnosing NAR was calculated to be 96% in a patient who presents with new-onset symptoms at the age of 35 years, no parental history of allergy, absence of outdoor symptoms during the spring, absence of symptoms around cats, and increased symptoms around perfumes and fragrances. 15 For a similar 45 year-old patient, the probability of having NAR was 98%. 15 Analysis of the association between predicted probabilities (ques tionnaire responses) and observed responses (physician diagnoses)

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TABLE V. Comorbid conditions associated with NAR 6 Medical comorbidities

TABLE IV. NAR-associated disease and differentiating clinical characteristics 2 NAR-associated disease Clinical characteristics CRS with nasal polyps

Quality of life comorbidities

Acute and chronic rhinosinusitis Acute and chronic otitis media

Sleep disturbances

Decreased smell, taste, nasal congestion, asthma, aspirin intolerance Facial pain, pressure, headache, mucopurulent discharge, decreased smell Congestion worse on the side of the deviation Nasal congestion; poor response to medication Can be severe congestion unilaterally or bilaterally; primary or compensatory Unilateral intermittent clear drainage worse with head in dependent position, associated with recent surgery or head trauma Child with recurrent infections (otitis media), snoring, congestion, sleep disturbance

Fatigue

Conjunctivitis

Absenteeism or presenteeism from work or school Decreased cognitive function Absenteeism or presenteeism from work or school

CRS without nasal polyps

Eustachian tube dysfunction

Headaches

Septal deviation

Chronic cough secondary to postnasal drainage Nasal dyspnea

Nasal valve collapse

Nasal polyps Sleep apnea

Turbinate hypertrophy with or without concha bullosa

Cerebrospinal fl uid leak

This condition is often associated with nasal valve collapse, which refers to any weakness or further narrowing of the anterior nasal valve resulting in change of air fl ow perceived as nasal conges tion. 2 Turbinate hypertrophy with or without concha bullosa can cause severe unilateral or bilateral obstruction producing nasal congestion. Turbinate hypertrophy can be primary (eg, from AR and NAR) or compensatory, secondary to congenital or trau matic septal deviation. 2 Cerebrospinal fl uid leak usually presents as a unilateral clear rhinorrhea without congestion following head trauma or surgery that worsens in the upright position; however, some cases may be spontaneous. 2 Measurement of b 2 -transferrin in the fl uid and poor response to ipratropium bromide are helpful in making a diagnosis. 41 Imaging studies such as mag netic resonance imaging or high-resolution computed tomogra phy scans are required to fi nd the leak and surgery is usually required to cure this condition. Adenoidal hypertrophy is among the most common anatomic causes of nasal obstruction in children and can be assessed with a lateral x-ray of the naso pharynx, and/or by a nasopharyngolaryngoscopic examination. 2 Nasal foreign bodies, common among young children, most commonly present with unilateral obstruction and foul-smelling purulent rhinorrhea. 2 Ciliary dyskinesia manifests as a primary rare genetic disorder, referred to as immotile-cilia syndrome, that may present with symptoms of chronic cough, nasal congestion. asthma, situs inversus, and congenital heart disease. Physical examination often shows characteristic pooling of secretions on the nasal fl oor. This condition is also associated with CRS with nasal polyps (in children and adults), bronchiectasis, recurrent otitis, and rhinitis as a secondary condition, resulting from chronic infections, irritants, or multiple nasal surgeries that might be transient and reversible. 2 Pharyngonasal re fl ux sec ondary to prematurity or neuromuscular diseases may present as congestion in early life. 2 In addition, esophageal re fl ux can cause nasal symptoms in adults and children and may even predispose to obstructive sleep apnea. 2 Finally, nasal tumors usually present with unilateral nasal obstruction that can be progressive and are often accompanied by epistaxis or pain. COMORBID ILLNESSES Poorly controlled NAR can be accompanied by several different comorbidities, which can signi fi cantly impact its man agement and further impair quality of life (Table V). 1 Common associated conditions include acute and chronic rhinosinusitis

Adenoid hypertrophy

Foreign body

Unilateral, mucopurulent discharge

Nasal tumors

Progressive unilateral congestion, bloody discharge, nasal or ear pain

Rhinitis of the elderly or senile rhinitis typically presents in patients older than 65 years and is characterized by clear, watery rhinorrhea. 10 Atrophic rhinitis is usually a result of atrophy of the glands of the nasal mucosa and presents with nasal crusting and dried nasal secretions as well as nasal obstruction caused by bacterial in fections or secondary to nasal surgery with over-resection of nasal turbinates. 10 Occupational rhinitis is frequently related to the irritant effects of substances that workers are exposed to in different workplace environments including janitorial services, health care, agriculture, fi re fi ghting, food service, laboratory an imal care, power plants and re fi neries, commercial painting, printing, mining, roo fi ng, paving, welding, woodworking, and swimming pool maintenance. 10,39 Rhinitis medicamentosa is rebound nasal congestion that oc curs after prolonged use of adrenergic agonists (eg, intranasal decongestants) causing adrenergic receptor downregulation leading to edematous nasal mucosa and hyperresponsiveness. 10,40 Localized or entopic allergic rhinitis may be confused with NARES because speci fi c IgE testing to aeroallergens is negative but it clinically responds to similar treatments used for AR. Diagnosis is con fi rmed by nasal provocation that elicits symptoms in response to the speci fi c allergen(s) endorsed by the patient. 14 Numerous structural conditions mimic or can occur with rhinitis (Table IV). Chronic rhinosinusitis with and without nasal polyps can present with nasal obstruction, nasal drainage, and NHR. Nasal septal deviation is a common cause of fi xed nasal obstruction leading to nasal congestion and is usually persistent with episodic worsening, alternating from side to side every 1 to 2 hours coinciding with the nasal respiratory cycle.