Definition

Allergic rhinitis may be defi ned as an infl ammation of the nasal mucous membranes caused by immunoglobulin E (IgE)-mediated (allergic) reaction to aeroallergens.

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Prevalence

The first recorded case of allergic rhinitis (catarrhus aestivus) was described by Sir John Bostock, who presented himself as a case report to the Medical and Surgical Society of London in 1819. ¹ At the dawn of the 20th century, there were only several thousand members of the U.S. Ragweed Association. One hundred years later, allergic rhinitis has become the most common allergic or immunologic disorder in the U.S. population ^2-4 and it now affects an estimated one in seven Americans. Allergic rhinitis is acknowledged as a significant health challenge on a global scale. ³ Allergic rhinitis is a major cause of patient visits to physicians in the United States, commonly complicates management of other conditions (e.g., asthma, chronic sinusitis), and if untreated or undertreated can lead to considerable morbidity including missed work or school, sleep disruption, diminished daytime performance, and impaired quality of life. ^{2, 5} The economic burden of allergic rhinitis is substantial. ⁴

A rising prevalence of allergic rhinitis has been found not only in children ⁴ but also in adults. ⁵ The peak in incidence of allergic rhinitis occurs during the young adult years. Although prevalence declines with age, allergic rhinitis is also an important health concern in older adults. ⁶ Incidence of allergic rhinitis is equal in male and female patients.

Epidemiologic studies have consistently demonstrated that allergic rhinitis and asthma commonly coexist. ² Allergic rhinitis is often associated with asthma and is a risk factor for developing asthma; in addition, many patients with allergic rhinitis demonstrate increased bronchial hyperresponsiveness to inhalation challenge with histamine or methacholine.

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Pathophysiology

Persons who have inherited the potential to develop IgE-mediated, or allergic, responses to otherwise innocuous inhalant allergens, with sufficient exposure, generate allergen-specific IgE after T-cell release of interleukins (IL) 4 and 13 and B-cell switching to produce IgE antibody, thereby becoming sensitized. The allergic reaction that underlies allergic rhinitis results from subsequent exposure to the allergen to which sensitization has occurred, which cross-links at least two IgE antibodies bound to the high-affinity IgE receptor on presensitized effector cells, mast cells, or basophils. ⁷

The allergic response includes an early and a late phase. ^2,7 early phase occurs promptly and has a duration of approximately 1 hour. The late phase typically begins in 3 to 6 hours, peaks at 6 to 8 hours, and subsides in 12 to 24 hours. Almost one half of subjects studied in laboratory settings exhibit this dual response. ⁸ The symptoms of the early phase generally include sneezing, pruritus, and clear rhinorrhea; symptoms characterizing the late phase may be indistinguishable but typically entail more prominent congestion. ^2,7 The late phase is promoted by factors generated in the early phase, which encourage release of inflammatory mediators and the activation and recruitment of cells to the nasal mucosa. ^2,3,8

Whereas histamine appears to be the major mediator of the early phase, the late phase is more closely associated with other mediators, chemokines, and cytokines that have inflammatory and proinflammatory effects leading to recruitment of inflammatory cells such as eosinophils and basophils. Eosinophils play an important role in the late phase, ⁷ including release of leukotrienes, which, data suggest, are of greater importance than histamine for nasal congestion ^9,10 During a clinically relevant exposure in a sensitized person (e.g., outdoors during the ragweed season or indoors with cats), aeroallergens enter the nasal passages on a virtually continual basis. Therefore, it is often difficult to separate the early and late phases of the allergic response in the real-world setting. One can imagine that in many cases, based on the incessant nature of aeroallergen exposure, affected persons experience a perpetual late-phase response.

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Signs and Symptoms

There are four major symptoms of allergic rhinitis: sneezing, pruritus, congestion, and drainage; however, many patients with allergic rhinitis do not complain of the entire symptom complex. ¹¹ Patients with allergic rhinitis commonly also experience ocular symptoms, so much so that the term allergic rhinoconjunctivitis is often used as an alternative to allergic rhinitis. ²

An appropriate history for allergic rhinitis includes questions to elicit information regarding onset and duration of symptoms, provoking factors or situations, concomitant ocular symptoms, and associated pruritus of other facial structures (e.g., throat, ears, palate). Of the four major symptoms, pruritus and sneezing are more specific for allergic rhinitis compared with conditions in the differential diagnosis of allergic rhinitis, which are shown in Box 1. The propensity for sneezing can entail paroxysms of 5 to 10 or more in rapid succession. Congestion is a bothersome symptom, as it is commonly described by patients with allergic rhinitis, and compared with other symptoms tends to be less responsive to currently available medications. Rhinorrhea is typically clear; purulent discharge might reflect a secondary infection.

 

Physical examination can reveal pale, boggy nasal mucous membranes and infraorbital congestion (allergic shiners), but can be relatively unremarkable unless patients are seen when symptoms are prominent. At such times, subtotal or complete nasal obstruction may be present, along with suffusion of conjunctivae.

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Diagnosis

Proper recognition of patients with allergic rhinitis requires a careful history and physical examination. The key components of the history that favor allergic rhinitis, as opposed to other causes of rhinitis (see Box 1), include seasonality of symptoms, occurrence of symptoms with certain exposures or situations (e.g., walking into a pet store), improvement of symptoms during spring, summer, and fall when in air-conditioned environments (buildings or automobiles), and the experience of prominent itching of the nose, eyes, ears, throat, or palate. As opposed to younger patients with chronic rhinitis, in older adults allergic rhinitis is less commonly confirmed, and alternative diagnoses for perennial rhinitis, including cholinergic hyperactivity, pharmacologic causes (e.g., α-adrenergic effects of antihypertensive drugs), and chronic sinusitis are found more often. ⁶

The diagnosis of allergic rhinitis requires a positive history, demonstration of IgE-mediated potential to inhalant allergens by cutaneous (or in vitro) testing, and correlation between history and cutaneous (or in vitro) test findings. Immediate hypersensitivity skin testing is recommended as the preferred diagnostic study, because it is associated with lower cost, is more sensitive, and entails no delay in obtaining results. ^2,12 Patients with skin disorders or who are unable to suspend antihistamine medications, such that skin testing would be uninterpretable, are candidates for in vitro testing to detect elevated levels of specific IgE to inhalant allergens. ^2,12

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Treatment

Once a diagnosis of allergic rhinitis is confi rmed, treatment strategies include avoidance, medications, and allergen immunotherapy.

Avoidance

The results of cutaneous (or in vitro) testing can be used to direct specific avoidance measures. Avoiding clinically relevant allergens can substantially reduce symptoms and reliance on medication, ² and it is arguably the most important aspect of managing allergic rhinitis. The inhalant allergens that can account for allergic rhinitis are listed in Box 1. Persons with allergic rhinitis are often sensitive to more than one allergen.

The occurrence and severity of symptoms among patients with seasonal allergic rhinitis caused by outdoor pollens and mold spores parallel the exposure to and levels of these factors in ambient air. Monitoring pollen and mold counts in one's vicinity is often of benefit, because the knowledge of these counts can be useful for planning outdoor activities. The pollen counts for the Cleveland vicinity during the pollen season of 2004 (May to October) are displayed in Figure 1. A predictable sequence of pollination is observed each year, such that trees predominate in the spring, grasses in the summer, and weeds in the late summer and early fall. Ragweed pollen (Figure 2) is the dominant weed in the midwestern and northeastern United States. Ragweed typically appears in ambient air during the second week of August, peaks in early September (usually Labor Day weekend), and then persists until the frost. Mold spore counts and counts of pollen grains, recorded simultaneously for three days each week in the Cleveland vicinity throughout the 2004 season, are shown in Figure 3. Molds are present in samples of ambient air at much higher levels than pollens; however, pollens are more efficient aeroallergens: Grass pollen counts in single digits may be sufficient to provoke symptoms in sensitized persons, whereas mold counts of several thousand are still considered low.

For persons who are allergic to outdoor pollens, air conditioning can dramatically relieve symptoms. ² By reducing indoor relative humidity, air conditioning also significantly reduces mold spore and dust mite allergen levels. ¹³ We now spend most of our time indoors,¹⁴ and the usefulness of air conditioning for reducing symptoms should not be underestimated.

Dust mites are a major source of allergens in house dust ^2,13 Dust mites have been isolated in dust samples taken from Africa, Asia, Europe, and North and South America. They are microscopic and rely on heat and humidity to survive and proliferate. ² Allergy to dust mites is common in patients with allergic rhinitis. Recommended avoidance measures to reduce exposures to dust mites include encasing the mattress, box spring, and pillow in impermeable covers; reducing indoor relative humidity; washing bedding weekly in hot water (55° C, 130° F); and removing carpets (if possible) in favor of tiled or hardwood flooring. ¹³

 

For persons who are allergic to cat or dog dander and who have pets, no avoidance strategy can approach the benefit of removing the pet from the home. ¹⁵ In view of emotional attachments to pets, as well as the potential therapeutic value of pets, ¹⁶ the decision to remove a pet from the home must be discussed openly with allergic patients and considered carefully from an individualized risk-to-benefit standpoint. Removing a cat or dog from the home might not have immediate clinical benefit because the allergen can persist for several months. When it is not possible to remove pets from the home, second-best measures include excluding the pet from the allergic person's bedroom, using high-efficiency particulate air (HEPA) cleaners or electrostatic air cleaners, and removing carpets and other upholstered items that can serve as a reservoir for allergens. ¹⁵ Although allergen reduction may be transient and the potential for clinical benefit has not been clearly established, bathing the pet (cat or dog) also may help.

Pharmacotherapy

Because avoidance measures will likely be incomplete, and patients with allergic rhinitis will continue to be exposed to clinically relevant levels of aeroallergens, virtually all patients with allergic rhinitis benefit from medication.

Antihistamines

The most commonly prescribed medications for allergic rhinitis are H₁ antihistamines. ² These drugs antagonize the action of histamine by blocking receptor sites on target cells. Antihistamines were introduced more than 50 years ago and continue to be widely used.

Although conventional or first-generation antihistamines are efficacious, they can be associated with drowsiness and performance impairment. ² Impaired driving performance has been documented with use of conventional antihistamines, even in persons with no subjective awareness of drowsiness. ¹⁷ Older adults may be more sensitive to the psychomotor impairment promoted by antihistamines and are at increased risk for complications such as fractures and subdural hematomas caused by falls. ⁶ Prominent anticholinergic effects, including dryness of the mouth and eyes, constipation, inhibition of micturition, and potential provocation of narrow angle glaucoma, can occur. Because of concomitant comorbid conditions (e.g., increased intraocular pressure, benign prostatic hypertrophy, preexisting cognitive impairment) that can increase the potential risk associated with regular or even intermittent use, first-generation antihistamines should be prescribed or recommended cautiously in older adults.

Second-generation antihistamines ( Table 1), which lack the prominent central nervous system or anticholinergic properties of conventional antihistamines, are generally preferred. ² Second-generation antihistamines include oral fexofenadine, oral levocetirizine, oral loratidine (available without a prescription), oral desloratidine, oral cetirizine, and intranasal azelastine.

Decongestants

Oral decongestants primarily reduce nasal congestion and can attenuate drainage, but they do not affect sneezing or itching. They are often helpful taken in combination with an antihistamine. These agents are available without a prescription. Use of these drugs can be problematic, ² especially in older adults, ⁶ in view of their propensity for promoting adverse central nervous system effects (e.g., tremor, irritability, insomnia, nervousness) and cardiovascular effects (palpitations, blood pressure elevation). These drugs can also raise intraocular pressure and provoke obstructive urinary symptoms.

Topical decongestants effectively relieve congestion. Benefit is usually prompt and dramatic; however, rebound congestion can follow as the vasoconstrictive action of these agents diminishes. A paradoxical effect then tends to occur with continuing use: The decongestive action lessens, but the sense of nasal obstruction increases. The pathophysiology of this condition, rhinitis medicamentosa, is not fully understood but is believed to entail down-regulation of -adrenergic receptors, making them less responsive to endogenously released norepinephrine and exogenously applied vasoconstrictors. Because rebound congestion can occur as soon as 3 days from beginning of treatment, ¹⁸ use of these agents is most favorable from a risk-to-benefit standpoint for this period, and patients should be advised to stop using topical decongestants after 3 days. Treatment of rhinitis medicamentosa consists of suspending topical decongestant use to permit the nasal mucosa to recover.

Intranasal Corticosteroids

Intranasal corticosteroids are the most efficacious agents for managing allergic rhinitis. ² Given the understanding that symptoms of allergic rhinitis reflect an inflammatory response promoted by aeroallergen exposure, use of an agent that can achieve a broad range of anti-inflammatory effects and acts through multiple mechanisms would be expected to be associated with maximal relief of allergic rhinitis symptoms compared with other agents.

The therapeutic effects of intranasal corticosteroids include vasoconstriction and reduction of mucosal edema, inhibition of mediator release, suppression of cytokine production, and inhibition of inflammatory cell infiltration. ² Intranasal corticosteroids are effective for reducing nasal congestion, rhinorrhea, and sneezing, and can also relieve ocular symptoms. ¹¹ Systemic effects are minimal at recommended doses. ² The major adverse effect of intranasal corticosteroids is local irritation or epistaxis; patients should be instructed to stop using intranasal corticosteroids at the first sign of bleeding or irritation and to direct the nasal spray laterally, away from the nasal septum.

Other Drugs

Intranasal ipratropium is effi cacious for rhinorrhea, but it has little benefi t with respect to other allergic rhinitis symptoms. ² This medication may be helpful if rhinorrhea is refractory to other medications or for persons with vasomotor or irritant rhinitis. ² Potential adverse effects include local irritation or epistaxis.

Intranasal cromolyn is available over the counter. This medication is well tolerated, but it appears to be more effi cacious for preventing infl ammation than for reversing it once it occurs. ² Although its frequency of use limits its usefulness, it poses no risk for systemic adverse effects and may be preferred for select patients (e.g., pregnant women, young children, older adults) based on this safety advantage. As with other topical agents, there is a risk of local irritation or epistaxis.

Oral antileukotrienes have been associated with statistically signifi cant improvement in symptom scores and quality of life compared with placebo in patients with allergic rhinitis. ¹⁹ The degree of therapeutic benefi t is equivalent to that of loratidine (a secondgeneration antihistamine), but antileukotrienes are not associated with wheal-fl are suppression. Therapeutic benefi t with intranasal corticosteroids is statistically superior. ²⁰ Many patients with allergic rhinitis have concomitant asthma, and antileukotrienes can treat both of these conditions with a single agent. ²¹

Therapeutic Usefulness

Table 2 displays the therapeutic usefulness of these pharmacotherapeutic agents for addressing the four major symptoms of allergic rhinitis in addition to ocular symptoms. ^2,11,18 In clinical practice, combination treatment with more than one of these agents is often required to achieve and maintain control of allergic rhinitis.

Evidence-based medicine aids the clinician in making data-driven treatment decisions. Number needed to treat (NNT) and number needed to harm (NNH) calculations have been derived to estimate the magnitude of treatment effects of these medications for allergic rhinitis. ²² NNT is the average number of patients who need to receive a treatment for one patient to benefi t, and NNH is the average number of patients who need to receive a treatment for one patient to be harmed. The lower the NNT and higher the NNH, the more effective and favorable a treatment is. NNT and NNH calculations for these medications are displayed in Table 2.

(c) 2005 The Cleveland Clinic Foundation. NNH, number needed to harm; NNT, number needed to treat; Adapted from Bousquet J, van Cauwenberge P, Khaltaev N, et al: Allergic rhinitis and its impact on asthma (ARIA). Allergy 2002;57 841-55.

Allergen Immunotherapy

Allergen immunotherapy is commonly administered for patients with allergic rhinitis (and/or asthma). Its effi cacy is well established for patients with allergic rhinitis2,23 and for patients with asthma (see elsewhere in this section, “Asthma.”) ²⁴

Allergen immunotherapy entails the incremental administration of inhalant allergens to induce immune system changes in host response with natural exposure to these allergens. ²³ Numerous randomized, double-blind, placebo-controlled trials have shown that allergen immunotherapy is associated with reducing symptoms and medication reliance. Using a published trial of immunotherapy in which 37 of 44 patients randomized to injections of timothy grass pollen or placebo, completed a 3-year study,26 in which statistically signifi cant reduction in symptoms and medication use for rhinitis and asthma in association with allergen immunotherapy was found, NNH was 417. This estimate indicates that 417 allergen immunotherapy injections were given for 1 person to experience a systemic reaction. Because of the risk of anaphylaxis from allergen immunotherapy, injections should only be given in a setting where adequate precautions are taken and life-threatening anaphylaxis can be treated. ²³ A wait time of 20- to 30 minutes after immunotherapy administration is also recommended ²³ to be certain a systemic reaction has not occurred.

A trial of immunotherapy merits consideration for allergic rhinitis patients who have secondary complications (e.g., sinusitis, otitis), who have concomitant (mild to moderate) asthma for which inhalant allergy is relevant, or for whom a program of optimal avoidance measures and medications is not effective, not feasible, or not preferred. ^2,23,25 Allergen immunotherapy also may be desirable for patients with allergic rhinitis who do not tolerate or are disinclined to take regular medications.

The decision to begin allergen immunotherapy should be individualized and is based on symptom severity, relative benefi t with pharmacotherapy, and comorbid conditions such as cardiovascular disease or beta-blocker exposure. ²⁷ The latter conditions are associated with heightened risk for more serious anaphylaxis, the major hazard of allergen immunotherapy. ²³

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Summary

• Prevalence of allergic rhinitis has increased dramatically.
• Allergic rhinitis can be managed successfully with a regimen of avoidance measures and regular medication.
• In properly selected patients with allergic rhinitis (or asthma, or both), allergen immunotherapy is effi cacious and can reduce symptoms and reliance on medication.
• Much of the morbidity associated with untreated or undertreated allergic rhinitis can be prevented with proper diagnosis and management.

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