Nonallergic Rhinitis, Allergic Rhinitis, and Immunotherapy: Advances in the Last Decade

Chronic rhinitis encompassing both allergic and nonallergic rhinitis affects a significant portion of the population worldwide, having a great impact on patient quality of life, and associated comorbid conditions, with an important societal economic burden. Allergists are often the first to evaluate and treat allergic and nonallergic rhinitis, addressing the individual triggers of the disease as well as the patient-specific responses to these triggers. This review focuses on the advances that have been made in the diagnosis, management, and treatment of nonallergic and allergic rhinitis over the past 10 years, including specific allergen immunotherapy, care pathways, and digital health. Chronic rhinitis encompassing both allergic and nonallergic rhinitis affects a significant portion of the population worldwide, having a great impact on patient quality of life, and associated comorbid conditions, with an important societal economic burden. Allergists are often the first to evaluate and treat allergic and nonallergic rhinitis, addressing the individual triggers of the disease as well as the patient-specific responses to these triggers. This review focuses on the advances that have been made in the diagnosis, management, and treatment of nonallergic and allergic rhinitis over the past 10 years, including specific allergen immunotherapy, care pathways, and digital health. Allergic and nonallergic rhinitis are 2 of the most common disorders seen by allergists, and immunotherapy is likely one of the most common procedures practiced by allergists. In honor of the 10th anniversary of The Journal of Allergy and Clinical Immunology: In Practice, this review aims to highlight the recent advances that impact the clinical care of patients with nonallergic rhinitis (NAR) and allergic rhinitis (AR), including diagnostics, therapeutics, including allergen immunotherapy (AIT), and integration of global and digital health strategies. NAR, in contrast to AR, is characterized by rhinitis in the absence of specific IgE (sIgE)-mediated hypersensitivity, or due to non-IgE mechanisms. The 2 major expert guideline updates addressing NAR in the past decade include a position paper from the European Academy of Allergy and Clinical Immunology published in 20171Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (180) Google Scholar and a 2020 Practice Parameter Update from the Joint Task Force of the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma, and Immunology.2Dykewicz M.S. Wallace D.V. Amrol D.J. Baroody F.M. Bernstein J.A. Craig T.J. et al.Rhinitis 2020: a practice parameter update.J Allergy Clin Immunol. 2020; 146: 721-767Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Both documents acknowledge the significant burden of NAR and call for improved understanding of this disease. In this section, we will emphasize recent advances and the state of the field in NAR. The worldwide prevalence of NAR in adults varies widely across populations and by definition—for example, whether there is the presence of rhinitis without sIgE, or whether there are symptoms suggesting irritant triggers. It is estimated, however, that NAR affects more than 200 million people worldwide.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (180) Google Scholar A systematic review by Savoure et al3Savoure M. Bousquet J. Jaakkola J.J.K. Jaakkola M.S. Jacquemin B. Nadif R. Worldwide prevalence of rhinitis in adults: a review of definitions and temporal evolution.Clin Transl Allergy. 2022; 12e12130Crossref PubMed Scopus (18) Google Scholar recently documented that using a rigorous definition of NAR, the median prevalence of NAR was 16.4% using a symptoms-based definition, and 31.4% based on a definition accounting for serum or skin testing for sIgE. In adults, NAR was reported in 24.4% to 67.1% of participants with rhinitis.3Savoure M. Bousquet J. Jaakkola J.J.K. Jaakkola M.S. Jacquemin B. Nadif R. Worldwide prevalence of rhinitis in adults: a review of definitions and temporal evolution.Clin Transl Allergy. 2022; 12e12130Crossref PubMed Scopus (18) Google Scholar In children, NAR may be more prevalent in early life, with prevalence decreasing in older children compared with AR.4Westman M. Stjärne P. Asarnoj A. Kull I. van Hage M. Wickman M. et al.Natural course and comorbidities of allergic and nonallergic rhinitis in children.J Allergy Clin Immunol. 2012; 129: 403-408Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Reported prevalence of NAR in school-age children ranges from 6% to 8% in a Swedish population4Westman M. Stjärne P. Asarnoj A. Kull I. van Hage M. Wickman M. et al.Natural course and comorbidities of allergic and nonallergic rhinitis in children.J Allergy Clin Immunol. 2012; 129: 403-408Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar to 25% in a Singaporean cohort.5Chiang W.C. Chen Y.M. Tan H.K. Balakrishnan A. Liew W.K. Lim H.H. et al.Allergic rhinitis and non-allergic rhinitis in children in the tropics: prevalence and risk associations.Pediatr Pulmonol. 2012; 47: 1026-1033Crossref PubMed Scopus (32) Google Scholar Variability in prevalence estimates likely reflect the type of definition used for the study. However, the extent of sIgE testing may also influence the published ranges. Importantly, very little is understood about the influence of environmental exposures, such as rural versus urban environment, microbial diversity, or lifestyle factors, on the prevalence of NAR. Despite the lack of allergic sensitization, multiple articles have examined the relation between NAR and asthma, and have found that NAR is indeed related to asthma risk. Shaaban et al6Shaaban R. Zureik M. Soussan D. Neukirch C. Heinrich J. Sunyer J. et al.Rhinitis and onset of asthma: a longitudinal population-based study.Lancet. 2008; 372: 1049-1057Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar showed in 2008 that in a longitudinal study of adult patients in Western Europe, NAR was associated with a 2.71-fold relative risk of asthma compared with that in those without rhinitis. Using the Tucson Children's Respiratory Study, Carr et al7Carr T.F. Stern D.A. Halonen M. Wright A.L. Martinez F.D. Non-atopic rhinitis at age 6 is associated with subsequent development of asthma.Clin Exp Allergy. 2019; 49: 35-43Crossref PubMed Scopus (12) Google Scholar showed that NAR in childhood at age 6 years was associated with a hazard ratio of 2.1 for subsequent development of asthma through age 32 years when compared with those without rhinitis.7Carr T.F. Stern D.A. Halonen M. Wright A.L. Martinez F.D. Non-atopic rhinitis at age 6 is associated with subsequent development of asthma.Clin Exp Allergy. 2019; 49: 35-43Crossref PubMed Scopus (12) Google Scholar However, using data from the Asthma Phenotypes in the Inner City study, Togias et al8Togias A. Gergen P.J. Hu J.W. Babineau D.C. Wood R.A. Cohen R.T. et al.Rhinitis in children and adolescents with asthma: ubiquitous, difficult to control, and associated with asthma outcomes.J Allergy Clin Immunol. 2019; 143 (.e10): 1003-1011Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar showed that asthma associated with NAR in children may indeed be less severe. As has been the case for other allergic and immunologic diseases over the past decade, emphasis in NAR has included classifying NAR into phenotypes, providing a framework to better understand the pathophysiology and treatment of this heterogeneous group of diseases. Multiple phenotypes of NAR have been described, with the classification describing the exposure thought to drive the disease. These include senile, gustatory, hormonal, occupational, medication-induced, NAR with eosinophilia syndrome (NARES), and vasomotor or "idiopathic" and are well reviewed in the aforementioned expert reviews.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (180) Google Scholar,2Dykewicz M.S. Wallace D.V. Amrol D.J. Baroody F.M. Bernstein J.A. Craig T.J. et al.Rhinitis 2020: a practice parameter update.J Allergy Clin Immunol. 2020; 146: 721-767Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar More recently, these phenotypes are being categorized by suspected physiologic mechanisms, inflammatory or neurogenic, which may ultimately determine the best treatment for the disease (Table I). Fortunately, research efforts continue to attempt to understand this heterogeneous group of disorders toward improving patient care.Table INon allergic rhinitis- phenotypes and characteristicsInflammatoryNeurogenic dysregulationPhenotypeCharacteristicsPhenotypeCharacteristicsNARESLocal & systemic eosinophilia with evidence of T2 inflammationRhinorrhea of the elderlyAffecting those aged >65 y, clear watery rhinorrhea improved with anticholinergic therapyAtrophicLoss of normal mucosal function and tissue destruction; bacterial colonization and granulomatous inflammationVasomotor/idiopathicNasal hyperresponsiveness to irritant stimuli (cold air, particulates, strong odors) due to upregulated sensory signalingOccupationalVariable inflammation with hypersensitivity to irritants in the workplaceRhinitis medicamentosaAlpha receptor tachyphylaxis in the setting of continuous intranasal decongestant use (ie, cocaine, oxymetazoline)HormonalEstrogen contributes to vascular congestion; evidence of H1-receptor upregulationGustatoryClear rhinorrhea while eating, due to neurologic reflex of the noncholinergic, nonadrenergic systemDrug-inducedNSAID/ASA use in NERDDrug-inducedDisruption in sympathetic/parasympathetic tone through use of alpha blockers, beta blockers, vasodilatorsASA, Aspirin; NERD, NSAID-Exacerbated Respiratory Disease; NSAID, nonsteroidal anti-inflammatory drug. Open table in a new tab ASA, Aspirin; NERD, NSAID-Exacerbated Respiratory Disease; NSAID, nonsteroidal anti-inflammatory drug. The archetypal phenotype for inflammatory NAR is NARES. In this disorder, patients suffer from profuse rhinorrhea, sneezing, and nonspecific reactivity. Despite the absence of sIgE to aeroallergens, nasal samples show significant eosinophilia, often more than 20%.2Dykewicz M.S. Wallace D.V. Amrol D.J. Baroody F.M. Bernstein J.A. Craig T.J. et al.Rhinitis 2020: a practice parameter update.J Allergy Clin Immunol. 2020; 146: 721-767Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar In some cohorts, patients with NARES have high rates of asthma, and others develop chronic rhinosinusitis with nasal polyps, suggesting that NARES may represent an early form of this disease. NARES is particularly responsive to the use of intranasal steroids, perhaps due to the underlying type 2 inflammation in this disease.9De Corso E. Seccia V. Ottaviano G. Cantone E. Lucidi D. Settimi S. et al.Clinical evidence of type 2 inflammation in non-allergic rhinitis with eosinophilia syndrome: a systematic review.Curr Allergy Asthma Rep. 2022; 22: 29-42Crossref PubMed Scopus (7) Google Scholar De Corso et al9De Corso E. Seccia V. Ottaviano G. Cantone E. Lucidi D. Settimi S. et al.Clinical evidence of type 2 inflammation in non-allergic rhinitis with eosinophilia syndrome: a systematic review.Curr Allergy Asthma Rep. 2022; 22: 29-42Crossref PubMed Scopus (7) Google Scholar recently reviewed this evidence, identifying increased local expression of chemotactic factors such as eotaxin 2, eotaxin 3, and other nonselective chemokines, such as monocyte chemoattractant protein-1, monocyte chemoattractant protein-3, and regulated on activation normal T-cell expressed and secreted in patients with NARES. However, additional immunologic characteristics are not well described. Occupational rhinitis can be caused by IgE-mediated sensitization to high- molecular-weight antigens, such as in allergic occupational rhinitis. Occupational symptoms can also be nonallergic, driven by exposure to low-molecular-weight chemical substances, such as cleaning products with noxious odors, and triggered by other irritant exposures such as cold dry air and particulates. In a 2017 article, Castano et al10Castano R. Yucesoy B. Johnson V.J. Castellanos L. Cartier A. Inflammatory proteins in nasal lavage of workers exposed to occupational agents.Clin Exp Allergy. 2017; 47: 1566-1573Crossref PubMed Scopus (5) Google Scholar studied protein expression after antigen challenge in patients with rhinitis to both low- and high-molecular-weight products. Participants with low-molecular-weight triggers had high baseline neutrophils in nasal lavage, and saw increase in those levels after challenge. In contrast to those with high-molecular-weight triggers, a panel of inflammatory proteins was not significantly induced. Atrophic rhinitis is characterized by dysfunctional, atrophic nasal mucosa, paradoxical sense of nasal congestion, thick crusts, and foul odor. Primary forms may be related to dry climate, and mucosal colonization with Klebsiella ozaenae or other pathogenic bacteria. Secondary forms can occur after irradiation, nasal surgery, or chronic granulomatous inflammation in the nose.11Shah K. Guarderas J. Krishnaswamy G. Empty nose syndrome and atrophic rhinitis.Ann Allergy Asthma Immunol. 2016; 117: 217-220Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar In addition to antibiotic therapy and moisturization techniques currently used, researchers are studying potential novel therapeutics including platelet-rich plasma injections12Kim D.H. Lee M.H. Lee J. Song E.A. Kim S.W. Kim S.W. Platelet-rich plasma injection in patients with atrophic rhinitis.ORL J Otorhinolaryngol Relat Spec. 2021; 83: 104-111Crossref PubMed Scopus (4) Google Scholar and topical vitamin E13Testa D. Marcuccio G. Lombardo N. Cocuzza S.G. Guerra G. Motta G. Role of alpha-tocopherol acetate on nasal respiratory functions: mucociliary clearance and rhinomanometric evaluations in primary atrophic rhinitis.Ear Nose Throat J. 2021; 100 (NP290-P5)Crossref Scopus (3) Google Scholar to improve airflow mechanics and restore normal mucociliary function. Vasomotor rhinitis (VMR), sometimes called idiopathic rhinitis, is characterized by nasal hyperresponsiveness14Segboer C.L. Holland C.T. Reinartz S.M. Terreehorst I. Gevorgyan A. Hellings P.W. et al.Nasal hyper-reactivity is a common feature in both allergic and nonallergic rhinitis.Allergy. 2013; 68: 1427-1434Crossref PubMed Scopus (62) Google Scholar and accounts for approximately half of the cases of NAR.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (180) Google Scholar,15Avdeeva K.S. Fokkens W.J. Segboer C.L. Reitsma S. The prevalence of non-allergic rhinitis phenotypes in the general population: a cross-sectional study.Allergy. 2022; 77: 2163-2174Crossref PubMed Scopus (12) Google Scholar Nasal hyperresponsiveness is the development of rhinitis symptoms—rhinorrhea, congestion, cough, and so forth—on exposure to nonspecific environmental stimuli such as changes in temperature, smoke, odors, and particulates. Cold dry air challenges may be useful to identify or quantify nasal hyperresponsiveness in VMR.16Van Gerven L. Boeckxstaens G. Jorissen M. Fokkens W. Hellings P.W. Short-time cold dry air exposure: a useful diagnostic tool for nasal hyperresponsiveness.Laryngoscope. 2012; 122: 2615-2620Crossref PubMed Scopus (46) Google Scholar The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as capsaicin receptor or vanilloid receptor, is found in c-fiber sensory neurons, including those from the trigeminal nerve in the nasal cavity. It detects physical and chemical stimuli such as high temperature, acidic conditions, and capsaicin. TRPV1 expression is upregulated in the nasal mucosa of patients with VMR, suggesting that this may be one pathway of neurogenic inflammation in VMR. On stimulation through TRP receptors, the peptidergic c fibers can release neuropeptides such as substance P, that can cause vasodilation, serum extravasation, and mucus hypersecretion17Fokkens W. Hellings P. Segboer C. Capsaicin for rhinitis.Curr Allergy Asthma Rep. 2016; 16: 60Crossref PubMed Scopus (28) Google Scholar and thus contribute to VMR symptoms.18Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133 (.e1-3): 1332-1339Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar Interestingly, topical capsaicin may actually improve VMR symptoms through downregulation or reduced activity of the TRPV1 receptor.17Fokkens W. Hellings P. Segboer C. Capsaicin for rhinitis.Curr Allergy Asthma Rep. 2016; 16: 60Crossref PubMed Scopus (28) Google Scholar Singh et al19Singh U. Bernstein J.A. Haar L. Luther K. Jones W.K. Azelastine desensitization of transient receptor potential vanilloid 1: a potential mechanism explaining its therapeutic effect in nonallergic rhinitis.Am J Rhinol Allergy. 2014; 28: 215-224Crossref PubMed Scopus (30) Google Scholar showed in a murine model that continuous use of azelastine, a topical antihistamine used for the treatment of NAR, may desensitize TRPV1 channels, providing one potential mechanism through which this drug could improve VMR symptoms in humans. In summary, NAR is a heterogeneous group of conditions from which many patients suffer worldwide. Preventative and therapeutic interventions are lacking overall. Future research toward understanding pathophysiology and treatment should emphasize carefully selecting patients by phenotype. An updated 2015 survey of individuals suffering from seasonal allergic rhinoconjunctivitis in the United States found that 75% to 80% rated their symptoms as moderate to severe.20Meltzer E.O. Rosen Farrar J. Sennett C. Findings from an online survey assessing the burden and management of seasonal allergic rhinoconjunctivitis in US patients.J Allergy Clin Immunol Pract. 2017; 5: 779-789Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar The most bothersome symptom, as in previous surveys, was nasal congestion, and the top 5 effects of allergic rhinoconjunctivitis were on feeling irritable, tired, and frustrated, and being unable to perform at their best and having reduced productivity. Most respondents agree that the current medications they were using for allergic rhinoconjunctivitis were effective, gave consistent relief, and had few side effects. Inheritance of AR is about 65%, suggesting that genes are an important reason why some people have AR and others do not. In a meta-analysis of genome-wide association studies using both discovery and replication phases in people with AR and controls, 41 risk loci for AR were identified including 20 loci not previously known to be linked to AR.21Waage J. Standl M. Curtin J.A. Jessen L.E. Thorsen J. Tian C. et al.Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018; 50: 1072-1080Crossref PubMed Scopus (75) Google Scholar Fine mapping of HLA regions suggested amino acid variants pertinent to antigen binding. Shared genetic loci between AR, allergic sensitization, and NAR suggest overlapping mechanisms. An important limitation of the meta-analysis is that most of the samples were from people of European ancestry. Longitudinal studies suggest that there may be race-based differences in the trajectory of atopic diseases.22Gabryszewski S.J. Chang X. Dudley J.W. Mentch F. March M. Holmes J.H. et al.Unsupervised modeling and genome-wide association identify novel features of allergic march trajectories.J Allergy Clin Immunol. 2021; 147 (.e10): 677-685Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Environmental factors are the other main reason why some people have AR. Outdoor air pollution, indoor exposures, and climate change all can affect the development and aggravation of AR.23Eguiluz-Gracia I. Mathiodudakis A.G. Bartel S. Vijverbery S.J.H. Fuertes E. Comberiati P. et al.The need for clean air: the way air pollution and climate change affect allergic rhinitis and asthma.Allergy. 2020; 75: 2170-2184Crossref PubMed Scopus (157) Google Scholar More than 90% of the world population lives in areas where air quality does not meet the standards of the World Health Organization. Indoor air pollutants include tobacco smoke, nitric oxide from gas-fueled cooking and heating, and allergens (furry pets, house dust mites, and molds). Climate change can impact AR through temperature changes, seasonal growth patterns of allergens, altering respiratory infection patterns, and extreme weather events such as flooding (mold) and thunderstorms. The environment also influences the microbiome of individuals; dysbiosis is linked to many disease states including emerging information about the nasal microbiome in AR. Specifically, the genera of Pseudoflavonifractor dominated in well- or partially controlled disease; notably, viral or fungal biome were not considered in this review. α diversity of the nasal microbiome is lower in those with AR compared with healthy controls, and the evenness and richness of the microbiota is related to asthma control.24Chen M. He S. Miles P. Li C. Ge Y. Yu X. et al.Nasal bacterial microbiome differs between healthy controls and those with asthma and allergic rhinitis.Front Cell Infect Microbiol. 2022; 12841995Google Scholar Finally, the severe acute respiratory syndrome coronavirus 2 pandemic, and physical efforts to limit virus spread, offers some lessons about symptom control in AR. Wearing either surgical or N95 masks reduced nasal but not ocular allergy symptoms in a study of nurses from Israel.25Dror A.A. Eisenbach N. Marshak T. Layous E. Zigron A. Shivatzki S. et al.Reduction of allergic rhinitis symptoms with face mask usage during the COVID-19 pandemic.J Allergy Clin Immunol Pract. 2020; 8: 3590-3593Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Surgical and N95 masks filter particles larger than 3 μM and 0.04 μM, respectively, suggesting that pollens of typical sizes between 10 and 100 μM are likely to be filtered. In addition, the impact of wearing a mask on temperature and humidity could influence nasal symptoms. A clearer understanding of epithelial barrier function may lead to new treatment options for AR. Nasal secretions taken from patients with AR decrease epithelial barrier integrity using an air-liquid interface nasal epithelial cell in vitro model.26Steelant B. Seys S.F. Van Gerven L. Van Woensel M. Farre R. Wawrzyniak P. et al.Histamine and T helper cytokine-driven epithelial barrier dysfunction in allergic rhinitis.J Allergy Clin Immunol. 2018; 141: 951-963Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar The more specific factors found to influence the epithelial barrier function included histamine, TNF-α, IL-4, IL-13, and IFN-γ; antagonism of histamine receptor-1, TNF-α, and IL-4–stabilized epithelial barrier function. Histone deacetylase activity is higher in nasal epithelial cells from people with AR, and blocking histone deacetylase activity in vitro and in vivo (in mouse model) restores epithelial integrity.27Steelant B. Wawrzyniak P. Martens K. Jonckheere A.-C. Pugin B. Schrijvers R. et al.Blocking histone deacetylase activity as a novel target for epithelial barriers defects in patients with allergic rhinitis.J Allergy Clin Immunol. 2019; 144: 1242-1253Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar Mechanisms for the Development of ALLergy studies have shed light on allergic diseases including AR at the clinical and mechanistic levels using data from several European birth cohorts. One study using integrated transcriptomics, replicated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans cohort (RNA sequencing) found that multimorbid allergic disease may be different than rhinitis alone.28Lemonnier N. Melén E. Jiang Y. Joly S. Ménard C. Aguilar D. et al.A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents.Allergy. 2020; 75: 3248-3260Crossref PubMed Scopus (43) Google Scholar This has also been suggested in some birth cohorts29Anto J.M. Bousquet J. Akdis M. Auffray C. Keil T. Momas I. et al.Mechanisms of the Development of Allergy (MeDALL): introducing novel concepts in allergy phenotypes.J Allergy Clin Immunol. 2017; 139: 388-399Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar and in a case-control study in asthma.30Burte E. Bousquet J. Siroux V. Just J. Jacquemin B. Nadif R. The sensitization pattern differs according to rhinitis and asthma multimorbidity in adults: the EGEA study.Clin Exp Allergy. 2017; 47: 520-529Crossref PubMed Scopus (42) Google Scholar These differences are likely to have symptom and treatment implications. Symptoms suggestive of AR and demonstration of sensitization to allergens likely to be clinically relevant is a typical approach to diagnosing AR. Additional considerations for diagnosis of AR include the possibility of local but not systemic sensitization and testing for sensitization using tools that take advantage of knowledge about allergenic molecules. Local AR describes a subset of patients who have negative systemic sensitization for environmental allergens but have a positive nasal allergen provocation test result and usually positive sIgE test results for basal activation tests from nasal secretions.31Campo P. Eguiluz-Gracia I. Bogas G. Salas M. Plaza Seron C. Perez N. et al.Local allergic rhinitis: implications for management.Clin Exp Allergy. 2019; 49: 6-16Crossref PubMed Scopus (80) Google Scholar It is potentially important because some studies suggest that people with local AR improve with AIT. Understanding sensitization patterns to allergenic molecules can lead to advice that allows for successful allergen avoidance, as in the example of dog allergen. Can f 5 is one of several allergenic molecules responsible for dog dander allergy and is found in the prostate gland and therefore only in male dogs. A randomized study design challenging children to male and female dog allergens confirmed that children who are monosensitized to Can f 5 are likely to be tolerant to female dogs.32Malby Schoos A.-M. Lund Chawes B. Bloch J. Hansen B. Stockhold J. Bonnelykke K. et al.Children monosensitized to Can f 5 show different reactions to male and female dog allergen extract provocation: a randomized controlled trial.J Allergy Clin Immunol Pract. 2020; 8: 1592-1597Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Selecting outcomes for treatment studies of AR has been advanced through multiple outcome validation studies. A systematic review of the validation of outcomes for AR studies found strengths and weaknesses of outcomes measures.33Calderon M.A. Casale T.B. Demoly P. Validation of patient-reported outcomes for clinical trials in allergic rhinitis: a systematic review.J Allergy Clin Immunol Pract. 2019; 7: 1450-1461Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar Specifically, validation was extensive for disease control and quality-of-life scores. Limitations for using disease control and quality-of-life scores include a relatively long administration time. Total symptom scores, nasal congestion symptom scores, and medication scores can be rapidly measured but are not extensively validated. Biologics are approved for treatment of multiple diseases managed by allergist-immunologists, including asthma, chronic spontaneous urticaria, atopic dermatitis, chronic rhinosinusitis with nasal polyposis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, and eosinophilic esophagitis. Recent advances in understanding the pathophysiology of AR and new clinical trial data are likely to pave the way for studies of these or other biologics for AR. A systematic review and meta-analysis of using omalizumab for inadequately controlled AR found that omalizumab was statistically significantly associated with symptom relief, decreased medication use, and improvement in quality of life.34Tsabouri S. Tseretopoulou X. Priftis K. Ntzani E.E. Omalizumab for the treatment of inadequately controlled allergic rhinitis: a systematic review and meta-analysis of randomized clinical trials.J Allergy Clin Immunol Pract. 2014; 2: 3320-3340Abstract Full Text Full Text PDF Scopus (106) Google Scholar A limitation of the analysis is that it is not clear whether these statistical differences are likely to be clinically significant for these outcomes. However, a trial of omalizumab for AR published after the systematic review found that nasal and ocular symptoms were clinically improved compared with standard of care.35Okubo K. Okano M. Sato N. Tamaki Y. Suzuki H. Uddin A. et al.Add-on omalizumab for inadequately controlled severe pollinosis despite standard-of-care: a randomized study.J Allergy Clin Immunol Pract. 2020; 8: 3130-3140Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar A trial of dupilumab for asthma found that some but not all patients with perennial AR had reductions in nasa