Continuing Education Activity

Allergic rhinitis (AR) is an atopic disease presenting with symptoms of sneezing, nasal congestion, clear rhinorrhea, and nasal pruritis. It is an IgE-mediated immune response that is against inhaled antigens in the immediate phase, with a subsequent leukotriene-mediated late phase. This activity describes the evaluation and treatment of allergic rhinitis and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the abnormal immune response in the etiology of allergic rhinitis.
• Explain the epidemiology of allergic rhinitis.
• Describe the use of intranasal steroids, antihistamines, leukotriene receptor antagonists, and immunotherapy in the treatment of allergic rhinitis.

Introduction

Allergic rhinitis (AR) is an atopic disease characterized by symptoms of nasal congestion, clear rhinorrhea, sneezing, postnasal drip, and nasal pruritis. It affects one in six individuals and is associated with significant morbidity, loss of productivity, and healthcare costs. Historically,  AR was thought to be a disease process of the nasal airway alone. Still, the development of the unified airway theory has classified AR as a component of systemic allergic response, with other associated conditions, such as asthma and atopic dermatitis, sharing an underlying systemic pathology.[1] AR can be classified as either seasonal (intermittent) or perennial (chronic), with approximately 20% of cases being seasonal, 40% perennial, and 40% with features of both.[2] In addition to nasal symptoms, patients with AR may also present with associated allergic conjunctivitis, non-productive cough, Eustachian tube dysfunction, and chronic sinusitis. Once diagnosed, AR is treatable with a variety of modalities, with intra-nasal glucocorticoids being the first-line therapy.[1]

Etiology

The allergic response is classified into early and late-phase reactions. In the early phase, allergic rhinitis is an immunoglobulin (Ig)E-mediated response against inhaled allergens that cause inflammation driven by type 2 helper (Th2) cells.[2] The initial response occurs within five to 15 minutes of exposure to an antigen, resulting in the degranulation of host mast cells. This releases a variety of pre-formed and newly synthesized mediators, including histamine, which is one of the primary mediators of allergic rhinitis. Histamine induces sneezing via the trigeminal nerve and also plays a role in rhinorrhea by stimulating mucous glands. Other immune mediators, such as leukotrienes and prostaglandins, are also implicated as they act on blood vessels to cause nasal congestion. Four to six hours after the initial response, an influx of cytokines, such as interleukins (IL)-4 and IL-13, from mast cells occurs, signifying the development of the late-phase response. These cytokines, in turn, facilitate the infiltration of eosinophils, T-lymphocytes, and basophils into the nasal mucosa and produce nasal edema with resultant congestion.[3]

Non-IgE-mediated hyperresponsiveness can develop due to eosinophilic infiltration and nasal mucosal obliteration. The nasal mucosa now becomes hyperreactive to normal stimuli (such as tobacco smoke and cold air) and causes symptoms of sneezing, rhinorrhea, and nasal pruritis.[4]

There are data to suggest a genetic component to allergic rhinitis, but high-quality studies are generally lacking. Monozygotic twins show 45% to 60% concordance, and dizygotic twins have a concordance rate of approximately 25% in the development of AR. Specific regions on chromosomes 3 and 4 also correlate with allergic responses.[5]

Epidemiology

The prevalence of allergic rhinitis based on physician diagnosis is approximately 15%; however, the prevalence is estimated to be as high as 30% based on patients with nasal symptoms. AR is known to peak in the second to fourth decades of life and then gradually decline.[6] The incidence of AR in the pediatric population is also quite high, making it one of the most common chronic pediatric disorders. According to data from the International Study for Asthma and Allergies in Childhood, 14.6% in the 13 to 14 year age group and 8.5% in the 6 to 7 year age group display symptoms of rhinoconjunctivitis linked to allergic rhinitis.[7] Seasonal allergic rhinitis seems to be more common in the pediatric age group, whereas chronic rhinitis is more prevalent in adults.[8]

A systematic review from 2018 estimated that 3.6% of adults had missed work, and 36% had impaired work performance due to allergic rhinitis. Economic evaluations have shown that indirect costs associated with lost work productivity account for the majority of the cost burden for AR.[9] 

Risk factors for developing AR include a family history of atopy, male sex, a presence of allergen-specific IgE, a serum IgE greater than 100 IU/mL before age 6, and higher socioeconomic status.[5] Studies in young children have shown a higher risk of AR in those with an early introduction to foods or formula and/or heavy exposure to cigarette smoking in the first year of life.[2] Although many recent studies have evaluated the link between pollution and the development of AR, no significant correlation yet exists. Interestingly, there are several factors identified that may have a protective effect on the development of AR. The role of breastfeeding in the development of AR is often debated, but it is still recommended due to its many other known benefits and no associated harms. There is no evidence that pet avoidance in childhood prevents AR; however, it is hypothesized that early pet exposure may induce immune tolerance. There is a growing interest in the "farm effect" on the development of allergies, and a meta-analysis of 8 studies showed a 40% lower risk in subjects who had lived on a farm during their first year of life.[10]

History and Physical

Taking a thorough, detailed history is an essential part of the evaluation of AR, and questions should focus on the types of symptoms, the time, duration, and frequency of symptoms, suspected exposures, exacerbating/alleviating factors, and seasonality.[10] Patients with intermittent or seasonal allergic rhinitis have symptoms of sneezing, rhinorrhea, and watery eyes, while patients with chronic AR often complain of postnasal drip, chronic nasal congestion, and obstruction.[8] These patients will often have a family history of allergic rhinitis or a personal history of asthma. Patients with intermittent rhinitis may report triggers such as pollens, animal dander, flooring/upholstery, mold, humidity, perfumes, and/or tobacco smoke.[11]

On physical examination, clinicians may notice mouth breathing, frequent sniffling and/or throat clearing, transverse supra-tip nasal crease, and dark circles under the eyes (allergic shiners). Nasal supratip crease is more common in children. Anterior rhinoscopy typically reveals swelling of the nasal mucosa and thin, clear secretions. The inferior turbinates may take on a bluish hue, and cobblestoning of the nasal mucosa may be present. Whenever possible, an internal endoscopic examination of the nasal cavity should be conducted to assess for nasal polyps and structural abnormalities. Pneumatic otoscopy can be used to assess for eustachian tube dysfunction, which can be a common finding in patients with allergic rhinitis. Palpation of sinuses may elicit tenderness in patients with chronic symptoms. These patients should also undergo careful examination for signs of asthma or dermatitis and should be questioned regarding aspirin sensitivity.[11]

Evaluation

Allergic rhinitis is largely a clinical diagnosis made based on a thorough history and physical. A positive response to empiric treatment with a nasal glucocorticoid can support the diagnosis. A formal diagnosis is possible with either serum testing for allergen-specific IgE or allergy skin testing.[6] As stated by the American Academy of Otolaryngology guidelines, allergy testing should be reserved for patients who are unresponsive to empiric treatment or require the identification of a specific allergen to target therapy.[1] Serum testing does not require trained technicians, and the patient does not need to stop taking antihistamines in advance. Intradermal allergy testing does require a trained professional to perform testing, but results are available immediately. In patients with seasonal symptoms, testing should be performed during the peak symptoms season in order to best identify specific triggers.[6] Skin testing is known to have slightly superior sensitivity to serum testing and is more cost-effective. Contraindications to skin allergy testing include patients with uncontrolled or severe asthma, unstable cardiovascular disease, pregnancy, and/or concurrent beta-blocker therapy. H2-receptor antagonists, tricyclic antidepressants, and anti-IgE monoclonal antibody omalizumab can interfere with allergy skin test response; therefore, cessation is advisable before testing.[10]

Radiographic imaging is not routinely recommended for the diagnosis of AR and is primarily used to rule out other conditions, such as rhinosinusitis.[10]

Treatment / Management

Avoidance of triggers, especially in those with seasonal symptoms, is encouraged, although it is not always practical. Precautions can be taken to avoid dust mites, animal dander, and upholstery, though this can require significant lifestyle changes that may not be acceptable to the patient. If removing a pet from the home is not feasible, isolating the pet to a single room in the house may be an option to minimize dander exposure. It may take up to 20 weeks to eliminate cat dander from the home, even after removing the animal.  Allergen-impermeable bedding covers, washing sheets in hot water, and the use of a vacuum cleaner with high-efficiency particulate air (HEPA) filters may also lessen symptoms.[5] 

Pharmacological options include antihistamines, intranasal steroids, leukotriene receptor antagonists (LTRAs), and immunotherapy.

Intranasal corticosteroid therapy can be as monotherapy or in combination with oral antihistamines in patients in patients with mild, moderate, or severe symptoms. Studies have shown intranasal corticosteroids are superior to antihistamines in effectively reducing nasal inflammation and improving mucosal pathology. Thus a topical intranasal steroid should be the first-line treatment for AR.[12] Commonly available nasal sprays in the United States include beclomethasone, budesonide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. Proper administration of nasal spray is critical in achieving an optimal clinical response and avoiding side effects; therefore, patients should always receive counsel on the appropriate use of devices. They should be used regularly, as their peak effect may take multiple days to develop. The spray bottle's tip should be placed just inside the naris and aimed laterally towards the ipsilateral eye to minimize contact of the product with the nasal septum. The most common side effect reported is nasal irritation, followed by epistaxis, both of which can be prevented by spraying away from the nasal septum.[11] Oral and injectable steroids have been shown to alleviate symptoms of AR but are not recommended for routine use due to their significant systemic side-effect profile.[10]

First-generation antihistamines include diphenhydramine, chlorpheniramine, and hydroxyzine, whereas fexofenadine, loratadine, desloratadine, and cetirizine are examples of second-generation antihistamines. Both first- and second-generation antihistamines are effective at controlling symptoms of AR. Still, first-generation antihistamines can be quite sedating due to their ability to cross the blood-brain barrier. These agents also act on muscarinic receptors, causing side effects of dry mouth, urinary retention, constipation, and/or tachycardia. Second-generation antihistamines have improved H1 selectivity, are less sedating, and have longer half-lives (12 to 24 hours) than those of the first-generation. Fexofenadine has no sedating effects, but loratadine and desloratadine may be sedating at higher doses. Cetirizine has the most potential for sedation of all second-generation antihistamines. There is no one agent recommended over others, as all have shown similar efficacy and safety profiles in terms of symptom relief.[5] Intranasal antihistamines, such as azelastine, have a rapid onset and are more efficacious than oral antihistamines in relieving nasal symptoms. They are recommended as first or second-line therapies for AR and can be used in conjunction with topical nasal steroid sprays with a synergistic effect.[10]

Leukotriene receptor antagonists (LTRAs) such as montelukast and zafirlukast can be beneficial in patients with AR, but they are not as efficacious as intranasal corticosteroids.[13] Their use is often in combination therapy with other agents for severe or refractory symptoms. For patients in whom avoidance measures and combination pharmacotherapy are not effective, allergen immunotherapy should be considered.  Subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT) are commonly used therapies. Weekly incremental doses are given for 6 to 8 months, followed by maintenance doses for 3 to 5 years. Typically, patients experience a prolonged, protective effect, and therapy can be ceased.[1]

Oral decongestants such as pseudoephedrine are useful in relieving symptoms but are not recommended for extended daily use due to their side-effect profile. Intranasal decongestants such as xylometazoline are alpha-agonists that are delivered directly to nasal tissue to produce vasoconstriction. Prolonged use of intranasal decongestants has a risk of causing rebound nasal congestion (rhinitis medicamentosa) and, therefore, should not be used for more than a week.[10] Sodium cromoglycate (Cromolyn) effectively reduces sneezing, rhinorrhea, and nasal pruritis, so it is a reasonable option. Surgical treatment is reserved for patients with nasal polyposis, inferior turbinate hypertrophy causing intractable nasal obstruction, or chronic sinus disease refractory to medical treatment.[5] Budesonide is the only FDA-approved agent for pregnant patients experiencing symptoms of allergic rhinitis.[1] Omalizumab, a monoclonal antibody, is beneficial in patients with AR, although the cost associated with therapy is a limiting factor in its use.[14] Nasal saline can be another option in conjunction with other treatment modalities. Isotonic solutions are more beneficial in adults, whereas hypertonic solutions may be more effective in children.[10]

Differential Diagnosis

The differential diagnosis for AR includes other forms of rhinitis that are not allergic. Children, particularly those under the age of 2 years, should also be assessed for congenital causes of nasal obstruction, such as choanal atresia and immunodeficiencies.[2][6][10]

• Vasomotor rhinitis - noninflammatory rhinitis that can be triggered by a change in temperature, odors, or humidity
• Infectious rhinitis - viral or bacterial infections, most commonly seen in the pediatric population
• Cerebrospinal fluid leak - clear rhinitis refractory to treatment
• Non-allergic rhinitis with eosinophilia syndrome (NARES) - infiltration of eosinophils in nasal tissue without allergic sensitization
• Chemical rhinitis - exposure to chemicals through occupation, household chemicals, sport/leisure exposure
• Rhinitis of pregnancy and hormonally-induced rhinitis
• Drug-induced rhinitis - e.g., NSAIDs, ACE inhibitors, nasal decongestants, cocaine
• Autoimmune, granulomatous, and vasculitic rhinitis - Granulomatosis with polyangiitis, sarcoidosis, etc.
• Nasal polyposis
• Nasopharyngeal neoplasm
• Sickle cell anemia - in a young child presenting with nasal polyposis and well-controlled asthma, sweat chloride testing is the appropriate next step in management to rule out cystic fibrosis.

Pertinent Studies and Ongoing Trials

In studies comparing the effects of intranasal corticosteroids on topical antihistamines and oral antihistamines, intranasal steroids were proven to be more beneficial in relieving sneezing symptoms, rhinorrhea,  and nasal pruritis and blockage and are, therefore, recommended as first-line therapy for all patients with AR.[15] There is great evidence for the efficacy of immunotherapy for AR and allergic asthma, and it is the only disease-modifying intervention in allergic conditions.[16]

Anti-H3 and H4 antihistamines are currently under study for use in AR, but no agents have received approval yet. Roflumilast, a phosphodiesterase-4 (PDE4) inhibitor approved for patients with COPD, has been proven to be beneficial in AR in one small study, but further studies to confirm results are lacking. A new route of administration for immunotherapy is the injection of allergens directly into lymph nodes. It has been proven to induce a 10-fold higher allergen-specific IgG response that is demonstrated by improved efficacy and safety. Dapilumab, a fully-humanized monoclonal antibody, improved AR-related nasal symptoms in a recent randomized, double-blind, placebo-controlled trial. It works by inhibiting the signaling of IL-4 and IL-13, which are both key drivers of immune diseases. Novel therapeutic approaches such as these are in development or clinical trials and look promising in the treatment of AR.[16]

Prognosis

The belief is that the prevalence of allergic rhinitis peaks in adolescence and gradually decreases with advancing age. In a longitudinal study, at the time of the 23-year follow-up, 54.9% of patients showed improvement in symptoms, with 41.6% of those being symptom-free. Patients who had an onset of symptoms at a younger age were more likely to show improvement. The severity of AR can vary over time and depends on various factors such as location and season.[17] Approximately 50% of patients receiving grass allergy immunotherapy noted improvement in symptoms that continued 3 years after discontinuation of therapy.[18]

Complications

Chronic rhinosinusitis, although distinct from allergic rhinitis, can be a complication of AR. It is characterized by nasal inflammation with symptoms of nasal congestion or discharge, ongoing for longer than 3 months. Chronic rhinosinusitis may also demonstrate findings of nasal polyps (nasal polyposis), which form as a result of chronic inflammation of the paranasal sinus mucosa. Nasal polyps are typically benign and present bilaterally. Unilateral nasal polyps should raise concerns for malignancy. The incidence of nasal polyps in the general population is approximately 4% and is more common in males. Treatment options include topical steroids and saline irrigation. Surgical removal is reserved for patients who do not respond to medical therapy.[1]

It is also known that sensitization to allergens in AR can alter the immunological parameters of the adenoids, resulting in adenoid hypertrophy.[4] Eustachian tube dysfunction commonly manifests in patients with AR and presents as ear fullness, otalgia, and ear-popping. Approximately 10 to 40% of patients with AR also have concurrent asthma, and some studies suggest asthma is more common in moderate to severe persistent rhinitis. Many studies have demonstrated AR to be an independent risk factor for asthma, especially in patients diagnosed with AR during infancy. Some other associated complications include otitis media with effusion, persistent cough, and eosinophilic esophagitis, although there is a need to define the link more clearly.[10] 

Patients undergoing allergen desensitization (allergy shots) can experience an acute exacerbation of rhinitis or asthma, or, in a worst-case scenario, the patient could progress to anaphylaxis. Therefore, staff members in offices that provide this therapy should be well-versed in the diagnosis and management of such severe reactions and have the appropriate emergency medications (especially epinephrine) and airway management equipment immediately available.[19][20]

Consultations

Allergic rhinitis is most often diagnosed and managed by primary care physicians/providers. However, patients who fail traditional therapies for AR are eligible for referral to a specialist, such as an allergist or an otolaryngologist (ENT) with an allergy focus. Patients who are deemed candidates for immunotherapy typically obtain a referral to allergists for therapy. Specific findings on the physical exam should also prompt a referral, such as multiple nasal polyps in a pediatric patient, which is highly suggestive of cystic fibrosis. Patients who present with bloody or unilateral nasal discharge (not basic epistaxis) should be urgently referred to an ENT to rule out malignancy. Any concern for cerebrospinal fluid leak causing rhinorrhea also warrants referral to an ENT specialist.[21]

Deterrence and Patient Education

Patients often underestimate the severity of this condition and fail to seek medical therapy. It is important to adequately control AR, especially due to the link between AR and asthma, with poor control of rhinitis predicting poor control of asthma.[22] Patient compliance with the treatment regimen is crucial for the alleviation of symptoms. Patients should receive educational materials with information about allergic rhinitis and its implications. Moreover, patient education on the proper administration of nasal sprays also plays an essential role in a patient's response to therapy.[23] Patients should be advised to look down and squirt nasal spray just inside the nostril, aiming toward the outer walls on both sides. It should be stressed that the patient should not take a deep breath or sniff hard after spraying.[15] Counseling patients on the avoidance of known allergens is a necessary but time-consuming task.[23]

Enhancing Healthcare Team Outcomes

According to the "ecology of medical care" model, only a minority of patients seek medical care for their symptoms, and most of these are managed by their primary care physician (PCP) and a nurse practitioner. Therefore, it is crucial to provide patients with information on self-management and when to contact their PCP. The involvement of community pharmacists and nurse practitioners can play a vital role in achieving these goals. However, patients who fail traditional therapies for AR are eligible for referral to a specialist, such as an allergist or an otolaryngologist (ENT) with an allergy focus. Patients who are deemed candidates for immunotherapy typically obtain a referral to allergists for therapy. Specific findings on the physical exam should also prompt a referral, such as multiple nasal polyps in a pediatric patient, which is highly suggestive of cystic fibrosis. Patients who present with bloody or unilateral nasal discharge (not basic epistaxis) should be urgently referred to an ENT to rule out malignancy. Any concern for cerebrospinal fluid leak causing rhinorrhea also warrants referral to an ENT specialist.[21]

PCPs, nurse practitioners, and allergy specialists often work closely in co-managing patients with AR. The interprofessional team must work as a team to educate the patient and family. After an initial evaluation and a treatment plan is in place, the nurse practitioner, physician assistant, and physician must work together to assure the patient improves and, if not, receives additional evaluation. Access to healthcare and specialists varies globally, but when available, PCPs, pediatricians, allergists, and/or ENT specialists working with specialty-trained ENT nurses and clinicians will result in the best outcomes.[21]