International consensus statement on allergy and rhinology

I.C.1 Definitions, classification, and differential diagnosis

AR is primarily driven by an immunoglobulin E (IgE)‐mediated type 1 hypersensitivity response, due to an allergen exposure. Classically, seasonal AR was thought to be associated with outdoor allergens and perennial AR with indoor year‐round exposure to allergens. However, climate change and polysensitization may make these classifications challenging. Intermittent AR is defined as symptoms for less than 4 days per week or less than four consecutive weeks. Persistent AR is defined as symptoms for more than 4 days per week for at least 1 month. Sensitization to allergens may be identified on skin or in vitro testing which assesses the presence of allergen‐specific IgE (sIgE). However, many people that are sensitized do not exhibit allergy symptoms, so correlation with clinical symptoms upon allergen exposure is critical. Classic AR symptoms include sneezing, rhinorrhea, and nasal congestion/obstruction. These symptoms are non‐specific, and the differential diagnosis of AR is broad. Section V of the ICAR‐Allergic Rhinitis 2023 document explores AR definition, classification, and differential diagnosis (Table I.C.1).

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I.C.2 Pathophysiology and mechanisms

Shortly after IgE receptor stimulation, mast cells secrete proteins due to stimulated gene transcription. Multiple cytokines and chemokines are released, which recruit inflammatory cells such as eosinophils, basophils, neutrophils, macrophages, and T cells.

Various inflammatory processes occur at different stages of AR. These processes are driven by the type 2 immune response. Considering the pathophysiology of AR, the ICAR‐Allergic Rhinitis 2023 document explores local and systemic IgE‐mediated inflammation, cellular infiltrates, cytokines and soluble mediators, neural mechanisms, histologic and epithelial changes, epithelial barrier alterations, association with vitamin D, alterations in nitric oxide and the microbiome, as well as the unified airway concept. Section VI of the ICAR‐Allergic Rhinitis 2023 document discusses AR pathophysiology and mechanisms.

I.C.3 Epidemiology

The prevalence of AR has been reported from 5% to 50% worldwide. Prevalence reporting is dependent on the method of diagnosis and age of participants studied, which may explain some of the variability in reported AR prevalence. There have been increased attempts to provide more uniformity in the terminology and diagnostic criteria for AR. The available literature suggests that AR had been previously increasing across the globe. While recent evidence indicates this upward trend may have leveled off, notable geographic differences exist. The rate of AR typically increases with age until young adulthood. The effects of geographic influences on epidemiology of AR and the role of climate change are active areas of research. Section VII of the ICAR‐Allergic Rhinitis 2023 document reviews the epidemiology of AR.

I.C.4 Risk factors and protective factors for the development of allergic rhinitis

Several risk factors for the development of AR have been investigated. There is conflicting data for many of these potential risk factors, and this area of work remains a topic of active investigation. Section VIII of the ICAR‐Allergic Rhinitis 2023 document explores risk factors and potential protective factors for the development of AR (Tables I.C.4.‐1 and I.C.4.‐2).

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I.C.5 Disease burden

ICAR‐Allergic Rhinitis 2023 reviewed the disease burden of AR as it relates to quality of life (QOL) and sleep disturbance. Several new studies have been added in each of these categories since ICAR‐Allergic Rhinitis 2018. AR also has substantial impact at a societal level, which may be quantified in direct and indirect costs, absenteeism or presenteeism, and other measures. Individual and societal burdens of AR are significant and addressed further in the full ICAR‐Allergic Rhinitis 2023 document (Table I.C.5).

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I.C.6 Evaluation and diagnosis

A thorough history is critical to AR diagnosis. This should be complemented by an appropriate physical examination, and nasal endoscopy may also be considered. Various diagnostic testing modalities may also be employed to solidify a diagnosis of AR or when considering an alternate etiology for the patient's symptoms. A summary of various diagnostic modalities for AR is presented in Table I.C.6.

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The section that follows includes the recommendation summaries for AR diagnostic modalities considered in the ICAR‐Allergic Rhinitis 2023 document.

I.C.7 Management

I.C.7.a Avoidance measures and environmental controls

Allergen avoidance is generally low risk and may provide some benefit in controlling AR symptoms. Both physical interventions and chemical applications may reduce allergen load in the environment, although assessment of the effects of these interventions on control of AR symptoms is lacking in some studies. ICAR‐Allergic Rhinitis 2023 evaluated allergen avoidance and environmental control measures for house dust mite, cockroach, pets, rodents, pollen, and occupational allergens. Section XI.A of the ICAR‐Allergic Rhinitis 2023 document summarizes studies of avoidance measures and environmental controls employed for the treatment of AR (Table I.C.7.a).

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The section that follows includes recommendation summaries for allergen avoidance and environmental controls that are included in the ICAR‐Allergic Rhinitis 2023 document.

Avoidance – house dust mite (HDM)

Aggregate grade of evidence: B (Level 1: 2 studies, level 2: 12 studies)

Benefit: Potential improvement in AR symptoms and QOL with reduced concentration of environmental HDM antigens.

Harm: None.

Cost: Low to moderate. However, cost‐effectiveness was not evaluated.

Benefits‐harm assessment: Benefit outweighs harm.

Value judgments: There is supporting evidence for the use of acaricides in reducing HDM concentration in children who have AR coexistent with asthma. In adults and children without concomitant asthma, the use of acaricides with/without bedroom‐based control programs for reducing HDM concentration are promising, but further, high‐quality studies are needed to evaluate clinical outcomes.

Policy level: Option.

Intervention: Acaricides used independently or alongside environmental control measures, such as air filtration devices, could be considered as options in the management AR.

Avoidance – cockroach

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 8 studies, level 3: 2 studies, level 4: 1 study)

Benefit: Reduction in cockroach count but allergen concentrations (Bla g 1 and Bla g 2) often above acceptable levels for clinical benefits. No studies included clinical endpoints related to AR.

Harm: None noted.

Cost: Direct costs include multiple treatment applications or multi‐interventional approaches. Indirect costs include potential time off work for interventions in home and substantial labor of cleaning measures to eradicate allergens.

Benefits‐harm assessment: Balance of benefits and harms since lack of clear clinical benefits.

Value judgments: Control of cockroach populations especially in densely populated multi‐family dwellings is important to control cockroach allergen levels.

Policy level: Option.

Intervention: Combination of physical measures (e.g., insecticide bait traps, house cleaning) and education‐based methods seem to have the greatest efficacy. Additional research on single intervention approaches is needed with cost analysis, as well as investigation of clinical outcomes related to AR.

Avoidance – pets

Aggregate grade of evidence: C (Level 2: 2 studies, level 3: 2 studies, level 4: 1 study)

Benefit: Decreased environmental allergen exposure with possible reduction in symptoms and secondary prevention of asthma.

Harm: Emotional distress caused by removal of household pets. Financial and time costs of potentially ineffective intervention.

Cost: Low to moderate.

Benefits‐harm assessment: Equivocal.

Value judgments: While several studies have demonstrated an association between environmental controls and reductions in environmental antigens, only a single, multi‐modality randomized controlled trial has demonstrated clinical improvement in nasal symptoms among patients with Fel d 1 sensitivity. The secondary prevention and treatment of asthma in sensitized individuals must also be considered.

Policy level: Option.

Intervention: Pet avoidance and environmental control strategies, particularly multi‐modality environmental controls among patients with diagnosed Fel d 1 sensitivity, may be presented as an option for the treatment of AR.

Avoidance – rodents

Aggregate grade of evidence: C (Level 2: 5 studies, level 3: 5 studies, level 4: 4 studies, level 5: 1 study)

Benefit: Reduces rodent allergen levels (specifically mouse allergen) but no information on AR outcomes.

Harm: Reduction in patient QOL due to removal of pet rodent to whom patient is emotionally attached. Change in job position or role if primary rodent exposure is work‐related.

Cost: Direct costs include the cost of interventions such as extermination and mitigating causal factors or loss of income if a job change occurs. Indirect costs include time off work for pest control appointments.

Benefits‐harm assessment: Balance of benefit and harm.

Value judgments: Careful patient selection based on exposure history. Heterogeneity of integrated pest management protocols makes quantification of benefit difficult.

Policy level: Option.

Intervention: Avoidance likely improves rodent‐specific allergen exposure, especially when the interaction can be eliminated such as when it is work‐related or with a pet rodent. Integrated pest management should be considered in select patients, such as pediatric inner‐city patients that suffer from asthma and are mouse sensitized.

Avoidance – pollen

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 3 studies)

Benefit: Decreased symptoms and medication use with potential for improved QOL.

Harm: Interventions may vary in cost and efficacy of each may be inadequately defined.

Cost: Generally low monetary cost depending on strategy.

Benefits‐harm assessment: Equivocal, most interventions with lower harm but not well‐defined benefits.

Value judgments: Most pollen avoidance measures are based on clinical and expert opinion although trial‐based evidence is available for some interventions.

Policy level: Option.

Intervention: Pollen avoidance strategies are generally well tolerated and lower cost, non‐medication‐based interventions that may have benefit with minimal harm to the patient, but further randomized controlled trials with larger populations would be needed to better characterize efficacy.

Avoidance – occupational

Aggregate grade of evidence: C (Level 3: 5 studies)

Benefit: Decreased allergen exposure may lead to reduction in symptoms, improvement in QOL, and possible reduced likelihood of developing occupational asthma.

Harm: Potential for socioeconomic harm with loss of wages or requiring changes in occupation.

Cost: Individually may vary if avoidance results in loss of income; for employers, potentially high cost depending on interventions or environmental controls required.

Benefits‐harm assessment: Where possible from a patient‐centered perspective, in occupational rhinitis complete avoidance is likely beneficial in improving health quality compared to ongoing exposures.

Value judgments: Based primarily on observational studies, allergen avoidance or decreasing exposure is recommended for all patients but can be nuanced depending on the resulting socioeconomic impact.

Policy level: Recommendation.

Intervention: Patients should be counseled to avoid or decrease exposure to inciting agents in occupational respiratory disease.

I.C.7.b Pharmacotherapy and procedural options

Pharmacologic treatments are frequently employed to control AR symptoms. Depending on the specific therapy and geographic region, these may be available by prescription or over‐the‐counter. The evidence for pharmacologic options for AR has been reviewed (Table I.C.7.b).

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The section that follows includes recommendation summaries for pharmacotherapies and procedural interventions that are included in the ICAR‐Allergic Rhinitis 2023 document. A standard listing of side effect and adverse effects of most AR management options may be found in Table II.C. within the full ICAR‐Allergic Rhinitis 2023 document.

Oral H₁ antihistamines

Aggregate grade of evidence: A (Level 1: 19 studies, level 4: 5 studies)

Benefit: Reduction in symptoms of AR.

Harm: Compared to first‐generation oral antihistamines, newer‐generation antihistamines have fewer central nervous system and anticholinergic side effects. The side effects of first‐generation antihistamines can be more pronounced in the elderly. See Table II.C. in full ICAR document.

Cost: Inexpensive. Given their improved side effect profile, newer‐generation oral antihistamines also have lower indirect costs than first generation oral H₁ antihistamines.

Benefits‐harm assessment: The benefits outweigh harm for use of newer‐generation H₁ oral antihistamines for AR.

Value judgments: First‐generation oral antihistamines are not recommended for the treatment of AR because of their central nervous system and anticholinergic side effects.

Policy level: Strong recommendation for the use of newer‐generation oral antihistamines for AR.

Intervention: Newer‐generation oral antihistamines can be considered in the treatment of AR.

Oral H₂ antihistamines

Aggregate grade of evidence: B (Level 2: 7 studies)

Benefit: Decreased objective nasal resistance, and improved symptom control in 4 studies when used in combination with H₁ antagonists.

Harm: Drug–drug interaction (p450 inhibition, inhibited gastric secretion, and absorption).

Cost: Increased cost associated with H₂ antagonist over H₁ antagonist alone.

Benefits‐harm assessment: Unclear benefit and possible harm.

Value judgments: No studies evaluating efficacy of H₂ antihistamines in context of INCS. There were 2 studies that showed no benefit for H₂ antagonist when used alone or as an additive to H₁ antagonist therapy.

Policy level: No recommendation. Available evidence does not adequately address the benefit of H₂ antihistamines in AR.

Intervention: Addition of an oral H₂ antagonist to an oral H₁ antagonist may improve symptom control in AR, but data is limited.

Intranasal antihistamines

Aggregate grade of evidence: A (Level 2: 44 studies)

Benefit: Rapid onset; more effective for nasal congestion than oral antihistamines; more effective for ocular symptoms than INCS; consistent reduction in symptoms and improvement in QOL in randomized controlled trials compared to placebo.

Harm: Patient tolerance, typically related to taste aversion; less effective for congestion than INCS. See Table II.C. in full ICAR document.

Cost: Low to moderate financial burden; available as prescription or nonprescription product.

Benefits‐harm assessment: Preponderance of benefit over harm. Intranasal antihistamine as monotherapy is consistently more effective than placebo. Most studies show intranasal antihistamines superior to INCS for sneezing, itching, rhinorrhea, and ocular symptoms. Adverse effects are minor and infrequent. Generic prescription and over‐the‐counter formulations now available.

Value judgments: Extensive high‐level evidence comparing intranasal antihistamine monotherapy to active and placebo controls demonstrates overall effectiveness and safety.

Policy level: Strong recommendation.

Intervention: Intranasal antihistamines may be used as first‐ or second‐line therapy in the treatment of AR.

Oral corticosteroids

Aggregate grade of evidence: B (Level 2: 6 studies, level 3: 1 study, level 4: 3 studies)

Benefit: Oral corticosteroids can attenuate symptoms of AR and ongoing allergen induced inflammation.

Harm: Oral corticosteroids have multiple potential adverse effects, including hypothalamic‐pituitary axis suppression. Prolonged use may lead to growth retardation in pediatric populations. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: The risks of oral corticosteroids outweigh the benefits, given similar symptomatic improvement observed with the use of safer INCS.

Value judgments: In the presence of effective symptom control using INCS, the risk of adverse effects from using oral corticosteroids for AR outweighs potential benefits.

Policy level: Strong recommendation against routine use.

Intervention: Although not recommended for routine use in AR, certain clinical scenarios may warrant the use of short courses of systemic corticosteroids, following a discussion of the risks and benefits with the patient. For example, oral steroids could be considered in select patients with significant nasal obstruction that precludes adequate penetration of intranasal agents (corticosteroids or antihistamines). In these cases, a short course of systemic corticosteroids may improve congestion and facilitate access of topical medications. No evidence supports this suggestion, and thus careful clinical judgment and risk discussion are advocated.

Intranasal corticosteroid sprays

Aggregate grade of evidence: A (Level 1: 18 studies, level 2: 29 studies, level 3: 3 studies)

Benefit: INCS sprays are effective in reducing nasal and ocular symptoms of AR. Studies have demonstrated superior efficacy compared to oral antihistamines and leukotriene receptor antagonists (LTRAs).

Harm: INCS sprays have undesirable local adverse effects, such as epistaxis, with increased frequency compared to placebo in prolonged administration studies. There are no apparent negative effects on the hypothalamic‐pituitary axis. There might be some negative effects on short‐term growth in children, but it is unclear whether these effects translate into long‐term growth suppression. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: The benefits of using INCS sprays outweigh the risks when used to treat seasonal or perennial AR.

Value judgments: INCS sprays are first line therapy for the treatment of AR by virtue of their superior efficacy in controlling nasal symptoms. Subjects with seasonal AR should start prophylactic treatment with INCS sprays several days before the pollen season with an evaluation of the patient's response a few weeks after initiation, including a nasal exam to evaluate for local irritation or mechanical trauma. Children receiving INCS sprays should be on the lowest effective dose to avoid negative growth effects.

Policy level: Strong recommendation.

Intervention: The demonstrated efficacy of INCS sprays, as well as their superiority over other agents, make them first‐line therapy in the treatment of AR.

Intranasal corticosteroids: non‐traditional application

Aggregate grade of evidence: B (Level 2: 4 studies, level 3: 1 study)

Benefit: Nebulized steroids or those used via irrigation show some benefit in the treatment of AR in limited studies. Furthermore, steroids inhaled or exhaled through the nose in patients with asthma and rhinitis also show some benefit for rhinitis. Nasal steroid drops are not approved for treatment of rhinitis but are used in certain countries.

Harm: Nasal steroid drops have significant systemic side effects. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: The risks of using corticosteroid nasal drops for AR outweigh the benefits. Limited evidence suggests that nasal steroid irrigations for rhinitis lead to significant improvement of symptoms. Scarce evidence does not support routine recommendation for this route of therapy.

Value judgments: In the presence of effective symptom control using traditional spray administration for INCS, there is no solid data to support other routes of administration.

Policy level: Recommendation against routine use.

Intervention: There is some evidence that inhaled steroids, when exhaled through the nose might improve AR symptoms. Similar benefit is seen when steroids are inhaled by first passing through the nose. These routes might be useful in patients with both rhinitis and asthma.

Injectable corticosteroids

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 11 studies, level 4: 2 studies)

Benefit: Injectable corticosteroids improved symptoms of AR in clinical studies.

Harm: Injectable corticosteroids have known undesirable adverse effects on the hypothalamic‐pituitary axis, growth, osteoporosis, glycemic control, and other systemic adverse effects, for varied periods of time after injection. Intraturbinate corticosteroids have a small but potentially serious risk of ocular side effects including decline or loss of vision. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: In routine management of AR, the risk of serious adverse effects outweighs the demonstrated clinical benefit.

Value judgments: Injectable corticosteroids are effective for the treatment of AR. However, given the risk of significant systemic adverse effects, the risk of serious ocular side effects, and the availability of effective alternatives (e.g., INCS sprays), injectable corticosteroids are not recommended for the routine treatment of AR.

Policy level: Recommendation against.

Intervention: None.

Oral decongestants

Aggregate grade of evidence: A (Level 2: 12 studies)

Benefit: Reduction of nasal congestion with pseudoephedrine. No benefit with phenylephrine.

Harm: Oral decongestants have known undesirable adverse effects. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Balance of benefit and harm for pseudoephedrine. Possible harm for phenylephrine.

Value judgments: Little evidence for benefit in controlling symptoms other than nasal congestion.

Policy level: Strong recommendation against for routine use in AR. In certain cases, combination therapy with an oral antihistamine may be beneficial to alleviate severe nasal congestion in short courses.

Intervention: Although not recommended for routine use in AR, pseudoephedrine can be effective in reducing nasal congestion in patients with AR; however, it should only be used as short‐term/rescue therapy after a discussion of the risks and benefits with the patient (comorbidities) and consideration of alternative intranasal therapy options.

Intranasal decongestants

Aggregate grade of evidence: B (Level 2: 10 studies, level 3: 2 studies) Limitation – only 3 studies included subjects with AR.

Benefit: Reduction in symptoms of nasal congestion/blockage and corresponding objective markers with intranasal decongestants compared to placebo.

Harm: Side effects include nasal discomfort/burning, dependency, dryness, hypertension, anxiety, and tremors. Potential for rebound congestion with long‐term use. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Harm likely outweighs benefit if used long‐term, with adverse effects appearing as early as 3 days.

Value judgments: Intranasal decongestants can be helpful for short‐term relief of nasal congestion.

Policy level: Option for short‐term use.

Intervention: Intranasal decongestants can provide effective short‐term relief of nasal congestion in patients with AR during an acute flare but recommend against chronic use due to risk of rhinitis medicamentosa.

Leukotriene receptor antagonists (LTRA)

Aggregate grade of evidence: A (Level 1: 13 studies; level 2: 21 studies)

Benefit: Consistent reduction in symptoms and improvement in QOL compared to placebo.

Harm: United States Food and Drug Administration (FDA) boxed warning regarding neuropsychiatric side effects, including suicidal ideation. Consistently inferior compared to INCS at symptom reduction and improvement in QOL. Equivalent or inferior effect compared to oral antihistamines in symptom reduction and improvement of QOL. See Table II.C. in full ICAR document.

Cost: Moderate.

Benefits‐harm assessment: LTRAs are effective as monotherapy compared to placebo. However, there is a consistently inferior or equivalent effect to other, less expensive agents used as monotherapy. The FDA boxed warning is associated with LTRAs as well.

Value judgments: LTRAs are more effective than placebo at controlling both asthma and AR symptoms in patients with both conditions. However, in the light of significant concerns over its safety profile and the availability of effective alternatives such as INCS and oral antihistamines, evidence is lacking to recommend LTRAs as monotherapy in the management of AR.

Policy level: Recommendation against LTRAs as first‐line monotherapy for patients with AR. Option for LTRA as monotherapy in patients with contraindications to other preferred treatments.

Intervention: LTRAs should not be used as monotherapy in the treatment of AR but can be considered in select situations where patients have contraindications to alternative treatments.

Intranasal cromolyn

Aggregate grade of evidence: A (Level 2: 25 studies)

Benefit: Disodium cromoglycate (DSCG) is effective in reducing sneezing, rhinorrhea, and nasal congestion.

Harm: Rare local side effects.

Cost: Low.

Benefits‐harm assessment: Preponderance of mild to moderate benefit over harm. Less effective than INCS and intranasal antihistamines.

Value judgments: DSCG is useful for preventative short‐term use in adult patients, children (2 years and older), and pregnant patients with known exposure risks.

Policy level: Recommendation as a second‐line treatment in AR.

Intervention: DSCG may be used as a second‐line treatment for AR in patients who fail INCS or intranasal antihistamines, or for short‐term preventative benefit prior to allergen exposures.

Intranasal anticholinergics (ipratropium bromide (IPB))

Aggregate grade of evidence: A (Level 2: 10 studies, level 3: 2 studies)

Benefit: Reduction of rhinorrhea with topical anticholinergics.

Harm: Care should be taken to avoid overdosage leading to systemic side effects. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Preponderance of benefit over harm in AR patients with rhinorrhea.

Value judgments: Benefits limited to controlling rhinorrhea. Can be used as add on treatment for AR patients with persistent rhinorrhea despite first‐line medical management.

Policy level: Option.

Intervention: IPB nasal spray may be used as an adjunct medication to INCS in AR patients with persistent rhinorrhea.

Biologic therapies

Aggregate grade of evidence: A (Level 1: 2 studies, level 2: 8 studies, level 3: 2 studies)

Benefit: Omalizumab treatment resulted in improvement of symptoms, rescue medication, and QOL as a monotherapy. Dupilumab data is less robust and needs further investigation.

Harm: Local reaction at injection site and risk of anaphylaxis.

Cost: High.

Benefits‐harm assessment: Benefit outweighs harm.

Value judgments: Biologic therapies show promise as a treatment option for AR; however, no biologic therapies have been approved by the US FDA for this indication.

Policy level: Option based upon published evidence, although not currently approved for this indication.

Intervention: Monoclonal antibody (biologic) therapies are not currently approved for the treatment of AR.

Intranasal saline

Aggregate grade of evidence: A (Level 1: 4 studies, level 2: 17 studies)

Benefit: Improved nasal symptoms and QOL, reduction in oral antihistamine use, and improved mucociliary clearance. Well‐tolerated with excellent safety profile.

Harm: Nasal irritation, sneezing, cough, and ear fullness. See Table II.C. in full ICAR document.

Cost: Minimal.

Benefits‐harm assessment: Preponderance of benefit over harm.

Value judgments: Nasal saline can and should be used as a first line treatment in patients with AR, either alone or combined with other pharmacologic treatments as evidence supports an additive effect. Hypertonic saline may be more effective in children. Data is otherwise inconclusive on optimal salinity, buffering, and frequency and volume of administration.

Policy level: Strong recommendation.

Intervention: Nasal saline is strongly recommended as part of the treatment strategy for AR.

Probiotics

Aggregate grade of evidence: A (Level 1: 4 studies, level 2: 5 studies)

Benefit: Improved nasal/ocular symptoms or QOL in most studies.

Harm: Mild gastrointestinal side effects.

Cost: Low.

Benefits‐harm assessment: Balance of benefit and harm.

Value judgments: Minimal harm associated with probiotics. Heterogeneity across studies makes magnitude of benefit difficult to quantify. Variation in organism and dosing across trials prevents specific recommendations for treatment.

Policy level: Option.

Intervention: Consider adjuvant use of probiotics for patients with symptomatic seasonal or perennial AR.

Combination oral antihistamine and oral decongestant

Aggregate grade of evidence: A (Level 2: 30 studies)

Benefit: Improved nasal congestion and total symptom scores with combination oral antihistamine‐oral decongestants.

Harm: Oral decongestants can cause adverse events in patients with cardiac conditions, hypertension, or benign prostatic hypertrophy and are not indicated in patients under age 12 or pregnant patients. Oral antihistamines are not indicated in patients under 2 years of age, and caution should be exercised in patients aged 2–5 years old. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Combination oral antihistamine‐oral decongestant medications carry relatively low risks of adverse events when used as needed for episodic AR symptoms in well‐selected patients. Risk may be higher if used daily or in patients with certain comorbidities. There is not a preponderance of benefit or harm when used appropriately as a treatment option.

Value judgments: Oral antihistamine‐oral decongestants may be an effective option for acute AR symptoms such as nasal congestion and sneezing. Caution should be exercised with long‐term use.

Policy level: Option for episodic or acute AR symptoms.

Intervention: Combination oral antihistamine‐oral decongestant medications may provide effective relief of nasal symptoms of AR on an episodic basis. Caution should be exercised in chronic or long‐term use as the adverse effect profile of oral decongestants is greater for chronic use.

Combination oral antihistamine and intranasal corticosteroid

Aggregate grade of evidence: A (Level 1: 1 study, level 2: 12 studies)

Benefit: The addition of oral antihistamine to INCS has not consistently demonstrated a benefit over INCS alone for symptoms of AR.

Harm: Oral antihistamines generally not recommended in patients under 2 years old, and attention to dosing is necessary in patients 2–12 years old. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Benefit likely outweighs potential harms in patients with significant nasal congestion symptoms in addition to symptoms such as sneezing and ocular itching. Addition of an INCS may be limited benefit versus potential harm in patients without significant nasal congestion symptoms.

Value judgments: Adding oral antihistamine to INCS spray has not been demonstrated to confer additional benefit over INCS spray alone. INCS improves congestion with or without oral antihistamine.

Policy level: Option.

Intervention: Current evidence is mixed to support antihistamines as an additive therapy to INCS, as several randomized trials have not demonstrated a benefit over INCS alone for symptoms of AR.

Combination oral antihistamine and leukotriene receptor antagonist

Aggregate grade of evidence: A (Level 1: 4 studies, level 2: 13 studies)

Benefit: Combination oral antihistamine‐LTRA was superior in symptom reduction and QOL improvement versus placebo and versus either agent as monotherapy.

Harm: FDA boxed warning due to risks of mental health side effects limiting use for AR. See Table II.C. in full ICAR document.

Cost: Generic montelukast added to generic loratadine or cetirizine is more expensive per month than generic fluticasone furoate nasal sprays, according to National Average Drug Acquisition Cost data provided by the Centers for Medicare and Medicaid Services.

Benefits‐harm assessment: Combination LTRA and oral antihistamine is superior to placebo, and superior to either agent as monotherapy. However, there is an inferior effect versus INCS, which is also less costly. In addition, there is a boxed warning associated with montelukast.

Value judgments: Combination therapy of LTRA and oral antihistamines is effective, but in light of concerns over the safety profile of montelukast, and the availability of effective alternatives such as INCS, evidence is lacking to recommend combination therapy in the management of AR.

Policy level: Recommendation against as first line therapy.

Intervention: Combination LTRA and oral antihistamines should not be used as first line therapy for AR but can be considered in patients with contraindications to other alternatives. This combination should be used judiciously after carefully weighing potential risks and benefits.

Combination intranasal corticosteroid and intranasal antihistamine

Aggregate grade of evidence: A (Level 1: 2 studies, level 2: 18 studies, level 4: 3 studies)

Benefit: Rapid onset; more effective for relief of multiple symptoms than either INCS or intranasal antihistamine alone.

Harm: Patient tolerance, especially due to taste. See Table II.C. in full ICAR document.

Cost: Moderate financial burden for combined formulation. Concurrent use of individual intranasal antihistamine and corticosteroid sprays is likely a more economical option.

Benefits‐harm assessment: Preponderance of benefit over harm. Combination therapy with intranasal antihistamine and INCS is consistently more effective than placebo or monotherapy. Low risk of non‐serious adverse effects.

Value judgments: High‐level evidence demonstrates that combination spray therapy with INCS plus intranasal antihistamine is more effective than monotherapy or placebo, as well as more effective than combination of INCS plus oral antihistamine. The increased financial cost and need for prescription limit the value of combination therapy as a routine first‐line treatment for AR. When a combined formulation is financially prohibitive, the concurrent use of two separate formulations (antihistamine and corticosteroid) is an alternative option.

Policy level: Strong recommendation for the treatment of AR when monotherapy fails to control symptoms.

Intervention: Combination therapy with INCS and intranasal antihistamine may be used as second‐line therapy in the treatment of AR when initial monotherapy with either INCS or antihistamine does not provide adequate control.

Combination intranasal corticosteroid and leukotriene receptor antagonist

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 8 studies)

Benefit: Some studies demonstrate improvement of symptoms and QOL with combination therapy. One meta‐analysis did not show benefit with the exception of ocular itching.

Harm: Boxed warning due to risks of serious neuropsychiatric events for LTRA limiting use for AR. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Boxed warning for AR limits use. If comorbid asthma and AR, treatment is an option with consideration of mental health risks.

Value judgments: Possibly useful for symptom control, especially in patients with comorbid asthma, however, boxed warning limits use in AR without asthma.

Policy level: Option as combination therapy if comorbid asthma present and mental health risks are considered. Not recommended for AR alone.

Intervention: Consider use in patients with AR and asthma, after weighing therapeutic benefits against risks of mental health adverse effects.

Combination intranasal corticosteroid and intranasal decongestant

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 5 studies, level 3: 1 study)

Benefit: Some evidence in randomized studies of benefit from addition of intranasal decongestant to INCS therapy in refractory AR patients. The evidence regarding the magnitude of effect is unclear, and a meta‐analysis that tried to estimate this effect was significantly limited by study heterogeneity and low sample size (two trials).

Harm: See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Balance of benefit and harm with current evidence base.

Value judgments: While combination therapy of intranasal decongestant and INCS is superior to INCS therapy alone with low risk of tachyphylaxis in patients with refractory AR, the magnitude of effect is still unclear. There may be a role in patients with AR refractory to INCS and intranasal antihistamine combination therapy prior to consideration of surgery or in patients uninterested in surgery.

Policy level: Option.

Intervention: Short‐term combination therapy with INCS and intranasal decongestant may be considered in patients with AR refractory to combination therapy with INCS and intranasal antihistamine prior to consideration of inferior turbinate reduction or in patients declining surgery.

Combination intranasal corticosteroid and intranasal ipratropium bromide

Aggregate grade of evidence: Unable to determine based on one study. (Level 2: 1 study)

Benefit: Reduction of rhinorrhea in INCS‐treatment‐refractory AR.

Harm: Usually no systemic anticholinergic activity if administered intranasally in the recommended doses. See Table II.C. in full ICAR document.

Cost: Low.

Benefits‐harm assessment: Benefit for combined INCS and IPB therapy in patients with treatment refractory AR and the main symptom of rhinorrhea.

Value judgments: No evidence for benefit in controlling symptoms other than rhinorrhea. Evidence is limited, but results are encouraging for patients with persistent rhinorrhea.

Policy level: Option.

Intervention: Combining IPB with beclomethasone dipropionate can be more effective than either agent alone for the treatment of rhinorrhea in refractory AR in children and adults. Although multiple consensus guidelines have recommended, and there is evidence to support this recommendation, it is important to note that there has only been one randomized controlled trial (RCT) to study the efficacy of combined INCS and IPB therapy compared to either agent alone, and this study was performed in a combined population of patients with AR and non‐allergic rhinitis.

Acupuncture

Aggregate grade of evidence: A (Level 1: 4 studies, level 2: 1 study)

Benefit: Improvement of QOL and symptoms. Fairly well tolerated with no systemic adverse effects.

Harm: Needle sticks associated with minor adverse events including skin irritation, erythema, subcutaneous hemorrhage, pruritus, numbness, fainting, and headache. Electroacupuncture can interfere with pacemakers and other implantable devices. Caution is recommended in pregnant patients as some acupoints can theoretically induce labor. Need for multiple treatments and possible ongoing treatment to maintain any benefit gained. Relatively long treatment period.

Cost: Moderate‐high. Cost and time associated with acupuncture treatment; multiple treatments required.

Benefits‐harm assessment: Balance of benefit and harm.

Value judgments: The evidence is generally supportive of acupuncture. Acupuncture may be appropriate for some patients to consider as an adjunct/alternative therapy.

Policy level: Option.

Intervention: In patients who are interested in avoiding medications, acupuncture can be suggested as a possible therapeutic adjunct.

Honey

Aggregate grade of evidence: D (Level 2: 3 studies, conflicting evidence)

Benefit: Unclear as studies have shown differing results and include different preparations of honey in the trials. Local honey may be able to modulate symptoms and decrease need for antihistamines.

Harm: Potential compliance issues with patients not tolerating the level of sweetness. Potential risk of allergic reaction and rarely anaphylaxis. Caution should be exercised in in pre‐diabetics and diabetics for concern of elevated blood glucose levels.

Cost: Cost of honey and associated healthcare costs with increased consumption.

Benefits‐harm assessment: Balance of benefit and harm.

Value judgments: More studies are required before honey intake can be widely recommended.

Policy level: No recommendation.

Intervention: None.

Herbal therapies

Aggregate grade of evidence: Uncertain.

Benefit: Unclear, but some herbs may be able to provide symptomatic relief.

Harm: Some herbs are associated with mild side effects. Also, the safety, quality, and standardization of herbal remedies and supplements are unclear.

Cost: Cost of herbal supplements.

Benefits‐harm assessment: Unknown.

Value judgments: There is a lack of sufficient evidence to recommend the use of herbal supplements in AR.

Policy level: No recommendation.

Intervention: None.

Septoplasty/septorhinoplasty

Aggregate grade of evidence: C (Level 3: 1 study, level 4: 3 studies, level 5: 11 studies)

Benefit: Improved postoperative symptoms and nasal airway.

Harm: Risk of complications (e.g., septal hematoma or perforation, nasal dryness, cerebrospinal fluid leak, epistaxis, unfavorable aesthetic change); persistent obstruction.

Cost: Surgical/procedural costs, time off from work.

Benefits‐harm assessment: Potential benefit must be weighed against low risk of harm and cost of procedure.

Value judgments: Properly selected patients with septal deviation impacting their nasal patency can experience improved nasal obstruction symptoms.

Policy level: Option for those with obstructive septal deviation.

Intervention: Septoplasty/septorhinoplasty may be considered in AR patients that have failed medical management and who have anatomic, obstructive features that may benefit from this intervention.

Inferior turbinate (IT) surgery

Aggregate grade of evidence: B (Level 1: 4 studies, level 2: 13 studies, level 3: 18 studies, level 4: 50 studies)

Benefit: Improvement in rhinitis symptoms including nasal breathing, congestion, sneezing, and itching. Improved nasal cavity area via objective measures, as well as increased QOL via subjective measures.

Harm: Risk of complications (e.g., swelling, crusting, empty nose syndrome, epistaxis).

Cost: Surgical/procedural costs, potential time off from work.

Benefits‐harm assessment: Potential benefit outweighs low risk of harm.

Value judgments: Current evidence suggests that patients with AR who suffer from IT hypertrophy will likely experience improvement in symptoms, nasal patency, and QOL.

Policy level: Recommendation in patients with medically refractory nasal obstruction.

Intervention: In AR patients with IT hypertrophy that have failed medical management, IT reduction is a safe and effective treatment to reduce symptoms and improve nasal function. More studies are warranted to directly compare IT surgery methods (e.g., radiofrequency ablation, laser‐assisted, microdebrider‐assisted) for the most efficacious and long‐lasting outcome.

Vidian neurectomy, posterior nasal neurectomy

Aggregate grade of evidence: B (Level 2: 3 studies, level 3: 5 studies, level 4: 7 studies, level 5: 2 studies)

Benefit: Improvement in rhinorrhea.

Harm: Risk of complications (e.g., dry eye and decreased lacrimation, numbness in lip/palate, nasal dryness, damage to other nerves).

Cost: Surgical/procedural costs, potential time off from work.

Benefits‐harm assessment: Potential benefit must be balanced with low risk of harm but consider that long‐term results may be limited.

Value judgments: Patients may experience an improvement in symptoms.

Policy level: Option.

Intervention: Vidian neurectomy or posterior nasal neurectomy may be considered in AR patients that have failed medical management, particularly for rhinorrhea.

Cryotherapy/radiofrequency ablation of posterior nasal nerve

Aggregate grade of evidence: C (Level 3: 2 studies, level 4: 4 studies, level 5: 5 studies)

Benefit: Improvement in rhinorrhea.

Harm: Risk of complications (e.g., epistaxis, temporary facial pain and swelling, headaches), limited long‐term results.

Cost: Surgical/procedural costs, cost of device, potential time off from work.

Benefits‐harm assessment: Potential benefit must be balanced with low risk of harm, especially considering limited long‐term results.

Value judgments: Patients may experience an improvement in symptoms.

Policy level: Option.

Intervention: Cryoablation and radiofrequency ablation of the posterior nasal nerve may be considered in AR patients that have failed medical management, particularly for rhinorrhea.

I.C.7.c Allergen immunotherapy

Unlike allergen avoidance, environmental controls, and pharmacotherapy, AIT has the benefit of initiating and sustaining immunologic alterations. Following AIT, which involves scheduled administration of allergen extracts at effective doses for a specified time frame, controlled trials demonstrate reduction in allergy symptoms and medication use.

The AIT portion of ICAR‐Allergic Rhinitis 2023 discusses AIT candidacy, benefits, and contraindications. Allergen units and standardization are addressed, along with allergen extract adjuvants and modified allergen extracts. Overall, there is high level evidence supporting the use of AIT for AR (Table I.C.7.c).

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Conventional subcutaneous immunotherapy (SCIT)

Aggregate grade of evidence: A (Level 1: 2 studies, level 2: 46 studies, level 3: 29 studies)

Benefit: SCIT reduces symptom and medication use, as demonstrated in multiple high‐quality studies.

Harm: Risks of SCIT include frequent local reactions and rare systemic reactions, which may be severe and potentially fatal if not managed appropriately. This risk must be discussed with patients prior to initiation of therapy.

Cost: SCIT is cost‐effective, with some studies demonstrating value that dominates the alternative strategy with improved health outcomes at lower cost. Direct and indirect costs of AIT vary based on the third‐party payer, the office/region, co‐payment responsibilities, and travel/opportunity related costs in being able to adhere to the frequency of office visits required.

Benefits‐harm assessment: For patients with symptoms lasting longer than a few weeks per year and for those who cannot obtain adequate relief with symptomatic treatment or who prefer an immunomodulation option, benefits of SCIT outweigh harm. The potential benefit of secondary disease‐modifying effects, especially in children and adolescents, should be considered.

Value judgments: A patient preference‐sensitive approach to therapy is needed. Comparatively, the potential for harm and burden associated with medications are significantly lower, although the potential for benefit is also lower (with no potential for any disease‐modifying effect or long‐term benefit) as medications do not induce immunomodulation. Logistical issues surrounding time commitment involved with AIT may be prohibitive for some patients. The strength of evidence for SCIT efficacy, along with the benefit relative to cost, would support coverage by third party payers.

Policy level: Strong recommendation for SCIT as a patient preference‐sensitive option for the treatment of AR.

Strong recommendation for SCIT over no therapy for the treatment of AR.

Option for SCIT over sublingual immunotherapy (SLIT) for the treatment of AR.

Intervention: SCIT is an appropriate treatment consideration for patients who have not obtained adequate relief with symptomatic therapy or who prefer this therapy as a primary management option, require prolonged weeks of treatment during the year, and/or wish to start treatment for the benefit of the potential secondary disease‐modifying effects of SCIT.

Rush subcutaneous immunotherapy

Aggregate grade of evidence: B (Level 2: 12 studies, level 3: 4 studies, level 4: 4 studies)

Benefit: Accelerates the time to reach therapeutic dosing which may improve compliance, lead to earlier clinical benefit, and be more convenient for the patient. Improvement of symptoms and decreased need for rescue medication.

Harm: Higher rates of local and systemic reactions with rush SCIT protocols compared to conventional and cluster SCIT. Inconvenience of visits to a medical facility to receive injections.

Cost: Direct costs may be similar or slightly less compared to conventional SCIT, which includes cost of extract preparation and injection visits. Indirect costs are improved due to the reduced number of appointment visits, which reduces work and school absenteeism.

Benefits‐harm assessment: Balance of benefit and harm.

Value judgments: Careful patient selection and shared decision making would reduce risks. Heterogeneity of protocols, extract types, and dosing across studies makes quantification of risk difficult.

Policy level: Option.

Intervention: Aeroallergen rush SCIT is an option for AR in appropriately selected patients that do not have adequate control of their symptoms with symptomatic therapies. If available at practice location, the use of depigmented‐polymerized allergen extracts for rush SCIT has a better safety profile compared with standard extracts.

Cluster subcutaneous immunotherapy

Aggregate grade of evidence: B (Level 1: 1 study, level 2: 12 studies, level 4: 2 studies)

Benefit: Accelerates the time to reach therapeutic dosing which may improve compliance, lead to earlier clinical benefit, and be more convenient for the patient. Improvement of symptoms and decreased need for rescue medication. Similar safety profile compared to conventional SCIT.

Harm: Minimal harm with occasional, but mild, local adverse events and rare systemic adverse events when premedication is used. Inconvenience of visits to a medical facility to receive injections.

Cost: Direct costs may be similar, slightly more, or slightly less compared to conventional SCIT, depending on how the practicing provider bills for the services. This includes cost of extract preparation, injection visits, and possibly rapid desensitization codes. Indirect costs are lower due to the reduced number of appointment visits, which reduces work and school absenteeism.

Benefits‐harm assessment: Preponderance of benefit over harm for patients that cannot achieve adequate relief with symptomatic management. Balance of benefit and harm compared to conventional SCIT but in slight favor of cluster SCIT due to convenience.

Value judgments: Careful patient selection and shared decision making would reduce risks. Heterogeneity of protocols, extract types, and dosing across studies makes risk quantification difficult.

Policy level: Option.

Intervention: Cluster SCIT can be safely implemented in clinical practice and offered to those patients eligible for SCIT that may prefer this protocol compared to conventional build‐up protocols due to convenience. Premedication should be strongly considered.

Sublingual immunotherapy (SLIT): general considerations

Aggregate grade of evidence: A (Level 1: 17 studies, level 2: 12 studies, level 4: 1 study)

Due to heterogeneity of SLIT study reporting, it is difficult to separate out overall versus aqueous SLIT versus tablet SLIT.

Benefit: SLIT improves patient symptom scores, even as add‐on treatment with rescue medication. SLIT reduces medication use. The effect of SLIT lasts for at least 2 years after a 3‐year course of therapy. In AR patients, there is some evidence that SLIT reduces the frequency of onset of asthma and the development of new sensitizations up to 2 years after treatment termination. Benefit is generally higher than with single‐drug pharmacotherapy; however, it may be less than with SCIT (low quality evidence).

Harm: Minimal harm with very frequent, but mild local adverse events, and very rare systemic adverse events. SLIT seems to be safer than SCIT.

Cost: Intermediate. SLIT becomes cost‐effective compared to pharmacotherapy after several years of administration. Total costs seem to be lower than with SCIT.

Benefits‐harm assessment: Benefit of treatment over placebo is small but tangible and occurs in addition to improvement with medication. There is a lasting effect at least 2 years off treatment. Minimal harm with SLIT, greater risk for SCIT.

Value judgments: SLIT improved patient symptoms with low risk for adverse events.

Policy level: Strong recommendation for the use of SLIT grass pollen tablet, ragweed tablet, HDM tablet, and tree pollen aqueous solution. Recommendation for SLIT for Alternaria allergy. Option for SLIT for animal allergy. Recommendation for dual‐therapy SLIT in bi‐allergic patients.

Intervention: Recommend tablet or aqueous SLIT in patients (adults and children) with seasonal and/or perennial AR who wish to reduce their symptoms and medication use, as well as possibly reduce the propensity to develop asthma or new allergen sensitizations.

Sublingual immunotherapy tablets

Aggregate grade of evidence: A (Level 1: 11 studies, level 2: 4 studies)

Benefit: Improvement of symptoms, rescue medication, and QOL.

Harm: Local reaction at oral administration site and low risk of anaphylaxis.

Cost: Intermediate. More expensive than standard pharmacotherapy, but persistent benefit may result in cost‐saving in the long‐term.

Benefits‐harm assessment: Benefit outweighs harm.

Value judgments: Useful for patients with severe or refractory symptoms of AR.

Policy level: Strong recommendation.

Intervention: SLIT tablets are recommended for patients with severe or refractory AR. Epinephrine auto‐injector is recommended in the FDA labeling for approved tablets due to the rare but serious risk of anaphylaxis. Tablets for select antigens are available in various countries.

Aqueous sublingual immunotherapy

Aggregate grade of evidence: B (Level 1: 7 studies, level 2: 5 studies, level 4: 1 study)

Benefit: Aqueous SLIT improves patient symptom scores and decreases rescue medication use. There is some indication of less benefit from aqueous versus tablet SLIT, but the lack of standardized dosing across multiple trials does not allow for adequate comparison.

Harm: Common mild to moderate local adverse events. Very rare cases of systemic adverse events. No reported cases of life‐threatening reactions

Cost: Intermediate. More expensive than standard pharmacotherapy, but there are indications of lasting benefit and cost‐saving in the long‐term.

Benefits‐harm assessment: Appreciable benefit in patient symptoms and minimal harm.

Value judgments: Aqueous SLIT improves patient symptoms and rescue medication usage with minimal risk of serious adverse events but common local mild adverse events. Single allergen therapy has been extensively tested. Multiallergen AIT requires future studies to validate its use.

Policy level: Recommendation.

Intervention: High‐dose aqueous SLIT is recommended for those patients who wish to reduce their symptoms and rescue medication use.

Epicutaneous/transcutaneous immunotherapy

Aggregate grade of evidence: B (Level 2: 5 studies)

Benefit: Epicutaneous AIT to grass pollen resulted in limited and variable improvement in symptoms, medication use, and allergen provocation tests in patients with AR or conjunctivitis.

Harm: Epicutaneous AIT resulted in systemic and local reactions, with a relative risk of 4.65 and 2.29, respectively. Systemic reactions occurred in up to 14.6% of patients receiving grass transcutaneous AIT.

Cost: Unknown.

Benefits‐harm assessment: There is limited and inconsistent data on benefit of the treatment, while there is a concerning rate of adverse effects. Three out of 4 studies on this topic were published by the same investigators from 2009 to 2015.

Value judgments: Epicutaneous AIT could offer a potential alternative to SCIT and SLIT, but further research is needed.

Policy level: Recommendation against.

Intervention: While epicutaneous AIT may potentially have a future clinical application in the treatment of AR, at this juncture there are limited studies that show variable and limited effectiveness, and a significant rate of adverse reactions. Given the above and the availability of alternative treatments, epicutaneous AIT is not recommended at this time.

Intralymphatic immunotherapy

Aggregate grade of evidence: A (Level 1: 2 studies, level 2: 11 studies, level 4: 3 studies)

Benefit: Shorter treatment period, decreased number of injections, smaller amount of allergen, lower risk of adverse events versus SCIT.

Harm: Local reaction at injection site and risk of anaphylaxis.

Cost: Cost savings due to shorter treatment duration and fewer injections. Additional cost for training required.

Benefits‐harm assessment: Benefit outweighs harm.

Value judgments: Apparent short‐term favorable effect, but long‐term effect is lacking.

Policy level: Option.

Intervention: More studies are essential to establish the long‐term effects of ILIT.

Combination subcutaneous immunotherapy and biologics

Aggregate grade of evidence: B (Level 2: 5 studies)

Benefit: Improved safety of accelerated cluster and rush SCIT protocols, with decreased symptom and rescue medication scores among a carefully selected population.

Harm: Financial cost and low risk of anaphylactic reactions to omalizumab.

Cost: Moderate to high.

Benefits‐harm assessment: Preponderance of benefit over harm.

Value judgments: Combination therapy increases the safety of SCIT, with decreased systemic reactions following cluster and rush protocols. Associated treatment costs must be considered. While two high‐quality RCTs have demonstrated improved symptom control with combination therapy over SCIT or anti‐IgE alone, not all patients will require this approach. Rather, an individualized approach to patient management must be considered, with evaluation of alternative causes for persistent symptoms, such as unidentified allergen sensitivity. Also, the studies did not compare optimal medical treatment of AR (INCS, antihistamine, allergen avoidance measures) to combination therapy versus SCIT alone. The current evidence does not support the utilization of combination therapy for all patients failing to benefit from SCIT alone.

Policy level: Option.

Intervention: Current evidence supports that anti‐IgE may be beneficial as a premedication prior to induction of cluster or rush SCIT protocols, and combination therapy may be advantageous as an option for carefully selected patients with persistent symptomatic AR following AIT. However, at the time of this writing, biologic therapies are not approved by the US FDA for AR alone. An individualized approach to patient management must be considered.

I.C.8 Pediatric considerations

The pediatric section is a new addition for ICAR‐Allergic Rhinitis 2023 and encompasses several literature reviews. AR takes a few years to develop in children. A family history of AR, atopy, or asthma is important to discuss as children may be at an increased risk of developing AR or other allergic diseases. The “allergic march,” described as a specific sequence of atopic disorders, should be considered in children with clinical suspicion. Diagnosis may be challenging in the pediatric population, and some diagnostic clues include chapped lips from mouth breathing, fatigue, irritability, poor appetite, and attention issues. Physical exam findings include posterior pharyngeal cobblestoning, clear nasal drainage, and enlarged/boggy inferior turbinates, “allergic” or “adenoid” facies, the allergic salute, allergic crease, allergic shiners, or Dennie–Morgan lines. The diagnosis of AR in children should be based on both clinical history and testing. SPT is generally accepted as the preferred method of testing in children. Treatment options for children under age 2 are limited. For older children, treatment options are similar to the adult population. AIT is also an option for children with persistent symptoms. AIT may reduce the risk of asthma development in pediatric patients with AR.

I.C.9 Associated conditions

There is evidence for the association of several comorbid conditions with AR, which are listed in Table I.C.9. Several additional conditions have been added since ICAR‐Allergic Rhinitis 2018.

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I.C.10 Special section on COVID‐19

Coronavirus disease 2019 (COVID‐19) case rates have changed practice strategies. AR has not been identified as a risk factor for severe COVID‐19. However, there have been challenges with overlapping symptoms of AR and COVID‐19. Telemedicine visits have been helpful for initial evaluation; however, many diagnostic techniques for AR require face‐to‐face encounters. Recommendations have continued to evolve during the pandemic. Standard therapies for AR were not shown to increase the risk of severe COVID‐19. Additionally, anti‐IgE therapy has not increased susceptibility or severity of COVID‐19 infection.

I.C.11 Summary figure for allergic rhinitis diagnosis and management

See Figure I.C.11 for summary diagnosis and management options for AR, based upon current evidence.

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I.C.12 Knowledge gaps

Evidence in the realm of AR continues to grow at a steady pace. We have seen substantial progress in many aspects of the AR literature in recent years. However, several knowledge gaps remain. Table I.C.12. lists knowledge gaps and future research needs that have been identified as a result of the work in ICAR‐Allergic Rhinitis 2023.

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The International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis 2023

ICAR‐Allergic Rhinitis 2023 contains the most complete and up‐to‐date information on how allergic rhinitis develops, how medical teams can identify it, how it may be treated, and other conditions that can be seen with allergic rhinitis. The document has been written and reviewed by a large group of medical and research experts from around the world. ICAR‐Allergic Rhinitis 2023 may be used by medical providers who treat allergic rhinitis.

What is allergic rhinitis?

Allergic rhinitis is a reaction that occurs from substances that we breathe in from the environment. Patients often have drainage and blockage from their nose, along with sneezing and itching. While there are many possible causes of these symptoms, allergic rhinitis is due to a specific trigger in the environment that the body is sensitive to. Allergic rhinitis may be associated with other diseases, such as asthma, sleep problems, sinus and ear problems, cough, and more.

How common is allergic rhinitis?

Allergic rhinitis is a common problem. Depending on the specific research study and the location where the study is done, allergic rhinitis has been reported in 5%–50% of the population. It is more common in children.

How severe is allergic rhinitis?

Allergic rhinitis can affect quality of life. It may also interrupt sleep. Allergic rhinitis medicines, other treatments, and medical visits cost money directly. There are added costs related to missing work or school – or not functioning as well at work. Research suggests that treating allergic rhinitis helps improve overall quality of life and sleep.

How is allergic rhinitis treated?

People may avoid their allergic triggers if they are aware of the specific things that they react to – and if these things can be easily avoided. Using different types of medications can also help control allergic symptoms. Immunotherapy, such as allergy shots or drops/tablets under the tongue, introduces the known allergen to the body in small amounts at first. Over time, the body will not react to the allergen. There are also some procedures and surgeries that can decrease drainage from the nose or improve breathing through the nose.

What disorders are associated with allergic rhinitis?

Asthma, atopic dermatitis (a condition of the skin), eye symptoms, food allergies, and sleep problems are all associated with allergic rhinitis. Some studies report that certain ear issues and sinus problems may be related to allergic rhinitis, although more studies should be done to understand these better.

V.A.1 Definition, classification, and severity of allergic rhinitis

AR is an immunoglobulin E (IgE)‐mediated, type 1 hypersensitivity response of the nasal mucosal membranes, resulting from allergen exposure in a sensitized individual.5 Symptomatically, it is characterized by anterior or posterior rhinorrhea, nasal congestion/blockage, nasal pruritis, and sneezing.13 AR is widely prevalent and can result in significant physical sequelae and recurrent or persistent morbidities.5 Additionally, it is strongly associated with asthma, supporting the unified airway theory which postulates that upper and lower airway inflammation share common pathophysiologic mechanisms.14 (See Section VI.K. Unified Airway for additional information on this topic.)

The prevalence of AR ranges from approximately 5%–50% worldwide, with the highest incidence in the pediatric population.15 While this range of AR prevalence is wide, it is important to recognize that published studies may vary in their definition of AR and some may define AR as sensitization to allergens. (See Section VII. Epidemiology of Allergic Rhinitis for additional information on this topic.) AR is essentially absent in infants and typically develops in school age children. Since sensitization takes years to develop, it is unlikely to manifest before 2 years of age. This is likely secondary to the rapidly evolving immune system inherent in a child's early development. AR often results from an overactive response of T helper (Th)‐2 lymphocytes and initiation of a systemic IgE‐driven reaction, which can dominate a child's immune system until completely mature.

In the atopic individual, exposure to allergens may prompt allergen‐specific IgE (sIgE) production. Subsequent exposure triggers both early and late‐stage reactions, leading to the clinical manifestations of AR. The early‐stage reaction typically occurs within minutes after re‐introduction of the sensitized allergen, producing a rapid onset of nasal itching, congestion, and rhinorrhea.16 The late‐stage reaction often occurs during the 4‐ to 8‐h period after allergen re‐introduction and results in congestion, hyposmia, increased anterior and posterior rhinorrhea, and nasal hyper‐responsiveness. (See Section VI. Pathophysiology and Mechanisms of Allergic Rhinitis for additional information on this topic.)

Allergic Rhinitis and its Impact on Asthma (ARIA) proposals have categorized AR by presumed cause and the timing during which it occurs. Classically, this has been categorized as seasonal AR (i.e., hay fever) and perennial AR. Seasonal AR is typically associated with outdoor allergens, such as pollens, and usually occurs during seasons with high pollen counts.5Perennial AR is typically associated with indoor allergens, such as house dust mites (HDM), insects, and animal dander, and has been considered to occur consistently throughout the year.5 Mold exposure may occur indoors or outdoors depending on the specific environmental situation.

Of note, the classification of seasonal versus perennial AR can potentially be in conflict. For example, seasonal AR may persist for longer periods secondary to the effects of climate change, with resultant prolonged elevations in pollen counts. Seasonal AR may also continue across multiple seasons secondary to polysensitization. Furthermore, manifestations of perennial allergy may not occur throughout the entire year. This is particularly the case for patients allergic to HDM, who may demonstrate mild or moderate/severe intermittent AR.17^, 18^, 19^, 20

Because of the priming effect on the nasal mucosa introduced by low levels of pollen exposure,21^, 22^, 23^, 24^, 25^, 26 and minimal but persistent nasal inflammation in patients with “symptom‐free rhinitis,”19^, 27^, 28 symptoms may not occur entirely in conjunction with allergen exposure. This may result in non‐specific exacerbations. Additionally, air pollution may also contribute to variations in allergen sensitivity, resulting in fluctuating symptom severity depending on location/air quality.29 (See Section VIII.B.3. Risk Factors for Allergic Rhinitis – Pollution for additional information on this topic.)

Subsequently, ARIA proposed a new method of classification based on the length and persistence of symptoms.30Intermittent AR is characterized by symptoms for less than 4 days per week or less than four consecutive weeks. Persistent AR is characterized by symptoms occurring more than 4 days per week for at least four consecutive weeks.31 Additionally, it was demonstrated that the previous categories of seasonal and perennial AR cannot be used along with the new classification of intermittent/persistent AR, as they do not represent the same stratification of the disease state. As such, intermittent AR and persistent AR are not synonymous with seasonal and perennial classifications.32^, 33^, 34^, 35

The ARIA guidelines have likewise proposed another stratification of severity (mild and moderate‐severe) with respect to these disabilities.18 AR can result in problematic symptoms, including sleep disturbance; impairment of daily, leisure, or sport activities; impairment of school or work; or troublesome symptoms. AR is considered mild if none of these occur. If one or more of these symptoms exist, AR is classified as moderate–severe.

V.A.2 Sensitization versus clinical allergy

Atopic diseases comprise of a range of linked conditions presenting as multiple heterogeneous clinical phenotypes ranging from single organ to multi‐system disease.36^, 37 Currently used taxonomy is largely organ‐based and does not fully take into account the mechanisms leading to symptoms.38 For example, the 2016 Melbourne epidemic thunderstorm asthma event saw a dramatic increase in asthma‐related hospitalizations and 10 deaths over a 30‐h period.39 Interestingly, most patients hospitalized with severe asthma attack did not have a diagnosis of asthma. They did have a diagnosis of AR40 and allergen‐specific immunotherapy (AIT) appeared to offer protection.41 It can be postulated that these patients suffered from a single IgE‐driven condition with a clear pathophysiological mechanism, for which there are available biomarkers (e.g., sIgE) and mechanism‐based treatment (e.g., AIT).42

Although patients with AR and allergic asthma are by definition sensitized, many individuals with allergic sensitization do not have symptoms of allergic disease,43 and in a proportion of patients with AR and allergic asthma, sensitization is not related to the presence or severity of symptoms.38 Furthermore, the reliability of skin testing depends greatly on allergen extracts and methods used.44 Thus, clinicians face a problem that sensitization on standard allergy tests does not prove that symptoms are caused by allergy. Some subtypes of allergic sensitization are benign and not associated with clinical symptoms, while others are pathologic and lead to a spectrum of disease from single‐organ disease to allergic multi‐morbidity.42 (See Sections XI.D.11.a.ii. Multi‐allergen Immunotherapy and XI.D.11.b.ii. Polysensitization and for additional information on this topic.)

Better ways of differentiating clinically significant sensitization are needed. Quantification of sensitization through standard diagnostic tests (i.e., sIgE titer, size of skin test wheal) can increase the specificity, both in terms of diagnostic accuracy and the capacity to predict the persistence of symptoms.45^, 46^, 47^, 48 However, the problem of false‐positive test results remains.48 Currently, nasal allergen challenges is the most accurate way to confirm clinical allergy. Recent studies show that this is highly sensitive and specific, with negative and positive predictive values greater than 90%.49^, 50 It can also be helpful in the diagnosis of local nasal allergy, which may otherwise be missed on skin testing or in vitro testing methods. However, in most healthcare systems, this procedure is restricted to centers with specialist expertise.

We can now assess sensitization in greater detail using component‐resolved diagnostics (CRD), which measures sIgE to multiple allergenic molecules and may be more informative than standard tests.51^, 52^, 53^, 54^, 55 Recent novel analyses of CRD data demonstrated that the pattern of interaction between allergen component‐specific IgEs predicts asthma56 and that networks of interactions between sIgE to multiple components are predictors of asthma severity across the lifespan.57 These findings offer clues about mechanisms contributing to presence and severity of allergic airway disease and suggest that it may be possible to develop biomarkers/prediction tools based on CRD to help in diagnosis,56 severity assessment,57 prediction of future risk,52 and ultimately, the prediction of response to treatment.58

V.B.1 Drug induced rhinitis

Rhinitis secondary to systemic medications can be classified into local inflammatory, neurogenic, and idiopathic types.59^, 60^, 61 The local inflammatory type occurs when usage of a drug causes a direct change in inflammatory mediators within the nasal mucosa. The neurogenic type occurs after use of a drug that systemically modulates neural stimulation, leading to downstream changes in the nasal mucosa. The idiopathic classification is applied when a well‐defined mechanism has not been elucidated. Rhinitis medicamentosa and hormone‐induced rhinitis are discussed in later sections (Table V.B.1).

Local inflammatory type. Systemic ingestion of nonsteroidal anti‐inflammatory drugs (NSAIDs) in specific patients can cause respiratory symptoms and may be associated with nasal polyposis and asthma due to abnormal arachidonic acid metabolism.62 NSAIDs inhibit cyclooxygenase (COX)‐1, leading to decreased prostaglandin (PG) E2 and increased leukotriene production due to an imbalance toward the lipoxygenase pathway. Reduction in PGE2, and increased leukotriene C4, D4, and E4 production contributes to eosinophilic and mast cell inflammation within the upper and lower respiratory tracts.59^, 63^, 64^, 65

Neurogenic type. Neurogenic‐type non‐allergic rhinitis is caused by drug‐induced modulation of the autonomic nervous system. Antihypertensives and vasodilators are among the many classes of drugs that cause neurogenic drug‐induced non‐allergic rhinitis. Other nonspecific drugs, such as psychotropics and immunosuppressants, have unknown direct mechanisms and are categorized as idiopathic type, but can also cause neuromodulatory effects. Modulation of the autonomic nervous system leads to downstream changes in the nasal mucosa, blood vessels, and secretory glands.66

Alpha‐ and beta‐adrenergic modulators. Alpha‐ and β‐adrenergic receptor modulators are indicated for various cardiovascular and respiratory diseases. The nasal mucosa is replete with sympathetic and parasympathetic end‐units that influence nasal physiology during systemic drug use. Alpha‐ and β‐adrenergic antagonists, and presynaptic α‐agonists cause decreased sympathetic tone and unopposed parasympathetic stimulation producing mucosal engorgement, nasal congestion, and rhinorrhea.67^, 68^, 69

Phosphodiesterase inhibitors. Phosphodiesterease (PDE) inhibitors prevent enzymatic breakdown of cyclic nucleotides. This inhibition has diverse effects including smooth muscle relaxation, vasodilation, and bronchodilation, making PDE inhibitors useful for numerous disease processes. PDE‐3 and PDE‐5 inhibitors are commonly used to treat intermittent claudication, heart failure, pulmonary hypertension, lower urinary tract symptoms, and erectile dysfunction.70^, 71 PDE‐3 and nonselective PDE inhibitors inhibit cyclic adenosine monophosate (cAMP) hydrolysis, which ultimately prevents platelet aggregation and encourages vasodilation with increased extremity blood flow. PDE‐5‐specific inhibitors encourage smooth muscle relaxation through inhibition of nitric oxide (NO)‐generated cyclic guanosine monophosphate (cGMP), causing vasodilation of the corpus cavernosum and pulmonary vasculature as well as changes in the lower urinary tract. NO/cyclic nucleotide mediated vasodilation occurs in the nasal mucosa causing nasal mucosal engorgement and edema72^, 73^, 74^, 75^, 76 (Table V.B.1).

Angiotensin converting enzyme inhibitors. Angiotensin converting enzyme inhibitors (ACEI) inhibit the conversion of angiotensin I to angiotensin II in the lungs and are commonly used for cardiac and renal diseases. ACEI upregulate the formation of bradykinin, an inflammatory peptide that causes vasodilation and smooth muscle contraction.77 Bradykinin B1 and B2 receptors have been demonstrated in nasal mucosa,78 and bradykinin application to nasal mucosa has resulted in increased sneezing.74^, 79 In addition to cough, rhinorrhea and nasal obstruction have been associated with ACEI.77

Illicit drug use. The nose provides a unique portal for illicit drug use due to well vascularized and easily accessible nasal mucosa. Applying a crushed solid, liquid, or aerosolized form of a drug to the nasal cavity avoids invasive intravascular or intramuscular administration. For some drugs, nasal administration increases bioavailability and shortens time to onset when compared to oral ingestion.80^, 81 In contrast to oral agents, intranasal administration bypasses portal filtration.

Cocaine is most commonly associated with nasal illicit drug use and exerts its effect by modulating dopamine transporters to inhibit synaptic reuptake, increasing dopamine for post‐synaptic stimulation.82 After application to nasal mucosa, cocaine is quickly metabolized by native mucosal esterases into its bioactive metabolite, which then passively diffuses across the nasal mucosa and the olfactory bulb, leading to elevated systemic and brain concentrations resulting in a psychotropic euphoria.83 Cocaine‐induced rhinitis is a result of vasoconstrictive events, which can be followed by rebound nasal mucosal edema and mucus production, similar to rhinitis medicamentosa.84^, 85^, 86^, 87 In the repeat user, vasoconstriction, direct trauma compounded by anesthetic effects, and/or injury secondary to contaminants may result in tissue necrosis.88^, 89^, 90^, 91 Similarly, prescription narcotics, antidepressants, anticholinergics, and psychostimulants can be abused by intranasal administration.78^, 92 Tissue necrosis has also been associated with intranasal opioid and acetaminophen abuse.93^, 94^, 95 Possible mechanisms of injury include hyperosmotic conditions, vasculitic‐like inflammation, or direct injury secondary to talc.95^, 96

Drug‐induced rhinitis is a subtype of non‐allergic rhinitis that can cause mucosal edema, vasodilation, and inflammatory mediator production. Vasoconstriction and mucosal injury often accompany illicit drug use. Drug‐induced rhinitis differs from AR as it is not allergen‐induced nor dependent on IgE mechanisms, although symptomatology may be similar.

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V.B.2 Rhinitis medicamentosa

Rhinitis medicamentosa is a drug‐induced rhinitis resulting from prolonged topical intranasal decongestant (INDC) use.31^, 97 Topical INDCs are readily available without a prescription and often lack appropriate warnings of prolonged use, potentially resulting in overuse and dependence. Although no consensus diagnostic criteria exist, rhinitis medicamentosa was originally associated with the triad of prolonged INDC use, persistent nasal obstruction, and rebound swelling of the nasal mucosa.97 Patients present with nasal congestion, often lack rhinorrhea or sneezing, and may note reduced efficacy, or tachyphylaxis, with further use of INDCs.87^, 98^, 99 Physical examination is variable, but often reveals nasal mucosal edema, erythema, and hyperemia (Table V.B.2).

Nasal anatomy and physiology. Vasculature within the nasal mucosa consists of resistance vessels (arterioles), whose sympathetic innervation is predominated by α‐2 adrenergic receptors, and capacitance vessels (venous sinusoids), that are innervated by α‐1 and α‐2 receptors. Stimulation of these receptors results in vasoconstriction with resultant decongestion due to decreased blood flow and increased sinusoid emptying.97^, 100 The two classes of nasal decongestants are imidazolines and sympathomimetic amines. Imidazolines are α‐2 receptor agonists, while sympathomimetic amines encourage presynaptic norepinephrine release. Norepinephrine stimulates α‐adrenergic receptors and weakly stimulates β‐adrenergic receptors. Both medication classes have a rapid onset, are potent, and are long‐acting.97^, 101

The exact pathophysiologic mechanism causing rhinitis medicamentosa is unclear, although several hypotheses exist: (1) chronic vasoconstriction causes recurrent nasal tissue hypoxia and ischemia, which may cause interstitial edema; (2) changes in endothelial permeability may result in increased edema; and (3) continuous INDC use may decrease endogenous norepinephrine and downregulate α‐receptors, through negative neural feedback, causing decreased adrenergic responsiveness.86^, 87^, 97^, 100^, 101^, 102 Inflammatory cells, local inflammatory mediators, uninhibited parasympathetic stimulation, and increased mucin production also contribute to symptomatology.

Histologic changes within the mucosa after prolonged INDC use include ciliary damage and ciliary loss, epithelial cell injury, epithelial metaplasia and hyperplasia, dilated intercellular spaces, goblet cell hyperplasia, and edema.103^, 104^, 105 Benzalkonium chloride, an antimicrobial preservative used in many nasal sprays, has been implicated in the mechanism of rhinitis medicamentosa. Studies have demonstrated that benzalkonium chloride is toxic to nasal epithelium and induces mucosal edema, propagating rhinitis medicamentosa, although the data are inconclusive.106^, 107^, 108^, 109^, 110 Neither duration, nor cumulative dose of INDC needed to initiate rhinitis medicamentosa is known. Rebound congestion has developed after 3 to 10 days of medication use,87^, 104 but may not occur until after 30 days.111^, 112 Other studies have demonstrated a lack of rebound congestion after 8 weeks of continuous use.111^, 112^, 113^, 114 Furthermore, doubling the dose of intranasal imidazoline did not increase the extent of rebound edema.111 Although inconclusive, studies suggest that INDC use should be discontinued after 3 days to avoid rebound congestion.98^, 115^, 116

Treatment of rhinitis medicamentosa. Despite the lack of formal treatment guidelines for rhinitis medicamentosa, discontinuation of INDCs is paramount. Patients should be educated regarding common over‐the‐counter products containing decongestants as labeling may be inadequate. Various treatments have been trialed including nasal cromolyn, nasal saline spray, oral/intranasal antihistamines, turbinate steroid injections, and oral/intranasal corticosteroids.98^, 100^, 117^, 118^, 119^, 120^, 121^, 122 Intranasal corticosteroids (INCS) are the most common treatment for rhinitis medicamentosa. Many initiate INCSs while weaning INDCs.101^, 105^, 120^, 121^, 122^, 123 Often there is an underlying undiagnosed rhinitis and/or anatomic issue that initiated decongestant use, and this should be addressed to relieve the drive to use INDCs. For refractory cases, oral steroids and inferior turbinate (IT) reduction have been considered.122

Rhinitis medicamentosa is typically associated with repeated exposure to INDCs, with increasing symptoms when the medication is withheld. In contrast, AR is classically associated with an allergic trigger with similar symptoms increasing upon allergen exposure and is dependent upon IgE‐mediated inflammation. It is possible that both may coexist, and a careful history should be obtained regarding these triggers to obtain an accurate diagnosis and provide appropriate treatment.

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V.B.3 Occupational rhinitis

Occupational rhinitis is an inflammatory disease of the nose, characterized by intermittent or persistent symptoms of nasal congestion, sneezing, rhinorrhea, itching, and/or variable nasal airflow obstruction due to causes and conditions attributable to a particular work environment.124^, 125 While many social activities or hobbies can result in overlapping symptoms, stimuli that are encountered outside the workplace are not considered occupationally related.126

The pathophysiological mechanisms of occupational rhinitis are the same as other forms of chronic rhinitis although symptoms may be intimately tied to work exposure.1^, 124^, 126 Occupational rhinitis may be classified as allergic, resulting from an immunological exposure to a sensitizing high molecular weight protein (HMW > 5 kDa) or non‐allergic, mediated by non‐immunological low molecular weight chemical irritant (LMW < 5 kDa).127^, 128 Non‐allergic occupational rhinitis is sometimes subdivided into annoyance (e.g., perfumes), irritant‐induced (e.g., formaldehyde or smoke), or corrosive rhinitis (e.g., ammonia or acids), the latter of which may include permanent inflammation of the nasal mucosa, ulcerations, and perforation of the nasal septum.1^, 124

Cross sectional studies of various workers show a wide range of occupational rhinitis prevalence rates (3%–87%),124^, 126^, 129 although rates are higher for HMW agents compared to lower for LMW agents.126 Occupations and commonly implicated agents are reported in Table V.B.3.130^, 131^, 132^, 133^, 134^, 135 Pre‐existing AR or allergic asthma, baseline total IgE >150 kIU/L, or occupations with frequent exposure to animals have been shown to be risk factors for occupational rhinitis.136^, 137

Occupational rhinitis tends to be three times more prevalent than occupational asthma,129 but the two disorders are often associated (up to 92% of cases).126 In most cases, work‐related nasal symptoms develop 5–6 months before the onset of bronchial symptoms.124^, 138 Consequently, occupational rhinitis may be considered a marker of the likelihood of developing occupational asthma. Previous practice parameters and consensus documents suggest that workers in certain high‐risk occupations be periodically monitored by survey and/or skin prick testing (SPT) so that risk mitigation strategies can reduce sensitization, and potentially limit progression of occupational rhinitis or the development of occupational asthma.1^, 139^, 140

The clinical presentation of occupational rhinitis does not differ from those of non‐occupational chronic rhinitis. Diagnostic assessment must include a thorough clinical and occupational history, aimed to investigate the type of symptoms and work‐related temporality, and to collect information on specific occupational exposures. Documentation of noxious compounds in the workplace should include examination of available Material Safety Data Sheets.124 The presence of a latency period between beginning of occupational exposure and symptom onset (months or even years) suggests an immunologic mechanism. This contrasts to non‐allergic irritant occupational rhinitis which may occur immediately upon first exposure.

Nasal endoscopy, assessing nasal patency, inflammation, and secretions minimize patient misclassification.1^, 141^, 142 Sensitization to a suspected HMW agent by SPT may be preferred over serum sIgE assessment as skin testing has been reported to be more sensitive and specific in various reports.143^, 144^, 145^, 146 However, the reliability of sIgE testing depends on the equipment, materials, and technique employed; therefore, a standardized approach and validated extracts are required, which are often not available especially for LMW agents.44^, 126^, 146^, 147^, 148 A truly definitive diagnosis can only be established by objective demonstration of the causal relationship between rhinitis and the work environment through nasal provocation test (NPT) with the suspected agent(s). However, irritant triggers, LMW agents, and delayed type reactions are often not easily identified by NPT49^, 124^, 146^, 149^, 150 (Figure V.B.3). Validated clinical assessment tools such as the Total Nasal Symptom Score (TNSS) or and/or sneeze counts administered pre‐and‐post exposure may aid in quantifying the severity of the response. At some institutions, rhinomanometry is also available to obtain additional quantitative data.

If NPT is negative, further evaluation of work‐related changes in nasal parameters at the workplace is recommended, especially in the presence of a highly suggestive clinical history.151 When possible, a formal site visit may allow the technician to directly observe the workplace environment, symptomatology, and Material Safety Data Sheets, and suggest specific workplace modifications. Due to the strict relationships between upper and lower airways, spirometry and exhaled NO assessment should be performed in patients with occupational rhinitis.1^, 126

The primary treatment of allergic occupational rhinitis is avoidance or reduction of culprit exposures.126 Pharmacologic treatment does not differ from that of non‐occupational rhinitis, although medications alone may be insufficient given the intensity and frequency of many workplace exposures.152 In allergic occupational rhinitis due to HMW sensitizers, AIT may be considered when validated extracts are available.153 However, AIT may have limitations in those individuals with continued high workplace exposure; therefore, simultaneous mitigation and avoidance strategies are essential.

Occupational rhinitis has both medical and socioeconomic implications,154 and may be the cause of leaving work.155 Since occupational rhinitis is acknowledged as a risk factor for the development of occupational asthma, the prevention and early identification of occupational rhinitis of exposed workers may provide an excellent opportunity to prevent the development of occupational asthma.156 (See Section XI.A.6. Allergen Avoidance – Occupational for additional information on this topic.)

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V.B.4 Chemical rhinitis

As exposure to environmental chemicals and pollutants increases in daily life, patients may present with rhinitis symptoms that do not necessarily fall within a traditional allergic profile. Chemicals may cause sensory irritation which can include congestion, sneezing, rhinorrhea, nasal discomfort, post‐nasal drainage, headache, olfactory function, and epistaxis. This is often associated with lower airway symptoms and conjunctival irritation.126 The differential diagnosis of chemical rhinitis is broad, including occupational rhinitis, but not all chemical rhinitis is occupational. Typically, the differential should include causes of both AR and non‐allergic rhinitis, as well as mixed rhinitis, recurrent acute rhinosinusitis (RARS), and chronic rhinosinusitis (CRS).

Exposures at home and work are important elements to obtain in the history. There are many chemicals with which specific occupations are closely associated, and household chemicals may play a role as well. Volatile organic compounds such as benzene, toluene, and the secondary production of formaldehyde can be found in cleaning products, furniture, plastics, flooring and can cause barrier dysfunction and inflammation in both the upper and lower airway.134^, 157^, 158 Larger chemical particles greater than 10 μm in diameter are generally deposited in the upper airway and agents such as ammonia, formaldehyde, nitrogen dioxide, or sulfur dioxide among others may readily disrupt the epithelial barrier.124

In general, inquiring about exposure to vapors, fumes, smoke, and dust can be helpful to determine if a patient has an element of chemical rhinitis. These responses are typically non‐IgE‐mediated by a reflex response which is often termed neurogenic inflammation.159 A subset of these individuals involved in single exposure incidents may develop persistent and chronic symptoms. This phenomenon has been described as reactive upper airways dysfunction syndrome when only rhinitis symptoms are present, and reactive airways dysfunction syndrome when asthma‐like symptoms are present.160^, 161

Chemicals known to cause respiratory inflammation and in some cases, allergic sensitization include diisocyanates, acid anhydrides, some platinum salts, reactive dyes, and many cleaning products that are used in hospitals and in the pandemic era including glutaraldehyde, quaternary ammonium compounds, and chloramine.134^, 162^, 163^, 164 There is still debate concerning the exact mechanism behind sensitization to these chemicals. However, smaller chemical compounds must associate with larger protein molecules in order to induce an immune response. As a result, evaluation of sensitization through skin testing and/or evaluation of sIgE can be helpful and in the future, immunoassays based on cellular responses may serve as better biomarkers of exposure to chemicals.165^, 166

V.B.5 Smoke induced rhinitis

Tobacco smoke exposure is associated with chronic rhinitis and CRS.167^, 168^, 169 Other smoke exposure sources besides conventional cigarettes, cigars, and pipes include electronic cigarettes, vaping, and cannabis. Although there is limited research on these other methods of smoke exposure, initial studies support that there may be an increased risk of rhinitis with some of these products and these exposures should be considered in the differential diagnosis.170^, 171 Symptoms common to both AR and smoke‐induced rhinitis include rhinorrhea and congestion, but smoke‐induced rhinitis is not driven by IgE‐mediated hypersensitivity which tends to also exhibit sneezing on exposure to a specific allergen.172^, 173^, 174^, 175

Symptoms of rhinitis are provoked by exposure to the chemicals in smoke and can correlate with serum cotinine levels in patients using tobacco.174 Furthermore, smoking in combination with occupational irritants are additive risk factors for nasal symptoms and may be independent of allergic sensitization.175 Although smoke‐induced rhinitis does not require allergen sensitization, there has been at least one report of potential allergenic compounds in smoke.176 Interestingly, active smokers show elevated total serum IgE, although they exhibit a lower skin test reactivity to specific allergens compared to non‐smokers despite well documented increased rates of lower respiratory disorders such as asthma, cough, sputum production, and wheezing.177 This may be due in part to the fact that tobacco smoke exposure results in decreased mucociliary clearance.178

One of the mechanisms to explain nasal irritation resulting from smoke exposure may be related to capsaicin‐sensitive neurons in the nasal mucosa.179 This neurogenic type of nasal inflammation is mediated by neuropeptides such as substance P, neurokinin A, and calcitonin gene‐related peptide (CGRP). These mediators are released by sensory nerve fibers in the nose and result in vasodilation, edema, and inflammation.180

Patients who are reactive to tobacco exposure are identified by both subjective (congestion, rhinorrhea, sneezing) and an objective response (increased nasal resistance) to controlled challenge with tobacco smoke. In a prospective study, patients were defined as demonstrating reactivity if nasal resistance increased by more than 35% by acoustic rhinometry in response to tobacco smoke; patients with less than 5% increase in nasal resistance were defined as nonreactive.178 Congestive responses have been demonstrated on challenge with both brief and prolonged exposure to tobacco smoke. In individuals who report a history of smoke induced rhinitis, only brief smoke exposure (45 parts per million [ppm] for 15 min) leads to increased nasal resistance as measured by posterior rhinometry (although there were no significant increases in histamine levels noted).181 However, prolonged exposure to moderate levels of smoke (15 ppm for 2 h) induced a congestive response lasting for an hour or longer in both individuals with and without a history of smoke‐induced rhinitis.178 While objective response may be short lived, patients reported symptoms lasting hours to days following exposure. Since significant symptom overlap exists, a thorough history and allergy testing can help further differentiate smoke‐induced rhinitis from other types of rhinitis.

V.B.6 Infectious rhinitis

Infectious rhinitis is a very common diagnosis in general practice. Differences in onset and pathogenic cause lead to various pathophysiologies and forms. Common conditions in general practice are acute viral and bacterial rhinitis. Nasal symptoms include clear or discolored nasal discharge, nasal obstruction, postnasal drip, cough, and facial pressure depending on the etiology. These symptoms may also be present in non‐infectious rhinitis; most commonly AR. This diagnostic distinction is important to avoid inappropriate treatment and diagnostic procedures. Distinctive clinical characteristics suggestive of AR are sneezing, nasal or ocular itching, the presence of an obvious allergic trigger, and the presence of recurrent seasonal‐related symptoms – these symptoms are less frequent in infectious rhinitis.31^, 182

Rhinitis symptoms are the result of nasal mucosa and/or sinus inflammation. The mucosa of the nose and sinuses are contiguous. Thus, the clinical presentations of rhinitis and rhinosinusitis are overlapping, and it is difficult to differentiate between them. Infectious rhinitis or rhinosinusitis are classified by duration and pathogenic cause into subtypes including acute viral (common cold), post‐viral, and bacterial.183 (See Sections V.B.15. Differential Diagnosis ‐ Rhinosinusitis and XIII.B. Associated Conditions ‐ Rhinosinusitis for additional information on this topic.)

Acute viral rhinitis, or the common cold, is responsible for most acute infectious rhinitis, especially in children.31 The incidence of acute viral rhinosinusitis is expected to be as high as 98%.184^, 185 Common organisms are rhinovirus, adenovirus, influenza virus, and parainfluenza virus.120 Viral rhinitis is a self‐limited illness and only requires supportive treatment. Most symptoms resolve by day five; nasal discharge and cough may last longer.186 Prolonged symptoms of more than 2 weeks duration suggest a non‐infectious etiology or post‐viral rhinosinusitis.

The relationship between viral infection and AR has been studied. The upregulation of intercellular adhesion molecule (ICAM)‐1, which is the major human receptor of rhinovirus, was shown in patients with underlying allergic disease.187^, 188^, 189 The increased expression of ICAM‐1 was demonstrated in both upper and lower allergic airway diseases compared with healthy controls.190^, 191^, 192 This enhances the susceptibility of airway epithelial cells to viral infection.

In some cases, viral rhinitis episodes are secondarily infected by bacterial organisms such as Streptococcus pneumonia, Haemophilus influenza, and Moraxella catharralis.184^, 185 This occurs in 0.5%–2.0% of all viral infections.183^, 184 Clinical presentation distinguishing viral from bacterial rhinitis/rhinosinusitis is often impossible.193^, 194^, 195^, 196 Inappropriate prescribing of antibiotics and diagnostic tools is often secondary to misdiagnosis of the symptoms and signs of viral and bacterial origin with up to 60% starting a course of antibiotics at first symptom presentation.197^, 198^, 199

The possibility of bacterial infection increases if there is deterioration in symptoms after day 5.186 Predicting criteria for bacterial infection have been suggested using clinical characteristics, the pattern of symptoms, and laboratory reports.183^, 200^, 201 However, the maximum sensitivity and specificity only reach 69% and 81%, respectively, among various criteria.199^, 202 Additionally, a collection of factors contribute to developing an infection of bacterial origin. These factors include dental infection or procedure, previous sinus surgery/nasogastric tube insertion/nasal packing, underlying immunodeficiency, structural nasal problems, and evidence of underlying nasal mucosa edema such as AR.186

V.B.7 Rhinitis of pregnancy and hormonally induced rhinitis

Rhinitis of pregnancy. Pregnancy‐induced rhinitis describes nasal symptoms that occur during pregnancy, are independent of other etiologies for rhinitis, and remit after delivery.203^, 204^, 205 Symptoms include rhinorrhea, sneezing, hyposmia, and nasal itching.206 In a multicenter study of 599 previously asymptomatic women, prevalence of rhinitis of pregnancy was 22%.207 A history of AR and smoking increase risk for its development.203^, 204^, 205

Quantifying the impact of pregnancy‐induced rhinitis has been done objectively and subjectively. Acoustic rhinometry, rhinomanometry, peak nasal airflow measurements, and saccharin testing confirm that changes to nasal airway patency occur.205^, 206^, 208 Electron microscopy demonstrates glandular hyperactivity, increased phagocytotic activity, and increased amounts of acid mucopolysaccharides in the ground substance.209 Studies using validated patient reported outcome measures (PROMs) (e.g., Nasal Obstruction Symptom Evaluation [NOSE] scale, Rhinitis Quality of Life Questionnaire [RQLQ])208^, 210 confirm the subjective component of pregnancy‐induced rhinitis.205^, 206^, 208

The precise pathophysiology of pregnancy‐induced rhinitis remains unknown.206^, 211^, 212 Estrogen, progesterone, and placental growth hormonal have all been implicated.203^, 204^, 205^, 208 Increased expression of histamine receptors secondary to β‐estradiol and progesterone in nasal epithelial and endothelial cells has been demonstrated and is proposed as a potential mechanism of nasal hyperreactivity in pregnancy‐induced rhinitis.213 Additionally, serum levels of placental growth hormone were significantly higher in patients with pregnancy‐induced rhinitis throughout their pregnancy.214

Pregnancy‐induced rhinitis has been implicated in potential risks for the mother and fetus.203^, 204^, 212 Mouth breathing from pregnancy‐induced rhinitis bypasses the benefits of nasal breathing, including preparation of inspired air for the lungs and NO release from the maxillary sinuses, which reduces pulmonary vascular resistance and contributes to increased pulmonary oxygenation.204^, 212 Additionally, maternal sleep disruption, when severe, can be associated with snoring and obstructive sleep apnea (OSA) and may contribute to increased risk for pre‐eclampsia and maternal hypertension.215 Intrauterine growth retardation and decreased Apgar scores are also possible.203^, 215

Treatment is conservative and relies on education. Reassurance regarding the temporary nature of pregnancy‐induced rhinitis is beneficial. Regular use of nasal saline lavage is safe and provides symptomatic relief.182^, 211^, 212 Counseling against the routine use of oral and topical decongestants is critical due to the risk for congenital gastroschisis, pyloric stenosis, endocardial cushion defects, renal anomalies, and limb defects. These risks are greater in the first trimester, but caution should be maintained throughout the pregnancy.182^, 211^, 212 INCS are generally considered safe for use during pregnancy; however, triamcinolone is associated with congenital respiratory defects.182 A treatment option under investigation is topical hyaluronate, which facilitates mucociliary clearance and hydration. In a 2019 pilot study of pregnancy‐induced rhinitis, sodium hyaluronate use decreased snoring, mucosa congestion, and nasal secretions and had no adverse events.216 More studies are needed before recommending its routine use during pregnancy.

Hormonally‐induced rhinitis. Cytological changes and cell turnover of the nasal epithelium during the phases of the menstrual cycle have been demonstrated. In general, estrogens are thought to cause nasal vascular engorgement, resulting in obstruction and rhinorrhea. As with pregnancy‐induced rhinitis, the mechanism of these changes remains unclear.182^, 217^, 218^, 219 The expression of histamine H₁‐receptors within the nasal epithelium and microvascular endothelial cells are increased in response to β‐estradiol and progesterone. These hormones may also induce eosinophil migration and/or degranulation.217

Rhinitis can also occur in patients with endocrine pathologies. Hypothyroidism can cause hypertrophy of mucous glands, increased submucosal connective tissue, and resultant nasal obstruction and rhinorrhea.217^, 218^, 220 These patients may also have prolonged mucociliary clearance time.221 Rhinitis with sinonasal mucosal hypertrophy and polyp formation can also be seen in acromegaly, though it is unclear if elevated serum levels of growth hormone are the cause.222

V.B.8 Food and alcohol induced rhinitis

Food‐induced rhinitis. Gustatory rhinitis is characterized by watery, unilateral, and/or bilateral rhinorrhea within a few minutes after the ingestion of food, usually hot and spicy foods such as tabasco sauce, hot chili peppers, horseradish, red cayenne or black pepper, and other foods that contain capsaicin. The rhinorrhea lasts as long as the food is ingested.182^, 223^, 224^, 225^, 226 Gustatory rhinitis can be confused with IgE‐mediated food allergy, but there is no sneezing, pruritus, or facial pain and the time course of the rhinorrhea is self‐limited.223 There is also no associated disturbance of smell or taste.227 Gustatory rhinitis occurs more often in patients with AR and patients who have a history of smoking, but not those with asthma or food allergies.225

The pathophysiology has been confirmed through pharmacologic observations and immunohistology studies to occur through a neural reflex arc initiated upon the stimulation of afferent sensory nerves. This leads to the stimulation of the parasympathetic efferent nerve supply to the submucosal glands in the nasal mucosa.224^, 226 It is additionally possible that interactions between the sympathetic and parasympathetic nervous system could lead to uninhibited activity of the parasympathetic system with resultant rhinorrhea.226 For example, the chemical capsaicin is known to cause gustatory rhinitis. The capsaicin receptor is a transient receptor potential vanilloid subtype 1 (TRPV1) receptor and exists in neuronal as well as non‐neuronal cells along the nasal mucosa and oral epithelium.228 A direct effect on goblet cell secretion may be triggered when capsaicin is ingested.227 A well‐known culprit of gustatory rhinitis is chili peppers, which contain capsaicin.227 A variety of other foods are associated with gustatory rhinitis including horseradish, wasabi, black pepper, hot mustard, and vinegar.225^, 226

Treatment of gustatory rhinitis is avoidance of the inciting food. Topical anticholinergic medications such as ipratropium bromide (IPB) are used when avoidance is impractical.224^, 226^, 227 The use of topical capsaicin and resection of the posterior nasal nerve (PNN) have been proposed as a last resort for intractable gustatory rhinitis.227^, 229

Alcohol‐induced rhinitis. Exacerbation of respiratory symptoms after ingestion of alcohol occurs in approximately 3%–4% of the general population. Among the nasal symptoms that occur, blockage is the most common and may be accompanied by rhinorrhea, sneezing and lower airway symptoms. This is reportedly more common in patients with AR, asthma, chronic obstructive pulmonary disease (COPD), and emphysema.230 Up to 75% of aspirin‐exacerbated respiratory disease (AERD) patients suffer exacerbations of respiratory symptoms when they consume alcohol.231^, 232^, 233 Symptom exacerbations occur relatively soon after alcohol ingestion, are often associated with the ingestion of small volumes, and seem to correlate with peak blood alcohol levels.233 Such symptoms can arise regardless of the type of alcohol ingested.230^, 232 These reactions to alcohol consumption are more prevalent in chronic rhinosinusitis with nasal polyp (CRSwNP) patients who suffer with severe and recurrent disease and are related to the severity of upper airway inflammation.233

In AERD patients, the severity of aspirin‐induced respiratory symptoms is positively correlated with the severity of alcohol‐induced reactions.233 Exacerbations of respiratory symptoms in response to alcohol have been shown to be decreased after aspirin‐desensitization in patients with AERD.231 Patients with AERD have elevated baseline cysteinyl leukotriene levels, which are proposed to mediate the upper and lower airway reactions to aspirin.231^, 232 Cardet et al.232 propose that cysteinyl leukotrienes mediate the response to alcohol in these patients as well, though the pathway for such a mechanism is unknown.

High alcohol consumption is observationally and genetically associated with high serum IgE levels, though not with allergic disease. Two possible mechanisms have been proposed as the etiology for this observation: (1) alcohol changes the balance of the Th1 and Th2 responses toward a Th2 immune response with a direct effect on B cells, or (2) alcohol induces increased uptake of endotoxins from the gut resulting in elevated IgE levels.234

V.B.9 Eosinophilic rhinitis and non‐allergic rhinitis with eosinophilia syndrome (NARES)

Non‐allergic rhinitis with eosinophilia syndrome (NARES) is a clinical disorder comprising symptoms consistent with perennial AR in which there is an absence of atopy but presence of local eosinophilia found on nasal cytology.235 The pathophysiology of NARES is not well understood, but a key component involves chronic local eosinophilic, self‐perpetuating inflammation, with non‐specific histamine release. It is one of the most common type of inflammatory non‐allergic rhinitis that was first described by Jacobs and colleagues in 1981.236

NARES patients report symptoms that are similar to those of perennial AR: nasal congestion, profuse aqueous rhinorrhea, sneezing, and nasal and ocular pruritis. A prominent feature of NARES is olfactory dysfunction. NARES patients demonstrate significantly higher thresholds on olfactory testing than seasonal and perennial AR patients.237 NARES is diagnosed by obtaining a careful history, findings on physical exam, not unlike those found in perennial AR patients (pale, boggy turbinates), and negative skin or in vitro allergy testing. Cytologic examination in NARES reveals the presence of prominent eosinophilia, usually 10%–20% on nasal smear, with a diagnostic criterion of 25% or more eosinophils.235^, 238 In addition, nasal biopsies from these patients commonly show increased numbers of mast cells with prominent degranulation.239^, 240

Research has supported the role of chronic inflammation in the development of NARES. Though there is still a lack of understanding as to the exact pathophysiology, studies have shown an increased transendothelial migration of eosinophils in nasal lavage fluid, which are attracted and activated by chemokines and cytokines.241^, 242 Specifically, NARES is characterized by elevated nasal fluid levels of tryptase (which is also seen in perennial AR) and eosinophilic cationic protein.243 Elevated levels of interleukin (IL)‐1β, IL‐17, interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, monocyte chemoattractant protein (MCP)‐1, and RANTES (regulated upon activation, normal T cell expressed and presumably secreted) in nasal fluid were found in NARES compared to controls.244^, 245

A correlation between the concentration of RANTES with nasal symptoms and eosinophil counts in perennial AR patients has been shown.246 However, levels of MCP‐1 and RANTES were significantly higher in the nasal fluid of NARES compared to perennial AR subjects. Elevation of these cytokines correlated with the ratio of nasal symptom scores/percentage of eosinophils in NARES patients, where nasal symptoms of nasal obstruction, rhinorrhea, hyposmia, sneezing, and itching were each measured using a 3‐point scale.246 Several studies from European cohorts have found a lack of nasal mucosal IgE in NARES patients.247^, 248 More recent studies of Chinese cohorts of NARES patients have found increased expression of Charcot‐Leyden crystals which correlated with severity of symptoms and degree of eosinophilia.249 Elevated cysteine protease inhibitor cystatin SN was also observed with greater loss of sense of smell.250 Neuropeptide mediated eosinophil chemotaxis, including substance P, CGRP, and cholecystokinin octapeptide, has also been described as a contributing factor to the symptomatology in NARES patients.251

NARES may occur in isolation, but it can be associated with (and may be a precursor for) AERD.235 NARES has also been identified as a risk factor for the induction or exacerbation of OSA252 and has been associated with increased tendency for lower airway hyperresponsiveness.253

The treatment of non‐allergic rhinitis centers on its underlying cause. NARES is primarily treated with INCS, which decrease neutrophil and eosinophil chemotaxis, reduce mast cell and basophil mediator release, and result in decreased mucosal edema and local inflammation.254^, 255 A combined analysis of three double‐blind, randomized, prospective, placebo‐controlled studies of 983 patients (309 of whom were classified as NARES) demonstrated a positive treatment effect using INCS with improvement in symptoms of nasal obstruction, postnasal drip, and rhinorrhea.256 Additionally, the intranasal antihistamine azelastine and leukotriene receptor antagonists (LTRA) have been shown to reduce symptoms of rhinitis, including postnasal drainage, sneezing, rhinorrhea, and congestion.152^, 257^, 258^, 259

V.B.10 Non‐allergic rhinopathy

Non‐allergic rhinopathy/rhinitis is a chronic rhinitis made by a diagnosis of exclusion of other etiological factors. These include CRSwNP, NARES, AERD, infectious rhinitis, anatomical abnormalities, rhinitis medicamentosa, drug side effects, cerebrospinal fluid (CSF) rhinorrhea, and rhinitis of pregnancy. Clinical characteristics of non‐allergic rhinopathy/rhinitis include primary symptoms of nasal congestion and rhinorrhea, postnasal drip in the absence of acid reflux, throat clearing, cough, Eustachian tube dysfunction (ETD), sneezing, hyposmia, and facial pressure/headache.67 These symptoms may be perennial, persistent, or seasonal, and are typically elicited by defined triggers, such as cold air, climate changes (e.g., temperature, humidity, barometric pressure), strong smells, tobacco smoke, changes in sexual hormone levels, environmental pollutants, physical exercise, and alcohol. Notably, the lack of a defined trigger does not preclude the diagnosis of non‐allergic rhinopathy.

The prevalence of non‐allergic rhinopathy, the second most common form of rhinitis, is between 7% and 9.6% in the adult population in the United States (US) and Europe.34^, 60 Vasomotor rhinitis is the most common cause of non‐allergic rhinitis, and is found in 71% of cases.260^, 261^, 262 Non‐allergic rhinopathy occurs with a female‐to‐male ratio of 2:1 to 3:167 and is typically seen after the age of 20.263 It is defined by the absence of an IgE‐mediated immune response.152 The term “non‐allergic rhinopathy” has been suggested to replace vasomotor rhinitis, as allergic inflammation is absent in the pathogenesis, although vasomotor causes may not account for the entirety of non‐allergic rhinopathy/rhinitis cases.

The nasal mucosa of patients with non‐allergic rhinopathy displays erythema and clear rhinorrhea. Allergy testing can be used to differentiate between non‐allergic rhinopathy and AR. Vasomotor rhinitis, the most common subtype of non‐allergic rhinopathy, has been linked to autonomic dysfunction and has been attributed to an imbalance between the parasympathetic and sympathetic systems.264

Local allergic rhinitis (LAR) is a distinct rhinitis that presents with features in between AR and non‐allergic rhinopathy.265 Patients with LAR demonstrate entopy or local IgE production in the nasal mucosa but lack skin test positivity. Individuals with LAR suffer from typical allergic symptoms upon allergen exposure but display a lack of systemic IgE sensitization. Local provocation is necessary to definitively exclude this diagnosis.265^, 266 The prevalence of LAR among non‐allergic rhinopathy has been reported to be 26.5%.267 (See Section VI.A.3. Local IgE Production for additional information on this topic.) Additional forms of non‐allergic rhinopathy include food‐induced rhinorrhea and age‐related rhinitis. (See Section V.B.8. Food and Alcohol Induced Rhinitis and Section V.B.11. Age‐related Rhinitis for additional information on this topic.)

Neurosensory abnormalities are thought to play an important role the development of non‐allergic rhinopathy.67 In previous evaluation of central responses to olfactory stimuli, subjects with non‐allergic rhinopathy underwent functional magnetic resonance imaging following exposure to different odors (vanilla and hickory smoke). Findings included increased blood flow to the olfactory cortex, leading to the hypothesis of an altered neurologic response.268^, 269

Medical management of non‐allergic rhinopathy includes topical nasal sprays that have variable responses which have been used alone or in combination: INCS,256^, 270 topical azelastine,271 and IPB.272 In addition adjunctive treatments include nasal saline sprays or lavage, especially with tenacious post nasal drip.264

For severely symptomatic patients refractory to medical therapy, surgical approaches targeting the vidian nerve and its branches have been shown to result in symptom control.229^, 273 These include botulinum toxin injections which result in temporary symptom improvement, endoscopic vidian neurectomy, endoscopic posterior nasal neurectomy, and cryoablation of the posterior nasal nerve. Posterior nasal neurectomy is purported to result in lower rates of dry eye complications than vidian neurectomy.274 Recent studies show that office based cryotherapy can achieve improvement in rhinorrhea and congestion for up to 1 year.275^, 276

V.B.11 Age‐related rhinitis

As the percentage of the adult population aged 65 years and older continues to increase, so does the prevalence of diseases associated with aging. Specific to rhinologic disease, the physiological process of aging results in neural, hormonal, mucosal, and histologic alterations that cause morphological and functional changes in the nasal cavity.277^, 278 This, in turn, can result in symptoms of rhinorrhea, nasal congestion, postnasal drip, dry nose, intranasal crusting, and decreased olfaction in the elderly population.279^, 280

Rhinorrhea. A questionnaire distributed to a cohort of adults in Pittsburgh demonstrated that 33% of the younger age group respondents (n = 76, mean age 19 years) regularly reported clear anterior nasal drainage as compared to 74% of the older age group respondents (n = 82, mean age 86 years).281 It is known that autonomic function declines with age as α− and β−receptors become less sensitive. Therefore, an imbalance of this system with decreased sympathetic tone and unopposed parasympathetic stimulation could result in a rise in glandular activity in the nasal cavity, leading to increased nasal drainage.281^, 282^, 283^, 284 This mechanism is similar to the process classically termed “vasomotor rhinitis,” where the autonomic response to certain stimulants causes the nasal mucosal blood vessels to dilate and the mucus glands to become overactive, resulting in hypersecretion and excessive drainage.285 Vasomotor rhinitis is the most common type of non‐allergic rhinopathy/rhinitis, and the highest prevalence of non‐allergic rhinopathy is seen in the elderly,260^, 280^, 286^, 287 supporting an autonomic nervous system mechanism as the physiologic reason for increased rhinorrhea in this population.

Nasal obstruction and congestion. Other changes that occur in the aging nose include thicker mucus secondary to a decrease in body water content,288^, 289^, 290 loss of nasal cartilage elasticity and tip support,278^, 280^, 290 mucus stasis secondary to a less effective mucociliary clearance system, 280^, 289^, 291 and age‐related central nervous system changes that affect the physiologic nasal cycle,288^, 292 all of which can result in nasal obstruction/congestion.

Nasal dryness and intranasal crusting. Nasal dryness and intranasal crusting in the elderly often occurs due to decreases in mucosal blood flow and an increase in epithelial degeneration.293 This, in turn, results in intranasal volume increase due to nasal mucosal atrophy.279 Schrodter et al.294 evaluated nasal mucosa samples from the middle turbinate (MT) of 40 healthy subjects 5–75 years old, and found an age‐related increase in atrophic epithelium (only seen in patients over 40 years) with thickened basement membranes. Nasal crusting may also occur due to a decrease in intranasal temperature and humidity in the aging nose.280

Allergic rhinitis. The worldwide growth of both the aging population and allergic disease has caused an increase in the prevalence of AR in the elderly,278 with the prevalence estimated to be around 5%–10%.290^, 295 However, epidemiologic data is overall lacking and AR in the elderly population is likely under‐diagnosed and under‐treated. Although there is symptomatic overlap between age‐related rhinitis and AR in the elderly, AR is a type I hypersensitivity IgE‐mediated reaction,296^, 297 whereas age‐related rhinitis is more similar to vasomotor or non‐allergic rhinopathy/rhinitis in that allergens do not play a role in the aforementioned physiologic changes of the aging nose. AR in the elderly should be treated similarly to AR in the younger population, with INCS, oral and topical antihistamines,290^, 298 and AIT.299 For age‐related/non‐allergic rhinitis rhinorrhea, saline lavage and topical anticholinergics may be therapeutic.277 However, both conditions can be concomitantly present in the elderly population, presenting as a “mixed rhinitis,” and should be considered in elderly patients who are refractory to typical medical management for a singular disease.

V.B.12 Atrophic rhinitis

Atrophic rhinitis is a chronic disease of the nose presenting with symptoms of nasal dryness and crusting, persistent fetid odor, recurrent epistaxis, and nasal obstruction.300^, 301 It is characterized by progressive atrophy of the nasal mucosa and bone, leading to anatomically wider nasal airways, albeit many patients paradoxically complain about the symptom of nasal obstruction. Upon removing crusts, the nasal cavity appears enlarged, with significant atrophy of the nasal turbinates. Atrophic rhinitis can be classified into primary or if occurring as a sequela of a causative factor, secondary.302 Both primary and secondary atrophic rhinitis are significantly different in their clinical presentation and underlying pathophysiology compared to AR.182

The prevalence of primary atrophic rhinitis varies across regions worldwide, with a higher prevalence in tropical countries such as India or Thailand compared to Europe or the US.303^, 304^, 305^, 306^, 307 It is also more commonly found in young to middle‐aged adults, with a predominance of females.303 Primary atrophic rhinitis has also been linked to environmental and socioeconomic factors. For example, it has been more commonly found in industrial workers, those with lower socioeconomic status (SES), and those in rural areas.303 While there are no universally accepted guidelines for diagnosing primary atrophic rhinitis, it usually consists of a structured medical history and physical examination, including nasal endoscopy.306^, 308

The differentiation with secondary atrophic rhinitis includes the exclusion of potential causative etiologies related to secondary atrophic rhinitis, such as excessive nasal surgery, chronic granulomatous infections (e.g., tuberculosis, syphilis, leprosy), autoimmune/inflammatory disorders (e.g., granulomatosis with polyangiitis [GPA] or sarcoidosis), and excessive drug use (nasal sprays and cocaine).309 Studies in the US on atrophic rhinitis patients revealed that secondary atrophic rhinitis accounted for more than 80% of atrophic rhinitis cases and was most commonly found in middle‐aged adults.304 Compared to the diagnosis of primary atrophic rhinitis, which mainly consists of excluding potential causative etiologies related to secondary atrophic rhinitis, a complete medical history to evaluate for causative factors represents the most correctly step for correctly diagnosing secondary atrophic rhinitis.300

To work up atrophic rhinitis, accurate and comprehensive medical history is important. Nasal endoscopy, cultures, and histopathology can also help clarify the diagnosis. Ly et al.310 identified seven key symptoms that can be used to establish the diagnosis of atrophic rhinitis: purulence, nasal obstruction, history of nasal/sinus surgeries (at least two), crusting, recurrent epistaxis, smell loss, and chronic inflammatory disease of the upper airway. While more symptoms are associated with a higher sensitivity to diagnose atrophic rhinitis, the authors proposed that the presence of at least two symptoms (excluding nasal obstruction) enhances the sensitivity and specificity to 95% and 77%, respectively, to support the diagnosis of atrophic rhinitis.310 Endoscopic findings usually include nasal crusting and enlarged lateral sidewalls.304

The underlying etiology and pathophysiology of primary atrophic rhinitis are still unknown, although persistent bacterial infection is commonly believed to be the causative agent. Microbiological cultures from the middle meatus can aid in the diagnosis.311 The most common bacteria found in affected individuals is Klebsiella ozaenae,303^, 304^, 312^, 313 albeit many other bacteria such as Staphylococcus aureus or Pseudomonas aeruginosa have also been isolated from nasal cultures.303^, 306 Histopathological changes in both primary and secondary atrophic rhinitis may include partial or total squamous metaplasia, granulation tissue, atrophy, reduction of the seromucous glands, and vascular changes (e.g., reduced vascularity, dilated blood vessels, and in some cases endarteritis).309 Interestingly, there have also been case reports which suggest primary atrophic rhinitis may have a genetic inheritance pattern.314

V.B.13 Empty nose syndrome

Empty nose syndrome (ENS) is a rare and complex acquired upper airway disease. “ENS” was coined nearly three decades ago to describe the “empty” or “wide open” nasal cavity examination and imaging in patients following turbinoplasty with excess loss of turbinate tissue or contour.304^, 315^, 316^, 317^, 318^, 319 Clinically, it is characterized by a spectrum of debilitating symptoms like nasal burning, dryness, and crusting, accompanied by symptoms quite unique to ENS like severe suffocation, paradoxical sensation of nasal obstruction, or excessive nasal airflow (i.e., “nose feels too open”).304^, 320^, 321

ENS is linked to several IT reduction approaches, such as total turbinectomy, IT trimming, and radiofrequency ablation.321^, 322 Presentation can be immediate or delayed, secondary to over‐aggressive IT reduction or suboptimal post‐surgical healing and scarring, respectively.316^, 323^, 324 While ENS is mostly associated with inferior turbinoplasty (ENS‐IT), ENS from MT tissue loss (ENS‐MT) has been reported.317

The physiologic basis for perceiving reduced and/or unpleasant nasal breathing may be related to altered signaling through trigeminal sensory receptors, specifically TRPM8. Resultant aberrant thermosensation and neurosensory deprivation manifest as muted airflow sensation.325^, 326^, 327^, 328^, 329^, 330 Damage to, and/or delayed recovery of, the trigeminal sensory nerve has also been implicated in the development of ENS in a minority of patients.331 Additionally, objective shifts in nasal airflow support a novel “aberrant airflow” hypothesis.332^, 333^, 334 Computational fluid dynamics modeling of nasal airflow demonstrates abnormally high velocity airflow to the middle meatus and dampened airflow vectors to the inferior meatus in ENS.

There has been welcome progress in the diagnosis and treatment of ENS in the past decade. In addition to a history of nasal surgery and abnormally expansive unilateral/bilateral nasal airway with concomitant IT tissue loss, thickened central nasal septum mucosa has been shown to be present in longstanding ENS.323 The validated patient reported outcome measure Empty Nose Syndrome 6‐item Questionnaire (ENS6Q) can be used to quantify the severity of six cardinal ENS symptoms on a 5‐point Likert scale. A score ≥11 indicates ENS.320 Placement of a cotton plug in the inferior meatus to simulate turbinate bulk (the cotton test) has been validated as an office‐based tool to assess/alleviate ENS symptoms.335 A positive blinded cotton test both confirms the ENS diagnosis and informs candidacy for possible treatment interventions.335

ENS has historically been a challenging disease to effectively treat due to debilitating nasal symptoms and, in a minority of patients, concerning psychiatric overtones.336^, 337^, 338^, 339^, 340 Past therapies were confined to reducing the daily burden of ENS symptoms via nasal maintenance strategies including moisturizers and emollients, increasing nasal airflow (supplemental oxygen, CPAP [continuous positive airway pressure] use), and psychiatric interventions like cognitive behavioral therapy.341^, 342

Current published interventions focus on restoring tissue volume to the truncated ITs or the adjacent inferior meatus. Submucosal injection of slow‐resorbing gel fillers can be trialed for the effect of “transient turbinate augmentation” lasting 1–3 months.343 A wide variety of biomaterials – including acellular dermis, implants, and xenografts – have been published as bulking options to sites of inferior meatus and IT tissue loss.344^, 345^, 346^, 347^, 348^, 349 Importantly, a procedure originally reported by Houser,318 now termed the inferior meatus augmentation procedure (IMAP), where missing turbinate contour is replaced with fashioned rounded rib grafts placed in the anterolateral nasal airway, has accumulated strong evidence for effectively treating ENS.350 IMAP has yielded statistically significant short351 and long352 term reductions in the ENS6Q and the Sinonasal Outcome Test (SNOT)‐22. Mechanistically, comparing computational fluid dynamics airflow modeling pre/post‐surgery, the cotton test and IMAP procedures both normalize disordered vectors of ENS airflow,353 highlighting a novel function of the turbinates in guiding and/or enhancing nasal airflow. Future ENS research will determine anatomic versus physiologic prognostic factors to identify “at risk” subpopulations for developing ENS336^, 337 and design more nuanced airflow metrics for upper airway function in health and disease.

V.B.14 Autoimmune, granulomatous, and vasculitic rhinitis

Differential diagnosis. Vasculitic, granulomatous, and autoimmune diseases may cause non‐specific sinonasal symptoms (e.g., nasal obstruction, rhinorrhea, facial pain, and loss of smell) often mimicking AR. Therefore, broadening the differential diagnosis to consider systemic etiologies when evaluating these sinonasal symptoms is crucial. Crusting, recurrent epistaxis, or negative skin and/or blood allergy tests are among the signs that should heighten one's suspicion of alternative systemic diseases.354^, 355

Granulomatosis with polyangiitis (GPA). This is an uncommon disease with highest prevalence amongst people of Northern European descent, with men and women equally affected and incidence peaking in the seventh decade of life.356 It is a chronic, relapsing, and idiopathic disease characterized by necrotizing and granulomatous inflammation affecting predominantly small to medium sized blood vessels.357 Potential triggers include Staphylococcus aureus as well as other infectious, environmental, chemical, or pharmacologic agents.

Sinonasal manifestations (e.g., nasal obstruction, crusting, epistaxis, anosmia, cacosmia, and paranasal sinus inflammation) are the presenting symptoms of GPA in about 73% of patients.358 Recurrent serous otitis, mastoiditis causing hearing loss, and lower respiratory tract symptoms (e.g., cough, breathlessness, stridor, wheeze) occur in 80%–90% of patients.354^, 359 Additionally, renal (75% of patients), ocular (50% of patients), and systemic manifestations (e.g., fever, arthritis, weight loss) are also possible.360

Diagnosis is often dependent on a multidisciplinary approach and based on a combination of suggestive local and systemic clinical manifestations, positive ANCA (anti‐neutrophil cytoplasmic antibody) serology, and histological evidence of necrotizing vasculitis or glomerulonephritis by a positive organ biopsy (skin, lung, or kidney).361^, 362

Before the introduction of effective therapy, GPA was a potentially life‐threatening disease. Treatment includes corticosteroids and immunosuppressive agents to induce remission. Cyclophosphamide and rituximab are often used for induction and maintenance. Patients can be transitioned to other immunosuppressive agents (e.g., azathioprine, mycophenolate, or methotrexate) with fewer potential side effects when disease remission is obtained.363

Eosinophilic granulomatosis with polyangiitis (EGPA). EGPA (formerly Churg–Strauss syndrome) is a small‐vessel vasculitis. Defining features include eosinophil‐rich, necrotizing granulomatous inflammation involving the respiratory tract. It is associated with asthma, eosinophilia, and CRSwNP. It is a rare disease with a prevalence of 10–15 people per million in Europe and appears in patients 40–60 years old.364 EGPA has different triggers and frequently progresses through three stages gradually appearing over years. An initial phase with rhinitis (75%), asthma, and CRSwNP is often followed by peripheral eosinophilia and additional organ involvement, and finally diffuse clinical manifestations secondary to small vessel vasculitis.365 Diagnosis should be suspected in patients with asthma, increased peripheral‐blood eosinophil count (>10%) and pulmonary infiltrates.365 CRSwNP is present in approximately 50% of patients. Nasal crusting, purulent, or bloody discharge can be present, but is less common than in GPA.366 Treatment includes high doses of corticosteroids with rituximab in specific cases. Mepolizumab, an anti‐IL‐5 antibody, has shown efficacy in the eosinophilic inflammation and was approved for the treatment of EGPA in 2017 by the Food and Drug Administration (FDA).355^, 367

Sarcoidosis. This is chronic multisystem disorder characterized by bilateral hilar lymphadenopathy and pulmonary infiltrates. Ocular and skin lesions are more common in young and middle‐aged adults.368 Sinonasal involvement occurs in 1%–4% of cases and symptoms are non‐specific: chronic crusting (70%–90%), nasal obstruction (80%–90%), anosmia (70%), and epistaxis (2%).355^, 357^, 369 Aggressive non‐caseating granulomas can cause hard or soft palate erosions as well as a saddle‐nose deformity. Intranasal findings include erythematous, edematous, and friable mucosa, as well as submucosal yellow nodules (representative of intramucosal granulomas).370 Diagnosis is usually made by a lung (transbronchial), skin, minor salivary gland, or lymph node biopsy.368

Sinonasal sarcoidosis treatment depends on its location, extension, and severity going from topical to systemic therapy (when nasal obstruction is severe). Endoscopic sinus surgery can be effective when medical treatment has failed, particularly in cases of sinus drainage blockage. Sinus surgery improves quality of life (QOL) but does not eradicate the disease nor prevent recurrence.371 Biological therapy with anti‐TNF agents has improved the therapeutic options in refractory organ‐threatening sarcoidosis.371

Systemic lupus erythematosus. This is an autoimmune disease that predominantly affects women (10:1) with an incidence of 5.6 per 100,000 people.372 Oral, nasal (nasal skin or vestibule), and pharyngeal mucosal lesions are seen in 9%–18% of cases.357^, 372 Diagnosis requires a detailed medical history, physical examination, and laboratory tests (ANA [antinuclear antibody] or anti‐dsDNA [double stranded DNA]).354^, 373

Therapy with corticosteroids, immunomodulators (e.g., prasterone, vitamin D, hydroxychloroquine), or immunosuppressants (e.g., azathioprine, cyclophosphamide, mycophenolate) is used for symptom control. Belimumab, an anti‐BAFF (B cell activating factor) monoclonal antibody, is the only therapy currently utilized for extrarenal disease due to its modest effect on lupus activity.374 Anifrolumab, an IFN‐type 1 monoclonal antibody, has substantial evidence in effectively and safely treating moderate to severe active lupus.375

V.B.15 Rhinosinusitis

The symptoms of AR may overlap with those of rhinosinusitis.7^, 376 Rhinosinusitis is a broad term that includes the diagnosis of acute rhinosinusitis (ARS), RARS, and CRS. Symptomatically, these conditions are characterized by nasal obstruction, nasal congestion, facial pressure or pain, anterior or posterior nasal discharge, and anosmia/hyposmia.7^, 183 AR and rhinosinusitis have several overlapping symptoms, namely rhinorrhea and nasal congestion, which can make it challenging to differentiate these conditions.7^, 377^, 378 It is important to differentiate between AR and rhinosinusitis to ensure the correct diagnosis and subsequent treatment.

ARS is defined as the sudden onset of sinonasal symptoms outlined above with associated sinonasal inflammation that lasts less than 4 weeks – it may be viral or bacterial in nature.7^, 183^, 184^, 201^, 379 In ARS, nasal discharge is often unilateral and purulent.183^, 201 Associated facial pressure and pain is described as moderate to severe.201 Viral ARS is typically present for less than 10 days, whereas a longer duration of illness suggests bacterial ARS.183^, 201 Progressive worsening over a short period of time (i.e., 5 days) is also suggestive of bacterial ARS.183^, 201 RARS is defined as at least four episodes of ARS per year.183^, 201^, 379^, 380 CRS is an inflammatory condition of the sinonasal cavity, defined as sinonasal inflammation persisting for more than 12 weeks with at least two of the sinonasal symptoms outlined above.7^, 183^, 184^, 201^, 379 In addition, patients must have objective evidence of sinonasal inflammation on either nasal endoscopy (polyps, edema, mucopurulent rhinorrhea) or on computed tomography (CT) scan of the sinuses.183^, 184^, 201^, 379

Comparatively, AR is characterized by nasal obstruction, nasal congestion, clear watery rhinorrhea (anterior or posterior), and allergic symptoms such as nasal itching, sneezing, and allergic conjunctivitis.377^, 378 AR is not typically associated with purulent or unilateral nasal discharge. Moderate to severe facial pain is also atypical and may indicate an episode of ARS or an acute exacerbation of CRS.7^, 183^, 201 AR symptoms are variable in duration and tend to have daily and/or local environmental fluctuations.7^, 183^, 201 As a result, AR symptoms have been classified by duration (intermittent vs. persistent) and severity. AR symptoms, in general, present for at least 1 h on most days; however, patients may have symptom‐free intervals.377^, 378 AR symptoms are also exacerbated by exposure to allergens in a time‐dependent fashion.377 The early reaction occurs immediately after exposure, lasting approximately 30 min (sneezing, nasal/ocular itching, rhinorrhea), while the late reaction occurs up to 6 h after exposure (nasal obstruction and congestion).377 Superimposed late reactions from multiple exposures may blunt the manifestation of acute phase symptoms and make the diagnosis of AR less obvious.

When attempting to determine whether a patient has AR, ARS, RARS, or CRS, it is important to elicit the onset and duration of symptoms. A history of allergic symptoms or allergen exposure‐related symptoms is more consistent with AR.377^, 378 The development of acute, unilateral, moderate to severe symptoms, and nasal purulence may be consistent with ARS or RARS.7^, 183^, 201 A prolonged duration of symptoms (greater than 12 weeks) as well as presence of smell loss, which is not as common in AR, should raise suspicion for CRS and prompt further investigation.7^, 183^, 201 Of note, these conditions are not mutually exclusive. It is possible to have concurrent AR and rhinosinusitis, and this should be considered when patient symptomatology or response to treatment does not fit a single diagnosis.7^, 183^, 376 (See Section XIII.B. Associated Conditions – Chronic Rhinosinusitis for additional information on this topic.) Careful consideration of these symptoms and environmental triggers may help guide clinicians to the correct diagnoses.

V.B.16 Non‐rhinitis conditions

There are a variety of non‐rhinitis conditions which can be included in the differential diagnosis of AR. In general, non‐rhinitis conditions can be differentiated from AR based on a thorough history and physical exam, with an emphasis on laterality, timing, and associated symptoms (Table V.B.16).

Anatomical conditions, such as septal deviation, turbinate hypertrophy, or nasal valve collapse, overlap symptomatically with AR largely by causing nasal obstruction.381 Septal deviations often have an asymmetry in airflow, with one side being more obstructed than the other.382^, 383^, 384 Nasal valve collapse is often associated with obstruction on inspiration or during exercise.381^, 382^, 385 Some congenital anatomical abnormalities such as piriform aperture stenosis or choanal atresia also cause nasal obstruction, which typically results in lifelong symptoms, which may or may not be identified in childhood.386 The majority of these structural conditions should be evident on a physical examination including nasal endoscopy.

Sinonasal neoplasms often present with nasal obstruction.387 The differential for sinonasal masses is extensive, including papillomas, hemangiomas, encephaloceles, osseous lesions, congenital masses, carcinomas, melanomas, and lymphomas.381^, 384^, 387^, 388^, 389 Sinonasal neoplasms are typically associated with unilateral nasal obstruction, but they can cause bilateral obstruction if they grow larger or if they block the nasopharynx.387 When sinonasal neoplasms cause unilateral nasal obstruction, they can also be associated with unilateral rhinorrhea, which is more likely to be thick or mucopurulent.387 Rarely, neoplasms can erode through the skull base and cause CSF rhinorrhea, discussed below.390^, 391 The onset of symptoms in sinonasal neoplasms usually spans weeks to months with a progressive worsening of symptoms.387 Associated symptoms including epistaxis, hypoesthesia, visual changes, epiphora, trismus, or dental changes should raise the clinical suspicion for a nasal mass versus AR.387^, 392^, 393 These symptoms would be highly atypical for AR and would warrant a careful physical exam, endoscopy, and sinonasal imaging, which can localize the sinonasal lesion if present.387

There are a variety of other less common non‐rhinitis conditions to consider in the evaluation of AR. CSF rhinorrhea is associated with episodes of thin, watery rhinorrhea, much like AR.394 Unlike AR, CSF rhinorrhea is most commonly unilateral and often reproducible with positional maneuvers.394 While many CSF leaks are spontaneous, a history of significant head trauma or previous sinonasal surgery preceding the onset of symptoms should raise suspicion for a CSF leak over AR.289^, 395 Retained foreign bodies or rhinolithiasis can also cause nasal obstruction and rhinorrhea, though these are usually associated with unilateral symptoms and purulent nasal drainage.289^, 396^, 397 Disorders which affect mucociliary clearance, including primary ciliary dyskinesia or cystic fibrosis, can also lead to nasal obstruction and rhinorrhea.398^, 399 These persistent rhinitis symptoms without allergic variation, with viscous secretions and systemic organ dysfunction are not consistent with AR and should raise suspicion for alternative diagnoses.382^, 398

There is increasing evidence suggesting an association between reflux disease and sinonasal symptoms.400 Reflux disease (gastroesophageal, laryngopharyngeal) has been associated with nasal congestion and postnasal drip.401^, 402 Congestion and inflammation of the nasal mucosa may result from acidic content directly affecting the mucosa or from esophageal‐nasal reflexes triggered by the vagal nerve.400^, 402 Reflux symptoms may warrant treatment but whether this improves sinonasal symptoms or not is unclear.400

While many of these non‐rhinitis conditions have symptoms that overlap with AR, a careful assessment of the laterality, timing, and associated symptoms can help differentiate these conditions from AR. Similarly, a careful physical examination and nasal endoscopy will aid in identifying the correct diagnosis. A high degree of clinical suspicion will help clinicians accurately diagnose AR versus alternative diagnoses.

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VI.A.1 IgE/IgE‐receptor cascade

In the last several years, much has been learned about the immunologic cascade that follows antigen cross‐linking of IgE bound to cellular receptors. Three different IgE receptors have been described. The type I high‐affinity IgE receptor (FcεRI) is found on mast cells and basophils through which it mediates cellular degranulation and cytokine production.403 It is also found on dendritic cells and macrophages where it mediates the internalization of IgE‐bound antigens for processing and presentation, and facilitates production of cytokines promoting the Th2 immune response.403 The low affinity cluster of differentiation (CD)23/FcεRII receptor is found on macrophages and epithelial cells and mediates the uptake of IgE‐antigen complexes.404 FcεRIII is expressed by B cells and regulates IgE production and facilitates antigen processing and presentation.405 This section will focus on the cascade that follows activation of the high‐affinity receptor FcεRI.

FcεRI consists of an α chain which is a transmembrane protein that binds the IgE FC portion, a β chain which is a receptor‐stabilizing and signal‐amplifying subunit with four transmembrane domains, and disulfide‐linked dimeric γ chains which act as signal‐triggering subunits.406 Secreted IgE binds to FcεRI on mast cells or basophils. When an antigen binds or cross‐links two IgE/FcεRI complexes, activation of mast cells and basophils is triggered and degranulation occurs causing the release of histamine, tryptase, cysteinyl leukotrienes, and platelet activating factors among others.405^, 407 This process is known as the early allergic response and is associated with vasodilation, edema, and bronchoconstriction.405^, 407

Within the β and γ subunits of the FcεRI receptor is the immunoreceptor tyrosine‐based activation motif (ITAM). Following receptor stimulation, ITAM on the β and γ subunits undergo phosphorylation by Src family protein tyrosine kinases and recruitment of another tyrosine kinase Syk.408 Through conformational changes and tyrosine phosphorylation, Syk is activated.409 Syk is critical for most activation events within the mast cell which lead to degranulation as well as the de novo synthesis and production of chemokines, cytokines, and lipid mediators.410^, 411

Within a few hours of IgE receptor stimulation by IgE cross‐linking, activated mast cells secrete a large amount of newly synthesized proteins, a result of de novo gene transcription prompted by receptor stimulation.412^, 413 Following stimulation of the FcεRI receptor, human mast cells have been demonstrated to upregulate 260 genes and downregulate 84 genes for up to 2 h.414 The upregulated genes include gene sets encoding cell surface molecules, cytokines/chemokines, signaling molecules, transcription factors, proteases, and other enzymes.406 The downregulated genes include gene sets involved in signal transduction, apoptosis, cell proliferation, and genes encoding receptors.415

Cross‐linking of the FcεRI receptors by antigen‐bound IgE leads to the activation of several transcription factors. These signal dependent transcription factors including signal transducer and activator of transcription (STAT)‐5, nuclear factor of activated T cells (NFAT), activator protein (AP)‐1, nuclear factor (NF)‐κB, and early growth response (EGR)‐2 function in FcεR1 upregulated gene expression.416 Ultimately, this complex process of de novo gene transcription and upregulation/downregulation of genes results in the production and release of cytokines and chemokines.417 This includes IL‐3, IL‐4, IL‐5, IL‐13, C‐C chemokine ligand‐5 (CCL5), and granulocyte‐macrophage colony stimulating factor (GM‐CSF).418^, 419^, 420 The effect of these cytokines and chemokines is the recruitment of inflammatory cells including eosinophils, basophils, neutrophils, macrophages, and T cells.418^, 419^, 420 This is referred to as the late allergic response characterized by airway inflammation, hyperresponsiveness, airway remodeling, and mucus hypersecretion.407

VI.A.2 Systemic mechanisms and manifestations of allergic rhinitis

Allergic diseases such as asthma, atopic dermatitis (AD), and AR share a common inflammatory pathway involving the adaptive immune system mediated by sIgE. The adaptive immune system can generally be categorized into Th1, Th2, and Th17 responses, named after the Th cells that orchestrate the corresponding immune responses. The Th1 response provides defense against intracellular pathogens, and has IFN‐γ as its canonical cytokine.421 The Th17 response also provides defense against pathogens, such as bacteria and fungi, and is characterized by neutrophilic inflammation and its canonical cytokine, IL‐17. The Th2 response provides defense against parasites and is marked by the expression of IL‐4, IL‐5, and IL‐13.421^, 422 These ILs represent integral mediators responsible for driving IgE‐ and eosinophil‐associated inflammation that often characterizes atopic disease.421 Type 2 innate lymphoid cells (ILC2s) are a newly characterized group of effector cells of the innate immune response that also have the capacity to produce large quantities of the type 2 cytokines, especially IL‐4, IL‐5, and IL‐13, playing a critical early role in the initiation of Th2 responses to aeroallergens during allergic inflammation.423^, 424^, 425

In AR, aeroallergens are inhaled onto the nasal mucosa. When mucosal epithelial integrity is disrupted, epithelial cells release alarmins and other damage‐associated molecular patterns (DAMPs).426^, 427 These mediators possess pro‐inflammatory properties and have been shown to assist in initiating and maintaining a Th2 immune response.428^, 429 For example, thymic stromal lymphopoietin (TSLP) is an important alarmin which can promote the recruitment of inflammatory cells (i.e., eosinophils, basophils, and mast cells) and the maturation of dendritic cells into Th2‐promoting subtypes, further enhancing Th2 polarization.430^, 431^, 432^, 433 It is theorized that in AR, this pathway is similarly activated and there are aeroallergens (e.g., dust mite allergens), that directly compromise the mucosa through protease activity or by activating pattern recognition receptors of which the toll‐like receptor (TLR) family is the most well‐known.434

On first exposure to an allergen, dendritic cells in the nasal mucosa process the allergen and then migrate to present it on MHC class II to naive helper T (Th0) cells in secondary lymphoid organs.422 Once exposed to antigen/allergen in the appropriate costimulatory environment, Th0 cells become activated and differentiate into allergen‐specific Th2 cells. Th2 differentiation requires co‐stimulation via the interaction of CD28 on T cells with CD80 and CD86 on antigen presenting cells and the presence of IL‐4.435^, 436 IL‐4 binds STAT‐6 on Th0 cells which activates the master switch GATA‐3 (GATA‐binding protein 3).430 As a result, Th2 cells release cytokines such as IL‐4, IL‐5, and IL‐13 which activate B cells and initiate IgE class switching.422^, 434 Class switching occurs via upregulation of ε‐germline gene transcription and clonal expansion, as well as the interaction between surface CD40 ligand on T cells with surface CD40 on B cells. This process allows B cells to differentiate into plasma cells that produce sIgE.435 The end result is the creation of a pool of memory Th2 and B cells.434 sIgE is released into circulation and binds to high‐affinity FcεRI IgE receptors on the surface of effector cells such as mast cells and basophils.434 During IgE‐mediated reactions, prostaglandin D2 (PGD2) which is mainly synthesized by mast cells has recently been shown to exert an important role in recruitment and activation of ILC2s, in addition to leukotrienes, and innate cytokines.437^, 438 Crosslinking of IgE on the surface of these effector cells causes degranulation and the release of inflammatory mediators such as histamine and leukotrienes, resulting in classic symptoms of AR.

AR has traditionally been thought of as resulting from an immune response leading to systemic IgE production.439^, 440 The classic example of systemic reactivity in AR is the cutaneous reaction elicited during traditional skin testing.441 The concept of LAR is discussed in the section that follows.

VI.A.3 Local IgE production

When systemic allergen sensitization is present, sIgE is detected via serum in vitro testing or allergy skin testing. However, systemic allergy testing methods do not provide direct information regarding the target‐organ immunological response.265^, 442^, 443^, 444 Studies in recent decades support the concept of local IgE production. LAR is characterized by allergic nasal symptoms in patients with negative systemic allergy testing. However, in these patients, positive NPT and/or detection of nasal sIgE and/or positive basophil activation test (BAT) demonstrate a localized allergic response.265^, 443^, 445^, 446^, 447^, 448^, 449

Local IgE production has been demonstrated in patients with AR450^, 451^, 452^, 453 and LAR.454^, 455^, 456^, 457^, 458^, 459^, 460^, 461^, 462^, 463 In LAR, sIgE in nasal secretions has been confirmed after natural exposure,455^, 456 after controlled exposure to aeroallergens by NPT,456^, 458^, 459^, 460^, 464 and also during periods of non‐exposure to aeroallergens.455^, 456 It is theorized that in LAR individuals, sIgE produced at the mucosal level can be enough to sensitize nasal effector cells, but not to reach skin mast cells or to be detected in the free state in serum.465

The immunopathology of local sIgE production in LAR is not completely understood. Flow cytometry of nasal lavage confirms a nasal IgE‐mediated inflammatory response in LAR patients, with increased eosinophils, basophils, mast cells, CD3+ and CD4+ T cells, and local sIgE, along with characteristic pro‐inflammatory mediators such as tryptase and eosinophil cationic protein (ECP) during natural exposure to aeroallergens.444^, 454^, 455^, 456^, 457^, 458^, 459^, 460^, 461^, 462^, 463^, 464^, 465^, 466

NPT studies to assess potential mechanisms of local sIgE production have revealed characteristic immediate/early and late phases of the allergic response in LAR. In these patients, nasal mucosal reaction to administered allergen is immediate and occurs mostly by stimulation of IgE‐coated mast cells and basophils. This results in the secretion of tryptase, histamine, cys‐leukotriene, and PGD2, which then stimulate the local sensory nerve and vascular receptors in nasal mucosa. Mast cells secrete chemotactic agents and platelet activating factor, contributing to the development of inflammation with local production of sIgE and eosinophil activation.462 As a result, serum IL‐5 levels increase and IL‐5 is transported into the pulmonary circulation, causing increased exhaled NO and bronchial hyperreactivity.461^, 463 Finally, in a study by Campo et al.,467 following NPT with nOle e 1 (the most significant allergen of Olea europea), 83% of LAR O. europaea sensitized subjects responded. Further, ECP levels in nasal lavage significantly increased after NPT in LAR patients indicating that secretion of ECP following NPT could potentially act as a confirmatory biomarker.

Additional studies have shown that sIgE produced in the nasal mucosa of patients with LAR sensitized to HDM and pollens has the capability of binding to the FcεRI high‐affinity receptor on basophils.450^, 468 Furthermore, the sIgE‐related mechanism of basophil activation in LAR has been demonstrated by performing BAT with wortmannin pretreatment, showing reversal of positive results when wortmannin was added to the assay.468 These findings suggest that after local IgE production, basophils might be the first target cells for sIgE produced in the target organ transported from the site of inflammation (nasal mucosa) to the general circulation.469

Studies report LAR prevalence is approximately 26% in Mediterranean countries (Portugal, Spain, Italy and Greece)470 and 7%‐10% in Asian countries (China and Korea).150^, 471^, 472 LAR may affect approximately 47% of children previously classified as non‐allergic rhinitis.444^, 464^, 466^, 473^, 474 Exposure to environmental factors such as temperature, humidity and pollution are associated with higher incidence of LAR.466^, 475 There is a low rate of conversion (∼3%) to systemic detection of allergen sensitivity, development of asthma, and worsening clinical progression is rarely seen.239^, 448^, 475^, 476^, 477

VIII.A.1 Single nucleotide polymorphisms (SNPs) associated with allergic rhinitis

Genome‐wide association studies. GWASs, with their unbiased approach that includes hundreds of thousands of common variants, have successfully identified important genes for complex diseases over the past decade (https://www.ebi.ac.uk/gwas/). Thirty‐four GWASs involving AR (or seasonal AR/hay fever) have been published up to November 2021, of which nine (one exome‐sequencing project) reported genome‐wide significant hits (Table VIII.A). SNPs in LRRC32 (leucine‐rich repeat‐containing protein 32) have been strongly associated with AR in five of the GWASs,791^, 792^, 793^, 794^, 795 as well as with asthma,792^, 796 eczema,793^, 797 and other allergy‐related co‐morbidities.791^, 796^, 798 LRRC32 is known to regulate T cell proliferation, cytokine secretion, and TGF‐β activation.799 These associations support the concept of shared genetic mechanisms for AR and other allergy‐related diseases. This concept is further supported by a GWAS on self‐reported cat, dust mite, and pollen sensitization (as well as AR), which revealed 16 shared susceptibility loci with strong association (p < 5 × 10⁻⁸; TLR‐locus top hit).792 Strong overlap between top loci for sensitization and self‐reported allergies also are found in two of the larger GWASs.792^, 800 In a recent GWAS specifically designed to evaluate pleiotropy between asthma, eczema, and hay fever, a total number of 136 SNPs were identified at the genome‐wide significant level (including 73 novel at the time), of which only six SNPs showed evidence for disease‐specific effects.801 In a follow‐up study, additional novel loci for comorbid allergic disease were identified by applying a gene‐based test of association.802 The only larger exome‐sequencing study published to date identified rare variants in IL33, a well‐known gene associated with other types airway inflammation, including asthma.803

As expected, larger studies with better power allow for improved ability to accurately detect novel loci and potentially novel AR‐related disease mechanisms. Recently, very large GWASs were able to confirm many of the previously identified susceptibility loci for AR, with top hits HLA‐DQB1/DQA1, IL1RL1, TLR1/10, WDR36, and LRRC32.794^, 795 A recent multi‐institutional study comprising over 50,000 cases of AR identified the novel loci IL7R, which encodes the receptor for IL‐7 (and TSLP) involved in immunoregulation, and CXCR5, a chemokine receptor involved in B cell migration.795

Candidate gene studies. The candidate gene approach for selecting disease‐relevant genes is based on known molecular biology or gene function relevant to disease pathophysiology. Such studies in AR have identified several well‐replicated genes, as summarized previously.804^, 805^, 806 Notably, results from many candidate gene studies often overlap with GWASs results. For example, SNPs in genes involved in antigen presentation (e.g., HLA‐DQA1), pathogen recognition (e.g., TLR2,7,8), IL signaling, and pro‐inflammatory signaling (e.g., IL13, IL18, TSLP) have been highlighted.804^, 805^, 806^, 807^, 808^, 809^, 810 However, many of the candidate gene study findings have not been well‐replicated across studies and populations.811^, 812 This could be due to lack of power from small sample sizes, inconsistent phenotype definition, or lack of true disease association.

VIII.A.2 Gene‐environment interactions and epigenetic effects

Epigenetic mechanisms, defined as changes in phenotype or gene expression caused by mechanisms (e.g., methylation) other than changes in the underlying DNA sequence, have been proposed to constitute a link between genetic and environmental factors. Recent studies show that DNA methylation in children is very strongly influenced by well‐known risk factors for allergic diseases, such as tobacco smoking/maternal smoking during pregnancy,813 air pollution exposure,814 and length of pregnancy.815 However, it is not currently known if these methylation changes are part of a causal pathway in the development of AR (and asthma), or if these epigenetic biomarkers are simply markers of exposure. Still, several studies have convincingly linked methylation profiles to AR816^, 817^, 818 and IgE‐related outcomes.819^, 820 Recently, methylation signatures in nasal epithelial brushes were shown to be strongly associated with AR (and also asthma).821 Also, epigenetic studies have highlighted shared molecular mechanisms underlying asthma, eczema and AR pathophysiology.822

In summary, a family history of AR remains one of the strongest risk factors for disease development, and strong associations with genes involved in antigen presentation (e.g., HLA genes), T cell activation (e.g., LRRC32), and innate immunity (e.g., TLRs) have been identified. Shared genetic mechanisms for AR and other allergy‐related diseases clearly exist. These novel findings lend insight into mechanisms underlying the pathogenesis of AR, as well as comorbid atopic conditions, and may aid drug discovery efforts for novel disease targets. With increasing evidence for the role of epigenetics in AR, future research should also focus on investigating mechanisms, thereby providing a functional explanation for the link between genetics variants, environmental exposures, and disease development.

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VIII.B.1 Inhalant allergens – in utero and early childhood exposure

VIII.B.1.a Mites

While there have not been any major new studies published on this topic since 2016, three older prospective birth cohorts (not included in ICAR‐Allergic Rhinitis 20181) concur with the conclusion that there is no established association of early mite exposure and the development of AR.826^, 827^, 828 Studies showing that early life dust mite exposure results in early sensitization (e.g., positive skin tests without symptoms) and AR later in childhood are often limited in that they fail to measure and account for dust mite allergen concentrations in the home.829 Likewise, other studies implement dust mite reduction interventions without pre and post dust mite allergen measurements and/or combine environmental changes with dietary changes830^, 831^, 832 (Table VIII.B.1.a).

It has been suggested that the effect of dust mite exposure on sensitization may follow a bell‐shaped dose response curve, with both very low and very high exposure being protective.833^, 834^, 835^, 836^, 837 Exposure levels that are less than 2 mg dust mite allergen/gram of house dust may be a “safe” level for atopic children for primary allergic disease prevention.838^, 839 The risk of allergic disease in childhood may also depend upon mono‐ versus polysensitization at age 1 or 2.840

Risk factors – in utero and early childhood exposure to mites

Aggregate grade of evidence: C (Level 3: 7 studies, Table VIII.B.1.a)

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VIII.B.1.b Pollen

Since ICAR‐Allergic Rhinitis 2018,1 no new studies were identified that addressed the impact of early pollen exposure on the development of AR; furthermore, the two previous studies were inconclusive.780^, 843 While very few studies longitudinally track pollen counts and the subsequent development of AR, several studies have demonstrated that the development of pollen sensitization in early life is associated with AR in later childhood.844^, 845 In fact, following initial pollen sensitization in children, there is a progressive increase in both the level and number of pollen sensitizations.846 While seasonal AR symptoms are rare before age 3, between 3 and 12 years, the percentage of new cases increases at a rate of approximately 2% per year.844^, 847^, 848 With the environmental changes associated with global warming, such as increased length of pollination season, we are starting to see higher rates of pollen sensitization in young children which will likely lead to increased AR in adolescence and adulthood849 (Table VIII.B.1.b).

Focusing on early life sensitization rather than pollen exposure may be a more productive research pathway. Sensitization to one or more allergenic molecules (e.g., Phl p 1) at age 4 has been shown to be a better predictor of AR at age 16, then a positive test to Timothy extract.850 Likewise, higher levels of Bet v 1 or finding multiple pathogenesis‐related class 10 allergens at age 4 helped to predict AR to birch in adolescence.851 With the difficulty of conducting longitudinal pollen studies and the inability to control the year‐to‐year variation in pollen counts or the young child's level of exposure, the use of CRD in early childhood may prove to be the best tool for predicting pollen‐induced AR in adolescence and adulthood.

Risk factors – in utero and early childhood exposure to pollen

Aggregate grade of evidence: C (Level 3: 1 study, level 4: 1 study; Table VIII.B.1.b)

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VIII.B.1.c Animal dander

Since the ICAR‐Allergic Rhinitis 2018,1 high quality studies have found that early life exposure to animal dander may be protective from the development of AR,852^, 853^, 854 while two lower quality studies concluded that it was a risk factor.855^, 856 A 2020 systematic review and pooled analysis of five cohort studies found a protective effect for early life exposure to cats and dogs.852 Two additional prospective birth cohorts found a similar protective effect.853^, 854 Animal exposure during the first 2 years of life offers the best possibility for protection.840^, 853^, 854^, 857 However, when reviewing all the major studies published since 2000 one finds that the majority of studies find early life animal dander exposure to be either a risk factor or unassociated with the development of AR. One possibility for this disparity is that lower quality studies were unable to account for all the confounding factors (e.g., atopic family history; community prevalence of pets; pet gender and breed; number of household pets; exposure to other indoor allergens, irritants, microorganisms; and child's microbiome).858 A combination of factors, such as the addition of probiotics to the child's diet, may enhance the protective effect of early animal dander exposure.859 At this time, it is not possible to make evidence‐based recommendations regarding early life animal exposure (Table VIII.B.1.c).

Risk factors – in utero and early childhood exposure to pets

Aggregate grade of evidence: C (Level 3: 18 studies, level 4: 28 studies*; Table VIII.B.1.c)

*Level 3 studies are listed in table; level 4 studies are referenced.

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VIII.B.1.d Fungal allergens

Further supporting the ICAR‐Allergic Rhinitis 20181 conclusions, all newly reviewed studies, many having a higher evidence level, concluded that early life exposure to fungal allergens or dampness is a risk factor for AR.889^, 890^, 891 Unfortunately, existing studies have not been able to establish a dose–response relationship for mold exposure and the subsequent development of AR nor have they been able to define a threshold below which no effect of mold exposure on the health of the general or high‐risk population would be expected.892^, 893 It may be that the presence of fungal diversity alone or in combination with microbial diversity could play an even greater role than levels of indoor mold.892 The role of outdoor fungal spores, which can vary widely by geographical location, has rarely been considered. While most studies adjust for demographic characteristics, the co‐exposure levels or symptoms produced by other allergens (e.g., HDM, pollen, pet dander) are rarely studied. Consistent results from well‐designed longitudinal studies are needed before one can determine the causal effect of early life exposure to fungal components on the future development of AR (Table VIII.B.1.d).

Risk factors – in utero and early childhood exposure to fungal allergens or dampness

Aggregate grade of evidence: C (Level 3: 3 studies, level 4: 12 studies; Table VIII.B.1.d)

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Summary for the effect of inhalant allergens (in utero and early childhood exposure) as a risk factor for the development of AR. The impact of early inhalant allergen exposure (HDM, pollen, animal dander, fungal allergens) on the development of AR remains ambiguous. Early life allergen exposures identified as significant risk factors for AR at age 6 are often found to be insignificant by age 12 or later. Despite several in‐depth reviews and a growing body of literature,852^, 892^, 900^, 901 no definitive conclusions may be drawn regarding risk‐benefit of early inhalant allergen exposure, and further research is welcomed to address this unmet need.

VIII.B.2 Food allergens

Historically, there has been concern that highly allergenic foods in the maternal as well as the infant's diet would lead to the development of food allergy and subsequently to other atopic diseases, such as AR. Since ICAR‐Allergic Rhinitis 2018,1 six publications have looked at the effect of early introduction of specific foods (e.g., fish and peanut) and diverse foods into the infant's diet and the subsequent development of AR.902^, 903^, 904^, 905^, 906^, 907 Older publications (not part of ICAR‐Allergic Rhinitis 2018) have looked at the effect of fish and tree nuts in the maternal diet908^, 909^, 910 and early introduction of specific or diverse foods into the infant's diet911^, 912^, 913^, 914 (Table VIII.B.2).

A maternal diet that avoids or strictly limits highly allergenic foods, for example, cow's milk, egg, peanut, and fish has not been shown to reduce the risk of AR.909^, 915^, 916^, 917 However, a maternal diet high in oily fish or tree nuts has been reported to reduce the risk of AR.908^, 918

Early sensitization to food has been linked to the development of AR in childhood.754^, 919^, 920 A meta‐analysis of high‐risk infants found that food sensitization at age less than 24 months increased the risk of AR during childhood.919 In a prospective birth cohort, food allergy at 4–10 years old, however, had no association with AR at age 18 or 26; whereas food sensitization (independent of symptoms) increased the risk of AR at both age 18 and 26.904 Additional cohort studies have found that food sensitization at age less than 24 months, especially when combined with inhalant sensitization, increases the risk of AR in childhood.920^, 921^, 922^, 923^, 924

Multiple studies have evaluated the effect of early introduction of highly allergenic foods into the infant's diet. In a prospective RCT, cow's milk, egg, and peanut were avoided during the last trimester of pregnancy and during lactation and infants avoided milk, egg, peanut, and fish for 1, 2, 3, and 3 years respectively. By age 7, the food avoidance group had no reduced rates of AR.915 In an open label RCT, there was no association of avoiding or consuming peanuts from 4 to 11 months on the risk of developing AR at age 5 years.903

In a subgroup meta‐analysis of observational studies, the introduction of fish into the infant's diet before 6–12 months was associated with a reduced risk for AR at 4 and 14 years.902 Three additional prospective birth cohort studies support this conclusion.906^, 913^, 914 One prospective birth cohort found that introduction of rye, oat, and barley before 5–5.5 months and egg before 11 months reduced the risk of AR at 5 years old.913 However, there are conflicting conclusions regarding the timing of introduction of complementary foods and risk for AR.925^, 926

While guidelines have recommended that all infants have a diverse diet, the evidence is both limited and conflicting on whether this reduces the risk of AR.927 Food diversity has been reported to increase,907 decrease,911 decrease if there are concurrent skin symptoms,907 or have no effect912 on the risk of developing AR in childhood.

Current guidelines as well as a Cochrane systematic review recommend an unrestricted maternal diet during pregnancy as avoidance of highly allergenic foods is unlikely to substantially reduce the risk of atopic disease, including AR, in the offspring.928^, 929^, 930^, 931 Furthermore, it is recommended that complementary foods are introduced into the diet of all infants, regardless of atopic risk, at 4–6 months of age as avoidance or delayed introduction has not been shown to reduce atopic disease.928 Guidelines have not made recommendation on the early introduction into the infant's diet of any specific foods to prevent the development of AR.

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VIII.B.3 Pollution

According to the World Health Organization (WHO), air pollution is defined as “contamination of the indoor or outdoor environment by any chemical, physical, or biological agent that modifies the natural characteristics of the atmosphere.”932 Pollutants, produced through traffic‐related combustion and industrial activity, generally include NO and nitrogen dioxide (NO₂), sulfur dioxide (SO₂), carbon monoxide and dioxide (CO and CO₂), as well as PM <10 μm (PM₁₀) and PM <2.5 μm (PM_2.5). The effect of air pollution on human morbidity is well‐known, though the relationship with AR is complex.1^, 933^, 934 It is thought that through oxidative stress pathways, pollutants may stimulate the expression of antioxidant genes and recruitment of inflammatory cells to the nasal mucosa, though the mechanisms remain unclear.935^, 936

At the time of ICAR‐Allergic Rhinitis 2018,1 the strongest evidence in the literature suggested minimal or no significant associations between air pollutants and AR development.782^, 937^, 938^, 939^, 940^, 941 Kim et al.942 found that the incidence of AR was not significantly associated with exposure to air pollutants, while Codispoti et al.943 reported that diesel exhaust particle exposure at age 1 was associated with allergen sensitization at ages 2 and 3, though not to a significant degree. In a pooled prospective cohort, air pollution was reported to not be associated with adverse effects on rhinoconjunctivitis.944

In more recent years, the interest in understanding a potential relationship between air pollution and AR has further increased. Li et al.945 reported a positive association between air pollution and AR while Burte et al.946 found that individuals with AR living in highly polluted areas were more likely to experience more severe nasal symptoms. Evaluating environmental air pollutants from 2013 to 2015, Teng et al.947 reported that levels of PM are strongly associated with the prevalence of AR. In another study, ozone and NO₂, oxidant air pollutants, were associated with an 8% increased risk of AR.948 A meta‐analysis by Zou et al.949 reported increased AR prevalence in children with exposure to high levels of NO₂, SO₂, PM₁₀, and PM_2.5. This was further supported by an SRMA by Lin et al.950 who reported that PM_2.5 exposure may be correlated with childhood AR. Hao et al.951 studied children aged 2–4 years and found that those with family stress and boys compared to girls were particularly vulnerable to increased risk of AR with early exposure to traffic‐related air pollution (Table VIII.B.3).

Co‐exposure of diesel exhaust and indoor or outdoor inhalant allergens were found to induce changes in lung protein concentrations, alter DNA methylation patterns of bronchial epithelial cells, and result in lung function impairment.952^, 953^, 954 In a controlled allergen challenge facility study by Ellis et al.,955 participants with ragweed‐induced AR aggravated by exposure to diesel exhaust particle were effectively treated with fexofenadine hydrochloride, resulting in reduced AR symptoms, compared to placebo.

The evidence demonstrating the role of air pollution on AR severity has certainly advanced. In 2018, the European Institute of Innovation and Technology launched the “Impact of air POLLution on sleep, Asthma and Rhinitis” (POLLAR) project, in efforts to use machine learning to better evaluate the relationship between sleep disorders, air pollution, and AR across six European countries.956 The recognition of the impact of pollution on AR is highlighted by the 2020 consensus paper published in the World Allergy Organization Journal which summarizes strategies to manage pollution‐induced AR symptoms.957

Much of the current literature demonstrating the detrimental effects of air pollution on AR prevalence and severity has been from Europe and Asia. As air pollution affects all countries, future studies from all continents are needed to explore this global problem.

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VIII.B.4 Tobacco smoke

Most prospective cohort studies and systematic reviews presented in ICAR‐Allergic Rhinitis 20181 have found no correlation between active or passive tobacco smoke and AR.962^, 963^, 964^, 965 One study suggested that tobacco smoke may have a protective effect against the development of AR.966 Similarly, pathophysiology studies examining this relationship have contradictory findings. It has been shown that tobacco smoke negatively impacts the barrier function of the bronchial epithelium leading to increased allergen penetration.967 A recent study in an AR mouse model showed that intranasal exposure to a tobacco smoke solution exacerbated the allergic response and increased eosinophil levels and IL‐5 expression in the respiratory epithelium.968 Conversely, nicotine has been shown to suppress type 2 responses to allergens, effectively acting as an immunosuppressant.969

Since the last ICAR‐Allergic Rhinitis 2018,1 two large meta‐analyses have investigated the impact of tobacco smoke on AR.970^, 971 Skaaby et al.970 performed a Mendelian randomization meta‐analysis of data from 22 studies in the Causal Analysis Research in Tobacco and Alcohol (CARTA) consortium and the UK Biobank. The smoking‐increasing allele of rs1051730/rs16969968 was associated with a lower odds ratio of AR in current smokers. They saw similar results in their observational analysis; current smokers had a lower risk of hay fever than never smokers, and, accordingly, they saw an inverse dose–response relationship between smoking heaviness and hay fever. These results suggest that smoking may decrease the risk of AR. Zhou et al.971 also systematically reviewed 16 studies in a meta‐analysis of maternal tobacco smoke exposure during pregnancy and AR. This study found that maternal passive smoking during pregnancy but not maternal active smoking during pregnancy increases the risk of their offspring developing AR (Table VIII.B.4).

Recent birth cohort and prospective cohort studies have contributed to our understanding of tobacco's effect on AR development. A meta‐analysis was performed on the Mechanisms of the Development of ALLergy consortium,972 including five European birth cohort studies and 10,080 participants followed from pregnancy to 14–16 years of age. In this cohort, maternal smoking was not associated with a significant increase in rhinoconjunctivitis during childhood and adolescence. However, in children who developed AR, maternal smoking of 10 or more cigarettes per day during pregnancy was associated with persistent, rather than transient, rhinoconjunctivitis. Abramson et al.172 performed an analysis of questionnaire and sIgE data from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) to assess secondhand smoking's impact on AR risk. They found that while those with AR were significantly less likely to be current or former smokers, there were no significant associations between secondhand smoking and AR.

It is known that AR represents a risk factor for asthma onset or worsening. A cross‐sectional study by Ciprandi et al.973 reported a clustering analysis to identify the subset of patients with AR at a higher risk of asthma development. This subset of patients had characteristics that included longer AR history and smoking, among others that also represent risk factors for evolving asthma. These results suggest that smoking may be a possible risk factor for asthma development in people with AR.

Another area of interest is electronic cigarettes and heated tobacco products and their impact on AR. In 2020, a survey study of Korean youth reported that current smokers of conventional tobacco cigarettes had a higher risk of AR than those using heated tobacco products and electronic cigarettes. However, the use of heated tobacco products and electronic cigarettes among conventional tobacco smokers increases the apparent risk of AR and asthma.974 Future research should focus on understanding the effects of these new products on a mechanistic level.

In summary, there have been few large prospective cohort studies or systematic reviews examining the effect of tobacco smoke exposure on the development of AR since ICAR‐Allergic Rhinitis 2018. The studies presented herein predominantly found no correlation between active or passive tobacco smoke and AR. However, some studies suggest that tobacco may decrease AR risk, a finding that warrants further investigation.

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VIII.B.5 Socioeconomic factors

SES describes the social standing of a group or individual and is determined by a combination of income, occupation, and education. The association of SES with AR was described as early as the 1800s.975 The concept of SES and its correlation with AR is similar to the hygiene hypothesis, which theorizes that a potential reduction in an individual's microbial colonization can result in an increase in allergic disease (discussed below).976 (See Section VIII.C.3. Hygiene Hypothesis for additional information on this topic.) As an example, Wee et al.977 conducted a large cross‐sectional study in over 60,000 school‐aged children and found that higher SES was associated with both improved hand hygiene and increased odds of developing AR. The role of SES in the development of AR has additional, complex underpinnings, and likely accounts for variations in a multitude of factors, including housing conditions, air quality, water supply, education, and access to care, to name a few (Table VIII.B.5).

The ISAAC studies are among the largest multi‐institutional studies evaluating prevalence of AR in children across the globe. Phase 1 and 3 ISAAC studies examined prevalence patterns of AR in ∼1.2 million children in 98 countries.756^, 757^, 758^, 759 Like most studies of AR prevalence, these studies were open, survey‐based cross‐sectional studies. A post‐hoc analysis of the ISAAC Phase 1 and 3 study data found a positive correlation between a country's gross national income per capita and national prevalence of AR. However, while statistically significant, the correlation was weak (r = 0.328 for 6–7 years, 0.206 for 13–14 years).758

Chen et al.978 performed a large survey‐based cross‐sectional study in 173,859 adults participating in a Kaiser Permanente multiphasic health check‐up from 1964 and 1972. Their study used educational level as a marker for SES and found that post‐graduate education was associated with increased odds of hay fever. A subsequent study by Li et al.979 conducted in 23,971 children aged 6–13 years old in eight metropolitan cities in China found that both parental education and household income per capita predicted a higher prevalence of allergic disease. Hammer‐Helmich et al.980 performed a cross‐sectional, survey‐based study of SES and its association with hay fever in 9720 participants aged 3, 6, 11, and 15 years in Denmark. They found parental education level was a socioeconomic factor associated with increased risk of hay fever (OR 1.68). Income showed no association.

Studies of SES and its impact on risk of AR highlight the role that study participant education may play on the reporting of AR symptoms, or its diagnosis. This is illustrated by a study performed by Mercer et al.,981 who evaluated 4947 children aged 13–14 in South Africa and found that residents living in low SES, but attending high SES schools, showed significantly higher prevalence of rhinitis symptoms than children in low SES schools. This suggests that education and access to medical care may affect differences in reporting in survey‐based, cross‐sectional studies.

Not all studies have demonstrated a positive relationship of AR with higher SES. A cross‐sectional study performed in Bolu, Turkey including 1403 subjects observed that poor living conditions and income was associated with a greater risk of self‐reported AR.982 Similarly, Lewis et al.983 examined allergen sensitization patterns in 458 adult women and found that lower SES was associated with increases in tIgE, number of allergen sensitizations, and sIgE levels. In a separate prospective cohort study performed in 4089 families in Sweden, Almqivst et al.984 found increased SES (using parent occupation as a measure of SES) to be associated with lower risk of AR at age 4. Similarly, a prospective cohort performed by Grabenhenrich et al.848 among 941 children up to age 20 in Germany showed no association between SES and AR development. And finally, using IgE‐based sensitivity testing (in addition to symptom‐based testing), Ahn et al.784 found that only high income (and not education or occupation) was associated with symptom‐based AR, but not IgE‐based AR.

Thus, while most of the available evidence indicates that higher SES is associated with increased risk of AR, the data is not uniform. SES is related to a myriad of factors, many of which play an important role in the development of AR.

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VIII.C.1 Breastfeeding

Breastfeeding is considered to have several benefits for mothers and infants. WHO guidelines recommend breastfeeding for 6 months and European Academy of Allergy and Clinical Immunology (EAACI) guidelines advise exclusive breastfeeding for 4–6 months.991^, 992 ICAR‐Allergic Rhinitis 2018 also documented that breastfeeding has been strongly recommended due to its multiple benefits in general; the policy level was “option” for the specific purpose of AR prevention.1 Several mechanisms have been suggested to explain how breastfeeding might prevent allergic disease. Breast milk contains immunomodulatory factors that stimulate host defense mechanisms and immune response.993^, 994 Although the association of breastfeeding with the development of allergic disease has been investigated in many studies, there is no consensus on whether breastfeeding is effective in preventing AR.

A recent SRMA revealed that exclusive or non‐exclusive breastfeeding for 6 or more months may have protective effects on the development of AR up to 18 years of age.995 A 2019 systematic review that included one cluster RCT and five prospective cohort studies examined the relationship between shorter versus longer durations of any human milk feeding (whether or not it was fed at the breast) and AR in childhood.996 The only statistically significant association was found by Codispoti et al.,997 noting that longer duration of breastfeeding was associated with a lower risk of AR in 3‐year‐old African Americans (odds ratio [OR] 0.8; 95% CI 0.6–0.9). The authors stated that published data are insufficient to determine whether the duration of any human milk feeding was associated with AR996 (Table VIII.C.1).

The results from a questionnaire‐based cross‐sectional study of 4–6‐year‐old Shanghai children suggested that exclusive breastfeeding for greater than 6 months reduced the risk of hay fever (OR 0.93; 95% CI 0.89–0.97) and rhinitis (OR 0.97; 95% CI 0.94–0.99) compared to those who were never breastfed.998 Food Allergy and Intolerance Research (FAIR) birth cohort in the Isle of Wight, UK, also showed exclusive breastfeeding for greater than 4 months reduced the risk of rhinitis (OR 0.36; 95% CI 0.18–0.71) from birth up to 10 years of age.991 A recent cohort study of children with AR compared to non‐allergic rhinitis in Korea showed that breastfeeding for 12 or more months had a significantly lower prevalence of AR compared with breastfeeding for less than 6 months, and the association was still valid, accounting for age, sex, mode of delivery, number of siblings, parental atopy history, and living area (OR 0.54; 95% CI 0.34–0.88).999 However, in one study using a large population‐based cohort (336,364 participants) from the UK, researchers found that breastfeeding increased the risk of hay fever when adjusted for body mass index, birth weight, SES, home area, and year of birth (OR 1.11; 95% CI 1.06–1.16).1000

These inconsistencies in studies, which are mainly observational surveys, can possibly be influenced by demographic, socioeconomic, educational, ethnic, cultural, psychological status, and study design.999^, 1001^, 1002 In addition, since it is difficult to distinguish between AR and viral respiratory infection at a young age, the protective effect of breastfeeding against viral infection has possibly been confused as a protective effect on AR.1003 Furthermore, differences in methodological factors such as duration of breastfeeding, any or exclusive breastfeeding, diagnostic criteria of AR, comorbid allergic disease, and the follow‐up period may account for discrepancies in assessing the association between breastfeeding and AR.

Overall, considering the literature review on the association between breastfeeding and AR, breastfeeding should be recommended due to various positive effects on general health and possible protective effects on AR.

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VIII.C.2 Childhood exposure to pets

Pet‐keeping families are concerned about the effects of pets on their children with regard to allergic diseases; however, the recommendations of guidelines for AR in relation to childhood pet exposure remain conflicting.1^, 1004^, 1005 ICAR‐Allergic Rhinitis 2018 stated that early pet exposure may reduce the development of AR and its protective effect is stronger in non‐allergic families with dog exposure.1

A recent SRMA investigating the association between pet exposure and the risk of AR revealed the protective effect of early cat exposure (RR 0.60; 95% CI 0.33–0.86) or dog exposure (RR 0.68; 95% CI 0.44–0.90) on the development of AR.852 Furthermore, early cat ownership in the first 2 years of life has been associated with a significantly lower risk of AR compared to non‐ownership (OR 0.51; 95% CI 0.28–0.92)860 (Table VIII.C.2).

A prospective birth cohort study in Finland revealed that having a dog in the house in the first year of life seemed to protect against AR (OR 0.72; 95% CI 0.53–0.97) by the age of 5 years compared to those without.853 Additional studies support the finding that exposure to pets during childhood reduces the risk of AR.1006^, 1007 Nevertheless, these studies did not make a firm conclusion about the protective effect of pet exposure on the development of AR. Heterogeneous factors such as the timing of exposure, duration of exposure, animal species, dose of exposure (number of household pets, environmental exposure vs. ownership), and avoidance behavior may be the reason.852^, 1008

Furthermore, some studies have shown conflicting results. A cross‐sectional survey conducted in first graders (6–8 years old) in Taiwan demonstrated that having a cat in the first year of life was associated with an increased risk of AR.856 In addition, one study in Chinese children aged 0–8 years old showed a negative effect of pet keeping (aOR 3.60; 95% CI 2.07–6.27) for AR after adjustment for avoidance behavior.1009 However, these results should be interpreted with caution because of ethnic differences, family inheritance, and other environmental risk factors that may confound of the association between pet keeping and AR. Although the exact mechanism of the effects of pet exposure on allergic disease remains unclear, it has been suggested that environmental exposure may increase or decrease the risk of AR according to the stage of immune system development.852^, 1010^, 1011^, 1012

Overall, the causal relationship between pet exposure in childhood and the protective effect of AR is inconsistent; thus, no strong advice can be provided regarding childhood exposure to pets. Nevertheless, pet exposure at birth or in the first year of life may reduce the risk of AR.

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VIII.C.3 Hygiene hypothesis

The hygiene hypothesis originated from the observation that frequent and recurrent infections in early childhood appear to protect against the development of AR later in life.1013 Over time, the hygiene hypothesis evolved to the biodiversity hypothesis, which expands the scope from the protective effect of infection from single microbes to the protective effect of microbial variety during development.1014 The microbiota hypothesis was later proposed to confine the causative microbes specifically to those living in or on the human body and their impact on our immune system.691^, 699

An SRMA was conducted to determine the effect of the number of siblings on AR development; this analysis assessed 53 studies with 300,062 participants.1015 They saw a strong inverse association between many siblings (three or more) and the development of AR. Similarly, a large international cohort study based on questionnaire data for children aged 6–7 and 13–14 years also saw an inverse association between the number of siblings and AR but only in affluent countries1016 (Table VIII.C.3).

It has also been observed in several studies that exposure to early‐life farming may protect against childhood allergic diseases particularly, exposure to farm animals and stables.1017^, 1018^, 1019^, 1020^, 1021^, 1022^, 1023^, 1024^, 1025^, 1026^, 1027 In a recent meta‐analysis by Campbell et al.,1017 the risk of sensitization measured by sIgE or SPT in childhood or adulthood was 40% lower among children who had lived on a farm during the first year of life. Further, a 2017 US case–control study showed farm exposure in utero provides even greater protection against sensitization in adulthood.1018 While an isolated exposure to bacterial endotoxin was claimed to have a similar protective effect, the results thus far have been inconclusive.1028^, 1029

Increased diversity in the gut and skin microbiome has been associated with a protective effect on atopy.686^, 689^, 691^, 694^, 1030^, 1031^, 1032 Recently, three large cohort studies have reported that reduced bacterial diversity in the infant's intestinal flora within the first 6 years of life predisposes them to a higher risk of developing AR.687^, 691^, 1033 Notwithstanding this, a meta‐analysis of 29 trials did not find supplementation of probiotics to pregnant mothers or infants beneficial in preventing atopy.1034 A publicly available American Gut Project questionnaire and database was used in a study to determine the fecal microbiota richness and composition in adults with AR.694 They found an imbalance (dysbiosis) of gut flora with higher Bacteriodes and reduced Clostridia taxa in this population. In addition, the role of Helicobacter pylori has been investigated, with inconsistent findings.1035^, 1036^, 1037 Interestingly, in a meta‐analysis of 21 studies assessing the association between H. pylori infection and allergic diseases, a significant inverse association was found between H. pylori infection with atopy from the case–control studies while an association was seen between allergic disease and H. pylori infection from the cross‐sectional studies.1037

Lower biodiversity on the skin and in the home living environment is associated with an increased risk of atopy.1031 Ruokolainen et al.1038 performed a comparative study of the microbiota of skin and nose in randomly selected school children from urban and rural areas. They saw that rural school children had increased microbial diversity on their skin and in their noses and this was associated with lower allergy prevalence compared urban school children.

In summary, there is some evidence of the protective effect of the hygiene hypothesis on AR from epidemiological studies but more studies that evaluate causality are needed. (See Section VI.J. Microbiome and Section XI.B.9. Probiotics for additional information on this topic.)

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IX.A.1 Quality of life

High quality evidence evaluating the impact of AR on QOL continues to show AR patients suffer from decreased general and disease‐specific QOL due to impacts on physical and mental health.1042^, 1043^, 1044^, 1045^, 1046^, 1047 These studies also show that treatment of AR with INCS, oral antihistamines, and AIT leads to improved QOL. Validation of QOL metrics in AR continues. There has been a trend toward use of disease specific QOL metrics, especially the RQLQ.1048 As this has become more accepted, the use of general health related QOL metrics such as Short Form 12 and 36 (SF‐12/36) has decreased.1049^, 1050 A measure of QOL used in CRS, the SNOT‐22, has now been studied in AR.1051 This study showed SNOT‐22 was able to assess QOL and response to treatment in AR. Olfaction, an objective measure of QOL also typically used in CRS, has also been studied in AR recently. Olfactory dysfunction was identified in 44% of patients with AR.1052 The use of SNOT‐22 and objective measures of olfaction could simplify implementation of QOL monitoring for both diseases from a clinical standpoint (Table IX.A.1).

Despite the availability of disease specific QOL instruments, many studies continue to rely on unvalidated methods to assess QOL. This leads to difficulty comparing outcomes between some studies. A recent SRMA evaluated the outcomes of medical therapy with INCS, oral antihistamines, or AIT for AR. Treatment with oral antihistamines and AIT had a statistically significant impact on QOL. Despite near universal acceptance of INCS for the treatment of AR, meta‐analysis of the impact of INCS on QOL could not be performed due to a lack of available data.1043 There are numerous individual RCTs evaluating the effect of INCS,1053 oral antihistamines,1054^, 1055^, 1056^, 1057 and AIT.1058^, 1059^, 1060^, 1061 The overarching findings in these individual RCTs is that these treatments improve QOL.

While numerous studies exist comparing changes in symptoms with treatment for AR,1062 direct, head‐to‐head comparisons of changes in QOL with different treatments for AR are lacking. There is only one study comparing the impact of monotherapy with INCS (mometasone) to combination therapy with INCS and oral antihistamine (mometasone + levocetirizine) or INCS and leukotriene D4 receptor antagonist (mometasone + montelukast) on QOL as measured with the 14‐question mini‐RQLQ. This study found that polytherapy with mometasone and levocetirizine or montelukast improved QOL more than mometasone alone; no difference was seen between montelukast or levocetirizine when added to mometasone.1063

New evidence evaluating the impact of AR on QOL in children and in the parents of children with AR is emerging. As expected, these studies show impacts on QOL in this population. More surprisingly, they show impacts on parental QOL as well.1064^, 1065^, 1066^, 1067 In one study, parents overestimate their children's QOL.1068 This focus on assessing QOL in children and adolescents with AR was built on prior work measuring general QOL in children with instruments such as KINDL.1069 Disease‐specific instruments (Pediatric Rhinoconjunctivitis Quality of Life Questionnaire [PRQLQ] and RhinAsthma Patient Perspective [RAPP]‐children) have now been developed to measure the impact of AR on QOL in pediatric and adolescent populations.1064^, 1070 In children and adolescents with persistent AR, those with nasal obstruction secondary to septal deviation or turbinate hypertrophy have the worst QOL.1067 Nasal endoscopy should be considered in patients in this population not responding to therapy to ensure nasal obstruction is not contributing.

Variations in QOL in AR patients have not been prospectively studied over time. Most studies are either cross‐sectional or have short follow‐up periods with few time points at which QOL is assessed. Control groups from RCTs and meta‐analyses of RCTs can provide insight into long‐term variation in QOL in AR, however. Two RCTs have studied the effect of oral antihistamines with a follow‐up period of at least 6 months.1056^, 1057 These RCTs show that both the placebo and treatment groups experience clinically and statistically significantly improvements in generic and disease specific QOL, but the improvement is greater in the treatment arm. A more recent meta‐analysis of a combination INCS and intranasal antihistamine showed short‐term but not long‐term QOL improvement with this treatment.1042 This latter finding, however, was based on a single study.1071 AIT RCTs have longer follow‐up periods (12 months to 3 years) and show similar results, with placebo patients either remaining at baseline or improving to a lesser degree than the treatment arms.1058^, 1059^, 1061 As expected, patients with seasonal AR have worse QOL during seasons in which they are exposed to allergens and improved QOL outside of these seasons.1072

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IX.A.2 Sleep disturbance

AR affects 20%–30% of adults and children with OSA and sleep disordered breathing (SDB).1103^, 1104 Multiple studies have investigated the relationship between AR and sleep in adults and children. The general conclusion from the aggregate data is that similar to overall and rhinitis specific QOL, AR negatively impacts sleep quality, and the successful treatment of AR reduces sleep disturbance. Overall, the data is of low to moderate strength, with the overall quality of the data being higher for adults than for the pediatric population. For the adult population, there is strong evidence supporting the conclusion that AR negatively impacts sleep.1105^, 1106^, 1107^, 1108^, 1109 This data deals with subjective reporting of daytime sleepiness, sleep quality, and symptoms usually through validated tools, in the setting of testing the effect of INCS and montelukast (Tables IX.A.2.‐1 and IX.A.2.‐2).

In children, lower quality data suggest that AR is associated with sleep disturbance in the form of increased risk of snoring, SDB, and OSA. However, the findings here are not uniform, with some studies suggesting that while the prevalence of AR is high in the OSA population, AR might not impact disease severity.1104^, 1110 Furthermore, AR has been suggested to be a risk factor for deterioration of OSA QOL after adenotonsillectomy.1111 Additionally, AR may increase the risk of nocturnal enuresis in children.1112

Two studies looked at variations in sleep symptoms with changes in nasal inflammation over time. Nasal cytokine level alterations are associated with changes in the polysomnogram (PSG)1113 and AR patients have worse PSG parameters and sleep disturbance when their symptoms are present or during their peak allergen season.1114 The data on PSG parameters in adults is mixed. Most studies that perform PSG found that AR worsens PSG parameters1103^, 1113^, 1114^, 1115^, 1116^, 1117^, 1118^, 1119^, 1120^, 1121^, 1122; however, two studies found either no difference or a modest change.1123^, 1124

AR patients have improvements of sleep quality, daytime sleepiness, sinonasal symptoms, and QOL after treatment with INCS1105^, 1106^, 1107^, 1125 or a combination of INCS and montelukast.1105 Additionally, AR has been associated with worse sleep fragmentation1118^, 1126 and snoring.1116^, 1127 In addition to reducing sleep disturbance, treatment of AR has been suggested to also improve CPAP compliance.1128 (See Section XIII.K. Associated Conditions – Sleep Disturbance for additional information on this topic.)

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X.A.1 History

A crucial component in the diagnosis of suspected AR rests on clinical history.5^, 31^, 1005^, 1205^, 1206 This includes symptoms experienced, timing of symptoms, duration, frequency, patient occupation/school/home environmental exposures that elicit symptoms, and any measures or medications that improve or worsen symptoms.5^, 31^, 1005^, 1205^, 1206^, 1207 Other comorbid conditions in the past medical history, such as asthma, OSA, family history of atopic disorders, and medications currently taken should be gathered.5^, 31^, 1005^, 1205^, 1206^, 1207 Patient response to self‐treatment with over‐the‐counter medications is helpful information, and with advancing technology mobile applications may allow for the potential collection of patient symptomatology to identify symptom patterns that may be very useful for treating providers.1208

Classic symptoms of AR include nasal congestion or obstruction, nasal pruritis, rhinorrhea, and sneezing. In addition, patients may complain of other symptoms associated with comorbidities including ocular pruritis, erythema, and/or tearing (allergic conjunctivitis), oral cavity or pharyngeal pruritis (allergic pharyngitis), throat clearing, and wheezing or cough (reactive airway disease and/or asthma).5^, 31^, 1005^, 1205^, 1206^, 1207 Snoring or sleep‐disordered breathing, aural congestion or pruritis, and wheezing are other frequent symptoms.5^, 31^, 1206^, 1207 In the coronavirus disease 2019 (COVID‐19) era, symptoms of hyposmia or anosmia, cough, and/or sore throat, which potentially may also be associated with AR, may cause confusion, and should prompt consideration for other diagnoses, such as active COVID‐19 infection.1207^, 1209^, 1210

Patients with suspected AR will commonly present with multiple complaints, frequently with two or more symptoms.1207^, 1208^, 1210 Perennial AR patients have a tendency to report more congestive symptoms (sinus pressure, nasal blockage/congestion, and snoring) than seasonal AR patients.1209 Also, perennial AR patients more frequently complain of sore throat, cough, sneezing, rhinorrhea, and postnasal drip.1207 Prior to the COVID‐19 pandemic, symptoms of rhinorrhea, sneezing, sniffing, hyposmia/anosmia, nasal obstruction, and itchy nose ranked highest in diagnostic utility among symptoms of AR; however, the diagnostic utility of hyposmia/anosmia, nasal obstruction, and congestion may be less given the overlap in COVID‐19 symptomology.1207^, 1209^, 1211

Despite the dearth of high‐level evidence, many guidelines suggest that history of two or more symptoms consistent with AR is sufficient for making the diagnose of AR5^, 31^, 1005^, 1205^, 1210^, 1211 (Table X.A.1). Since AR lacks pathognomonic physical examination findings, physical examination alone to diagnose AR has been shown to have poor predictive value.1212 The reliability and predictive value of the patient history for AR exceeds that of the physical exam alone.1212 In clinical practice, the presumptive diagnosis of AR is often made by only history, even more so during the pandemic with increased utilization of telemedicine where a physical examination is limited.1210^, 1211^, 1213

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X.A.2 Physical examination

Whenever possible, it is important to include physical examination as part of the evaluation of suspected AR patients.5^, 31^, 1005^, 1205^, 1210^, 1213 Telemedicine may complicate this part of the evaluation, but a limited visual examination may be obtained.1213 An assessment of head and neck organ systems should be completed with the use of any necessary personal protective equipment.31^, 1005^, 1205^, 1213 If there are patient complaints of wheezing or coughing with allergic triggers or comorbid conditions of asthma, the physical examination may include auscultation of the lungs.5

An unremarkable physical examination is common for AR patients, particularly those with intermittent exposure.1209 Observation alone may reveal possible signs suggestive of AR, which can be useful during telemedicine visits. These signs include mouth‐breathing, nasal itching or a transverse supratip nasal crease, throat clearing, periorbital edema, or “allergic shiners” (dark discoloration of the lower lids and periorbital area).31^, 1205 Ear examination may reveal retraction of the tympanic membrane or transudative fluid, although evidence for association of effusion with AR is low level. Anterior rhinoscopy may reveal IT hypertrophy, congested/edematous nasal mucosa, purplish or bluish nasal mucosa, and clear rhinorrhea.31^, 1005^, 1205 Eye examination may reveal conjunctival erythema and/or chemosis.31^, 1205

Physical examination by itself is more variable and poorly predictive of the diagnosis of AR when compared to history‐taking, with the average sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV) of the patient history higher than those of the physical examination.1212 Most guidelines recommend a physical examination as part of the diagnosis of AR, despite a lack of high level evidence; however, pandemic conditions and the utilization of telemedicine may limit the completeness or possibility of physical examination1213 (Table X.A.2). Without a physical examination, other potential causes of symptoms such as CRS may not be fully evaluated or eliminated, so if there are limits placed by telemedicine, additional diagnostic measures may need to be considered, such as a CT scan of the sinuses. A patient history combined with a physical examination improves diagnostic accuracy.1212

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X.A.3 Nasal endoscopy

Diagnostic nasal endoscopy may complement the evaluation of patients with suspected AR. Several case series and cross‐sectional studies have evaluated the association of endoscopic findings with the diagnosis and severity of AR (Table X.A.3).

Ziade et al.1214 studied a prospective cohort of adult patients with AR symptoms and skin testing confirmation, showing that mucosal edema and bluish discoloration of the ITs were highly predictive of the severity of AR disease (p < 0.05) when comparing patients with mild versus moderate/severe AR. Conversely, early studies by Jareoncharsri et al.1215 and Eren et al.1216 evaluated a population of adults and children with AR confirmed by allergy testing, concluding that findings of nasal endoscopy do not provide a reliable diagnosis or correlate with specific nasal symptoms of AR.

Additionally, Ameli et al.1217 evaluated a large cohort of children with suspected AR and confirmed with skin testing, reporting that endoscopic findings of IT or MT septal contact as well as pale mucosa and large adenoid volume were highly predictive for AR. Notably, there were conflicting results in a previous study by the same group that reported no predictive role of pale mucosa as an endoscopic sign for AR.1218 The possible explanation could be related to the smaller sample analyzed in the previous study.

Polypoid change of the MT has also been correlated with the diagnosis of AR as shown by White et al.,1219 who described 16 patients with polypoid changes/polyps of the MT, all of which had positive allergy testing. Hamizan et al.1220 reported that multifocal, diffuse, and polypoid edema – the highest grades of MT edema – had the strongest association with allergy, with positive predictive values of 85.15%, 91.7%, and 88.9%, respectively. Brunner et al.1221 compared the clinical characteristics of patients with isolated polypoid change of the MT versus paranasal sinonasal polyposis, finding a higher prevalence of AR in patients with polypoid MT changes compared to patients with conventional sinonasal polyposis (83% vs. 34%, p < 0.001).

Central compartment atopic disease (CCAD), first described in the multi‐institutional case series by DelGaudio et al.1222 in 2017, is a phenotype of nasal inflammatory disease which presents with isolated polypoid changes involving the superior nasal septum with or without the MT and/or superior turbinate, and is strongly associated with inhalant allergy. All patients in the series had positive allergy testing. In a subsequent case series, the same authors found that 81.9% of patients with AERD had central involvement of disease, with 100% of patients with endoscopic central compartment disease having clinical AR.1223 (See Section XIII.B.3. Central Compartment Atopic Disease for additional information on this topic.)

Despite early inconsistent reports, the current body of evidence has shown that certain nasal endoscopy findings, particularly central compartment polypoid changes, are predictive factors for the presence and severity of AR and nasal endoscopy may aid in the identification or exclusion of other possible causes of symptoms, such as nasal polyposis or CRS.

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X.A.4 Radiologic studies

Radiographic workup is not recommended for the routine diagnosis of AR. Although some radiographic findings have been associated with AR, there are no high‐quality studies demonstrating a role for imaging in the diagnosis of AR.

For patients that undergo imaging, certain radiologic patterns described in the literature may indicate an allergic role in their disease process. Several studies have demonstrated association between inflammatory changes to the central compartment mucosa and aeroallergen reactivity, resulting in the CRS phenotype of CCAD.1224^, 1225^, 1226^, 1227^, 1228 Other studies have described evidence of radiographic changes among patients with known AR, including the association for smaller maxillary sinuses and enlargement of the septal swell region.1229^, 1230

Radiology studies incur additional cost and demonstrate little diagnostic value for AR. There is also concern for ionizing radiation with CT scanning, along with risk for future malignancy.1231^, 1232^, 1233 These factors preclude the routine utilization of radiographic studies for the diagnosis of AR.

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X.B.1 Skin prick testing

SPT, in conjunction with clinical history and physical examination, can confirm the diagnosis of AR and help to differentiate AR from non‐allergic types of rhinitis. The confirmation of an IgE‐mediated process can guide avoidance measures and direct appropriate pharmacologic therapy. Allergy testing is crucial for the initiation of AIT, and therefore, skin testing should be utilized in eligible patients when AIT is being considered.

SPT is performed with lancets, which come in a variety of forms. Generally, lancets are designed to limit skin penetration depth to 1 mm. However, varying amounts of pressure applied to the delivery device can alter the depth of skin penetration, which ultimately influences the skin reaction to an antigen.1235 Prick testing devices can come as single or multiple lancet devices. Multiple lancet devices have the advantage of being able to rapidly apply multiple antigens to the skin at one time with a more consistent amount of pressure.1236^, 1237 Wheal size, sensitivity, and reproducibility all differ from one device to another; therefore, any clinician performing SPT must thoroughly familiarize themselves with the testing device they choose to utilize in their practice.1236^, 1237^, 1238 The lancet can be dipped into a well containing an antigen and then applied to the skin, or droplets of antigen can be placed on the skin and then using the lancet, a prick made through the droplet. When an antigen is applied to the skin of a sensitized patient, the antigen cross‐links IgE antibodies on the surface of cutaneous mast cells resulting in degranulation and release of mediators (including histamine) which leads to the formation of a wheal and flare reaction within 15–20 min.1239^, 1240

The volar surfaces of the forearms and the back are the most common testing sites for SPT. Choice of site is directed by the age and size of the patient, the presence of active skin conditions in a testing location, or significant tattooing in the testing area, which could impact interpretation. Reactivity of different body sites can vary, as the back is overall more reactive than the forearm. Within each site, there may be variability as well, as middle and upper parts of the back are more reactive than the lower back. Tests should be applied 2 cm or greater apart as placing them closer to one another can allow spreading of allergen solution between test sites.1241 After approximately 20 min, the results are read by measuring the size of the wheal by its greatest diameter. Wheals that are greater than or equal to 3 mm in diameter, when compared to the negative control, are considered positive.

The number and choice of antigens used in testing vary considerably between clinical practices. A panel of antigens representing an appropriate geographical profile of allergens that a patient would routinely be exposed to is recommended. Positive (histamine) and negative (saline, 50% glycerin or 50% glycerinated human serum albumin with saline) controls should always be included. Regarding allergen extracts, variability in quality and potency between commercially available extracts has been demonstrated.1242^, 1243 Therefore, whenever possible, standardized allergens should be used.1244 With advancements in molecular biology, new techniques for extraction, characterization, and production of allergens have been developed allowing for production of recombinant or purified allergens which may increase the sensitivity, specificity, and diagnostic accuracy of tests.1245

Given the limited depth of penetration, SPT is safe with very rare reports of anaphylaxis and no reported fatalities.1246 SPT can be performed in any age group and is of value in pediatric populations given the speed at which multiple antigens can be applied and the limited discomfort experienced during testing. Aside from an excellent safety profile, SPT has reported sensitivity and specificity of around 80%.1244^, 1246^, 1247 It is felt to be more sensitive than serum sIgE testing with the added benefits of lower cost and immediate results.1246^, 1248^, 1249 Despite numerous studies aimed at comparing SPT, single intradermal tests, and serum sIgE testing, evidence marking one form of testing as superior to the others is lacking.1005

Skin testing is not appropriate in all patients. Absolute contraindications to SPT in the evaluation of AR include uncontrolled or severe asthma, severe or unstable cardiovascular disease, and pregnancy. Skin conditions including dermatographia and AD are relative contraindications to SPT given the possibility of false positives. Concurrent β‐blocker therapy is also a relative contraindication.1250 Certain medications and skin conditions can interfere with skin testing and are covered in detail in other sections. (See Section X.B.4. Issues that may Affect the Performance or Interpretation of Skin Tests for additional information on this topic.)

Several errors may occur during SPT and impact the results and reliability. Since heterogeneity can be introduced when using multiple different test devices, it is recommended that the same device type can be used routinely in one's clinical practice to improve the reliability, comparability, and interpretation of testing.1251 Personnel who apply tests should be appropriately trained and periodically monitored for quality control. Common errors with SPT include placing the test sites too close together (less than 2 cm), pressing too hard or creating deep punctures that cause bleeding, insufficient penetration of the skin by the puncture instrument, and spreading of allergen solutions across the field during the test by wiping away the solution.1251

There is a large body of evidence detailing the use of SPT in clinical practice. Based upon several prospective studies and systematic reviews, SPT has been demonstrated to be a safe method of allergy testing with sensitivity and specificity of greater than 80% (Table X.B.1). It has not been shown to be inferior to serum sIgE testing or single intradermal testing and is less expensive than serum sIgE testing. SPT does carry a risk of anaphylaxis, but no deaths from SPT have been reported. It is also associated with some discomfort during testing; however, the discomfort is generally less than that experienced during an intradermal test. Reviewing the available literature, a preponderance of benefit over harm exists for SPT. Therefore, the use of SPT is recommended in situations where the diagnosis of AR needs to be confirmed or a patient with presumed AR has failed appropriate empiric medical therapy and AIT is being considered.

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X.B.2 Intradermal skin testing

Intradermal skin testing is one of the oldest forms of allergy testing, originally described in 1911. In this technique, 0.02–0.05 ml of diluted allergen extract is introduced into the dermis with a needle. The dilutions used are 100‐ to 1000‐fold less concentrated than those used for SPT. The response is measured at 10–15 min after injection. A significant wheal and flare reaction suggests the presence of preformed IgE bound to the surface of cutaneous mast cells, and thus a type 1 hypersensitivity to the tested allergen. Intradermal testing is considered to be more sensitive than SPT, but not necessarily more capable of identifying clinically relevant allergy.1246 Intradermal testing may be used as a primary diagnostic modality and its performance for some allergens, such as Alternaria, may be similar to SPT or in vitro testing.1259 A more common approach is to perform intradermal testing after a negative SPT to identify lower level allergic sensitivity. Some allergists also use intradermal testing in a titrated fashion (using multiple allergen dilutions) with the goal of more accurately quantifying allergic sensitization or as a means to select a starting dose for AIT.1260 Intradermal dilutional testing (IDT) is roughly equivalent to SPT in the diagnosis of inhalant allergy,1253 and IDT endpoint correlates with SPT wheal size.1261 However, the role of intradermal testing for aeroallergen sensitivity is controversial due to concerns about the performance characteristics (sensitivity and specificity) of single intradermal tests relative to SPT.1262

As with any skin test, intradermal skin testing should be performed in conjunction with appropriate positive and negative controls. A negative control should include appropriately diluted test solutions (e.g., glycerin for aqueous glycerinated extracts). A positive control should contain diluted histamine base (e.g., 10 mg/ml).1246 Measurement of the wheal and flare response is used to determine a positive result; however, thresholds for a positive test may vary because studies have not been performed to standardize test grading. A wheal size 2–4 mm larger than the negative control is often used as the threshold for a positive test.1246^, 1262

Assessment of the sensitivity and specificity of intradermal testing is hampered by multiple variables in the published studies. These include the concentration and volume of allergen injected, the definitions of a positive test, variation in allergens tested, and the “gold standard” comparator used for analysis.1263 As a stand‐alone diagnostic test for AR, using studies with nasal provocation as the reference standard, estimates for sensitivity for intradermal testing range between 60% and 79%, while specificity is in the range of 68%–69%.143^, 1253 In comparison, a meta‐analysis of SPT trials had pooled estimates of 88.4% sensitivity and 77.1% specificity for SPT,1264 suggesting superiority of SPT as a stand‐alone allergy diagnostic test. Nevertheless, intradermal tests are still used when a highly sensitive skin test is desired. This may be particularly important when testing with non‐standardized allergen extracts (e.g., molds, trees) (Table X.B.2).

Intradermal tests are also employed when SPT is negative but history strongly suggests an allergic sensitivity, and may be particularly useful in patients with lower skin sensitivity.1246 Negative intradermal testing may be helpful in ruling out IgE‐mediated disease.1262 On the other hand, the addition of intradermal testing in the setting of SPT negativity may result in 20% more positive allergy skin testing results, and the clinical significance of these results is an important question that needs to be resolved.1265 Positive intradermal tests may merely be due to non‐specific irritant phenomena.

Because intradermal testing has traditionally been considered more sensitive than SPT, it is often used as an add‐on test in the setting of a negative SPT result when allergy is suspected. Theoretically, an intradermal test will be able to identify a clinically significant sensitivity that is otherwise not detected on SPT. However, many studies have failed to show an added benefit of intradermal testing in this setting. For example, Krouse et al.1255 showed that adding intradermal testing to SPT only increased the sensitivity from 87% to 93% for Timothy grass allergy when nasal provocation was used as the comparator. In a similar study with Alternaria, Krouse et al.1254 determined that adding intradermal testing to SPT increased the sensitivity from 42% to 58%. These studies suggest marginal increase in sensitivity that may vary based upon the allergen being tested.

Nelson et al.1266 studied individuals with a history of seasonal AR and clinical history of grass allergy. One group had negative SPT but positive intradermal tests, while another group had negative SPT and negative intradermal tests. In both groups, 11% of individuals had a positive nasal challenge with timothy grass, demonstrating that the addition of an intradermal test did not improve the diagnostic accuracy of skin testing as judged by the “gold standard” of nasal provocation plus clinical history. Additionally, in a study of patients with clinical cat allergy and negative SPT, a positive intradermal test did not increase the likelihood of a positive cat allergen challenge.143 There was no difference between those who had positive or negative intradermal testing (24% vs. 31%). Thus, while about 30% of patients with a clear clinical history of cat allergy had a positive cat allergen challenge despite a negative SPT, the addition of an intradermal test did not improve the diagnostic accuracy of skin testing.

Schwindt et al.1267 studied 97 subjects with allergic rhinoconjunctivitis symptoms. SPT was followed by intradermal testing if SPT was negative. If patients were SPT negative and intradermal test positive, a nasal challenge was performed against five different allergens. If SPT with the multi‐test II device was negative, only 17% of subjects had a positive intradermal test that corresponded with clinical history. None of these positive intradermal results corresponded with a positive nasal challenge. Taken together, these studies suggest that intradermal testing may not improve the diagnosis of allergy in subjects with a negative SPT.

Intradermal testing for inhalant allergens is considered safe. However, systemic reactions, such as anaphylaxis, and even death, have been reported after intradermal testing. The risks of intradermal testing may be reduced by testing with more dilute solutions in individuals with suspected high‐level sensitivity or by performing SPT as an initial screening test. The risk of intradermal testing is significantly higher in medication allergy and IgE‐mediated food allergy and therefore not recommended.1268

In summary, intradermal testing is an option for the diagnosis of AR due to aeroallergens, especially when using non‐standardized allergen extracts. This form of testing demonstrates no clear superiority over SPT when comparing sensitivity and specificity, though results may vary by allergen tested. Single dilution intradermal testing has not been adequately studied in comparison to IDT, though IDT results may approximate SPT results, especially in patients with high level sensitivity. For some allergens such as Alternaria, there appears to be a gain in sensitivity when intradermal testing is used as a confirmatory test following negative SPT.

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X.B.3 Blended skin testing techniques

The combined use of SPT and intradermal testing for a specific allergen is referred to as “blended” allergy testing.1261^, 1274^, 1279 One example, originally described by Krouse and Krouse1280 as a method to establish an “end‐point” for a specified allergen, was described as “modified quantitative testing” (MQT) and serves as an example of a blended technique. MQT involves an algorithm where SPT is used initially to apply an antigen. Depending upon the SPT result, an intradermal test may or may not be applied.1261^, 1274^, 1279^, 1280 With these results, the algorithm is used to determine an endpoint for each antigen tested.1261^, 1274^, 1279^, 1280 The endpoint is considered to be a safe starting point for AIT.1280 Other protocols may combine the use of SPT and intradermal testing but not for the purposes of establishing an endpoint.1273^, 1281 Instead, an intradermal test may be used following a negative SPT to determine allergen sensitization.1273^, 1281

AIT based on the results of MQT has shown to be successful and to induce immune system changes in line with other skin testing techniques.1280 However, literature is lacking in protocols involving blended skin testing (Table X.B.3).

Specifically for MQT, advantages attributed to it include the provision of both qualitative data (sensitization to a specific allergen) and quantitative data (testing endpoint upon which AIT starting dose can be based) in less time than IDT.1261^, 1274^, 1279 Disadvantages include the additional risk and time involved in placing intradermal tests. MQT has been shown to be more cost‐effective when the prevalence of AR in a population is 20% or higher when compared to IDT and in vitro testing methods.1206^, 1282

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X.B.4 Issues that may affect the performance or interpretation of skin tests

X.B.4.a Medications

Medications that inhibit mast cell degranulation or block histamine H₁ receptors antagonists may suppress appropriate skin test responses. For this reason, it is important to assess the medications patients are taking prior to allergy skin testing.

There is substantial variation in the suppressive effects that H₁ antihistamines have on the allergen and histamine induced wheal and flare responses,1283^, 1284 with the duration of suppression dependent on the tissue concentration and half‐life of the medication.1285 Orally ingested antihistamines typically suppress skin test responses for 2–7 days after stopping the medication.1286^, 1287 Topical antihistamines may also suppress skin wheal and flare responses.1288 Furthermore, H₂ receptor antagonists like ranitidine can reduce skin whealing responses,1289^, 1290 and a combined suppressive effect of H₁ and H₂ antihistamines on skin whealing has been demonstrated.1291 Antidepressants with antihistaminic properties (such as doxepin) impair the wheal and flare,1292 but newer antidepressant classes such as selective serotonin reuptake inhibitors do not alter allergy skin test reactivity1293 (Tables X.B.4.a.‐1 and X.B.4.a.‐2).

Omalizumab, a monoclonal anti‐IgE antibody, suppresses the allergy the skin test response by interfering with IgE‐mediated mast cell degranulation. A placebo‐controlled RCT noted significant reduction in the allergen‐induced skin wheal response after 4 months of omalizumab1294; whereas skin test response returned to normal within 8 weeks of discontinuation of omalizumab in another study.1250

Hill and Krouse1295 and Simons et al.1296 found no effect of montelukast on intradermal skin tests, and Cuhadaroglu et al.1297 noted that allergic patients treated with zafirlukast had no change in SPT results. Therefore, leukotriene modifying agents do not appear to affect skin test results.

Most studies indicate that systemic steroid treatment does not alter skin test results,1298^, 1299 but some less rigorous retrospective studies contradict these findings.1300^, 1301 Topical steroid treatment does suppress the wheal and flare reaction in treated skin areas, according to several studies.1302^, 1303^, 1304^, 1305 Allergy skin tests should not be performed in areas that are being treated with topical steroid medications in order to avoid false negative results.

Several classes of medications have not been adequately studied with respect to their effect on allergy skin test responses. Benzodiazepines have been implicated as possibly suppressing skin test responses.1306^, 1307 Calcineurin inhibitors demonstrate conflicting findings. Tacrolimus has been shown to inhibit SPT whealing,1305 whereas pimecrolimus does not appear to affect skin whealing responses.1308 Herbal preparations are understudied in this area, so it is unclear which of these agents could interfere with allergy skin test responses. More et al.1309 performed a double‐blind placebo‐controlled, single dose crossover study in 15 healthy volunteers, examining the histamine induced skin test response. None of the 23 herbal supplements evaluated suppressed the histamine induced wheal response.

All allergy skin testing should be performed after application of appropriate positive controls (e.g., histamine) to verify that the histamine induced skin test reaction is intact at the time of testing. This practice helps to mitigate against unknown factors – potentially medications – causing inappropriate interpretation of skin test results.

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X.C.1 Serum total IgE

IgE is the hallmark immunoglobulin in atopic disease. Atopy, or reactivity to otherwise innocent allergens can be determined by dermal reactivity (e.g., SPT), or by determining sIgE to a certain allergen in serum. The total IgE (tIgE) level in serum can also be determined. As atopy is not disease‐specific, the question arises whether serum tIgE has any place in the evaluation and diagnosis of AR.

From the literature, roughly two study approaches to determine the role of tIgE are identified: population‐based studies (e.g., birth cohorts, school health surveys, or general population approaches) and hospital‐based studies including patients visiting otorhinolaryngology or allergy clinics. Data from the first approach show conflicting evidence. In some studies, tIgE is related to AR diagnosis;1312^, 1313^, 1314^, 1315 in others it is less clear.1316^, 1317 Moreover, it seems from these studies that other comorbidities, especially asthma, give rise to elevated tIgE.1314^, 1315 However, the presence of asthma is not accounted for in most studies, possibly confounding the outcomes. Another weakness of population‐based studies is that the diagnosis of AR depends on questionnaires, symptom scores, or self‐reported diagnosis. This might lead to overdiagnosis of AR in these studies as the distinction with non‐allergic rhinitis, common colds, or other nasal diseases can be challenging (Table X.C.1).

Hospital‐based studies have the advantage of improved diagnostics but have the risk of selection bias. At any rate, these studies also show a mixed picture about the role of tIgE in the diagnosis of AR. Overall, the levels of tIgE are higher in AR versus non‐allergic rhinitis1318^, 1319^, 1320 or versus controls.1321^, 1322 Some studies investigated the correlation between serum sIgE and tIgE1323^, 1324 showing a good overall fit. In hospital‐based studies, the influence of asthma is seen as well1325 but again not accounted for in most reports.

Taken together, an elevated tIgE is indicative of an atopic condition,1326 though not necessarily AR specifically. As such, tIgE is not required in the diagnostic pathway for AR. Many authors conclude that obtaining a serum tIgE can be helpful but is only a preliminary or supportive criterion for AR. Especially if an SPT is performed, there seems to be little added value of obtaining a serum tIgE, as it requires venipuncture which can be bothersome for children. In population‐based studies, tIgE can be supportive of AR, given that the study methodology allows for differentiation between atopic conditions such as asthma or AD in the study population.

Although in general obtaining a serum tIgE is not advised as a routine diagnostic approach, it can be needed or helpful in specific situations. For example, it has been suggested that monitoring of the efficiency of AIT may be done by evaluating the ratio between sIgE and tIgE; this is discussed in detail in a position paper from EAACI.1327 Allergic broncho‐pulmonary aspergillosis is the only clinical condition described to date, where the presence of high levels of tIgE is strictly related to disease severity.1251 However, these specific cases are exceptions to the rule that serum tIgE is not needed for the diagnosis and evaluation of AR.

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X.C.2 Serum allergen‐specific IgE

Determining the presence of sIgE that verifies allergen sensitization is the cornerstone of diagnostic testing in suspected allergic conditions. The assessment of sIgE can be done by skin tests, serological immunoassays, and/or cellular immunoassays.1251

Serological immunoassays detect and measure the level of serum sIgE. Innovations in molecular biology have revolutionized the procurement, characterization, and production of allergens through recombinant and phage methods.1328 The ability to perform serum sIgE immunoassays with recombinant or highly purified allergens has increased the sensitivity, specificity, and diagnostic accuracy of these tests.1245 Additionally, development of miniature computer‐driven autoanalyzers and nanotechnology‐based devices, enhanced signal detection instrumentation, and new solid phase chip and particle materials have improved the diagnostic accuracy and consistency of in vitro tests.1329^, 1330 Furthermore, increased knowledge of molecular allergen components allow clinicians to predict the risk of severe allergic reactions and to identify the most appropriate AIT extract selections for each patient.1330

Derived from the original radio allegro‐sorbent test (RAST), new methods of sIgE immunoassay, like enzyme‐linked immunosorbent assay (ELISA), fluorescent enzyme immunoassays, and/or chemiluminescent assays are available. These measurements of serum sIgE can be done using single allergen (singleplex: one assay per sample) or through a predefined panel that includes several allergens (multiplex: multiple assays per sample). Singleplex tests allow the clinician to choose select allergens as dictated by the clinical history.1251 Multiplex tests provide results of a broad array of preselected allergens.

The multiplex test is important in diagnosis of polysensitized patients. Multiplex platforms are slowly being implemented in many allergy care centers outside of research and tertiary care centers, although currently the most widely used systems are singleplex. Some, like Thermo Fisher ImmunoCAP, have an extensive amount of scientific literature demonstrating their efficacy.1331 Each test has certain characteristics based on the detection method used, the dynamic range of reading of the instrument, time and conditions for the incubation, amount of allergen in the tube, and characteristics of the anti‐IgE.1251^, 1330 There are three different kinds of serum sIgE assays available: qualitative, semi‐quantitative, and quantitative. Qualitative assays are useful to determine if the patient is sensitized to common allergens, providing positive, negative, or borderline sIgE results to a mix of allergens without measuring the IgE concentration. Semi‐quantitative assays grade response by reporting a series of classes (e.g., class I–VI). Quantitative assays report sIgE antibody concentration. Most singleplex platforms are quantitative assays; multiplex is semi‐quantitative.

Multiplex platforms or panels of 10–12 selected allergens (i.e., pollens, cat, and mite) will detect up to 95% of patients who would have been identified on a larger battery.1332^, 1333 If the test is negative, absence of allergy is probable.1329

Serum sIgE testing may also be beneficial for selecting allergens for AIT. In polysensitized patients, it can be difficult to determine the most relevant allergen(s) on SPT. In these situations, molecular allergy using components will help to discriminate the most relevant allergens and thus better guide AIT.1334 In addition, serum sIgE seems to correlate with the severity of AR symptoms.1335^, 1336^, 1337^, 1338^, 1339 Since patients with more severe symptoms appear to respond better to AIT than those with milder symptoms, serum sIgE may help in the selection of candidates for AIT and possibly predicting the response.1335^, 1340

SPT has advantages and disadvantages when compared to sIgE tests. As a general concept, SPT is more sensitive, whereas serum sIgE detection is more quantitative than SPT.1251

There are several advantages of serum sIgE over skin testing. The safety profile is excellent as the risk for anaphylaxis is non‐existent. It is the preferred testing method in individuals at high risk for anaphylaxis.1341 Undergoing SPT is also limited by the presence of certain medical conditions.1341 When SPT is contraindicated, serum sIgE testing offers a safe and effective option for determining the presence of IgE‐mediated hypersensitivities. Additionally, where certain medications can alter SPT results, serum sIgE testing is not similarly impacted. Finally, in very young patients in which SPT may prove too stressful, serum sIgE can be considered.

There are some important limitations to serum sIgE testing. While patients are accepting of both in vitro and in vivo allergy testing, many prefer SPT because it allows for immediate feedback and visible results.1340 Unless molecular allergy diagnostic approach with allergenic components is used (precision allergy medicine diagnosis or PAMD@),1330 serum sIgE to regular allergens cannot accurately predict the risk of severe allergic reaction. If PAMD@ is not used, cross‐reacting allergens and poly‐sensitizations can confound in vitro testing, leading to false positive results.1342

While SPT results may vary based on the quality of the extracts, as well as clinicians administering and interpreting the test, serum sIgE testing results can vary from one laboratory to another. One study sent blinded samples of the same sera, diluted and undiluted, to 6 major commercial laboratories and compared the results to the expected curve from an ideal assay. Out of the six laboratories, only two demonstrated precision and accuracy in their results.1343 Further studies have demonstrated poor agreement on results from testing the same sera by different commercially available assay systems.1343^, 1344^, 1345 These factors introduce notable heterogeneity in serum sIgE testing. Clinicians should be familiar with the platform used for serum sIgE testing at their institution and to understand any limitations inherent to that platform.

Studies have shown that serum sIgE testing has a sensitivity range of 67%–96% and specificity range of 80%–100%.143^, 1249^, 1257^, 1345^, 1346 Further, serum sIgE correlates well with NPT and SPT for AR diagnosis.1249^, 1257^, 1278^, 1345^, 1347 While there is good evidence to show that serum sIgE is often equivalent to SPT, it is generally accepted that SPT is more sensitive.143^, 1005^, 1348 A recent position paper from the World Allergy Organization (WAO) stated that skin tests are still considered first line and that serum sIgE testing should be considered as a complimentary or alternative diagnostic tool.1251 Based on the literature, serum sIgE testing is a reasonable alternative to SPT and is safe to use in patients who are not candidates for SPT. All sIgE tests should be evaluated within the framework of a patient's clinical history (Table X.C.2).

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X.C.3 Nasal allergen‐specific IgE

AR is frequently diagnosed by history alone in clinical practice.182 When objective testing for confirmation of the diagnosis is needed, SPT or in vitro testing for serum sIgE is performed. However, the nasal mucosa of patients with AR has been shown to produce sIgE locally, providing a potential alternative method for objective testing for AR.450^, 451^, 452^, 453^, 529^, 1354

Collection of nasal secretions is typically done by nasal lavage, through absorption of the secretions with absorbent materials, or directly with solid sIgE testing substrates.458^, 1355^, 1356^, 1357 Collection of mucosal tissue can be achieved with either tissue biopsy or with a cytology brush.450^, 1358 There is no consensus on which technique is superior, and most appear to yield similar results in identifying nasal sIgE.1359^, 1360 Cut‐off values for nasal sIgE levels that indicate a diagnosis of AR are debated and consensus has yet to be established. It is generally accepted that levels of nasal sIgE will be lower than levels of serum sIgE in patients with AR1357^, 1361^, 1362 (Table X.C.3).

Outside of a few circumstances, the clinical utility of nasal sIgE testing in patients with AR is limited. However, in patients with negative SPT and negative serum sIgE with a history suggestive of AR, nasal sIgE testing may detect sIgE in their nasal secretions and/or mucosa.446^, 455^, 456^, 458^, 461^, 463^, 473^, 1356^, 1363 This phenomenon is referred to as LAR. LAR is a type of rhinitis characterized by typical allergic symptoms with local sIgE production and positive response to NPT, without positive SPT or serum sIgE testing.445 (See Section VI.A.3. Local IgE Production and Section X.D.2. Local Allergen Challenge Testing for additional information on these topics.) The strictest diagnostic criteria for LAR require a positive NPT and evidence of sIgE in nasal secretions or nasal mucosa, as some studies have shown sIgE in control patients with negative results on NPT.248^, 1365^, 1366^, 1367