The lecture below can be accessed on the Disease Management section of the Cleveland Clinic, under Allergy and Immunology (to go to this link and see others in the series, please click here)

Allergic Rhinitis

David M. Lang

Published: November 2013

Definition

Allergic rhinitis (AR) may be defined as an inflammation of the nasal mucous membranes caused by immunoglobuin E (IgE)-mediated (allergic) reaction to aeroallergens.

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Prevalence

The first recorded case of AR (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, AR has become the most common allergic/immunologic disorder in the U.S. population,2–4 and now affects an estimated one in seven Americans. AR is acknowledged as a significant health challenge on a global scale.3 AR is a major cause of patient visits to physicians in the U.S., frequently complicates management of other conditions (e.g., asthma, chronic sinusitis), and if untreated or undertreated can lead to considerable morbidity including missed work/school, sleep disruption, diminished daytime performance, and impaired quality of life.2,5The economic burden of AR is substantial.4

A rising prevalence of AR has been found not only in children,4 but also in adults.5 The peak in incidence of AR occurs during young adult years. Although AR prevalence declines with age, it is also an important health concern in older adults.6 There is an equal incidence of AR in males and females.

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

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Pathophysiology of Allergic Rhinitis

Individuals 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 4 and 13, and B-cell “switching” to produce IgE antibody – thereby becoming “sensitized.” The allergic reaction that underlies AR 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 both an early and a late phase.2,7 The 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 half of subjects when studied in laboratory settings will 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 both 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 individual (e.g., outdoors during the ragweed season or indoors in cat-infested environments), aeroallergens enter the nasal passages on a virtually continual basis; for this reason, it is frequently 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 individuals experience a perpetual late phase response.

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Signs and Symptoms

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

An appropriate history for AR 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 AR compared with conditions in the differential diagnosis of AR, which is shown in Table 1. The propensity for sneezing may entail paroxysms of 5 to 10 or more in rapid succession. Congestion is a bothersome symptom, as it is commonly described by patients with AR, and compared with other symptoms tends to be less responsive to currently available medications. Rhinorrhea is typically clear; purulent discharge may reflect the presence of a secondary infection.

Table 1: Differential Diagnosis of Allergic Rhinitis
Vasomotor or irritant rhinitis
Chronic sinusitis
Nonallergic rhinitis with eosinophilia
Gustatory rhinitis
Atrophic rhinitis
Rhinitis medicamentosa
Rhinitis associated with drugs (e.g., antihypertensive agents, oral contraceptives)
Rhinitis associated with systemic disease (e.g., hypothyroidism, Wegener’s granulomatosis, Sjögren’s syndrome)
Structural factors (septal deviation, nasal polyposis, nasopharyngeal carcinoma)

Physical examination may 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 individuals with AR requires a careful history and physical examination. The key components of the history that favor AR, as opposed to other causes of rhinitis (Table 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-fall seasons when in air conditioned environments (buildings or automobiles), and the experience of prominent itching of nose, eyes, ears, throat, and/or palate. As opposed to younger patients with chronic rhinitis, in older adults AR is less frequently confirmed and alternative diagnoses for perennial rhinitis, including cholinergic hyperactivity, pharmacologic causes (e.g., alpha-adrenergic effects of anti-hypertensive drugs), and chronic sinusitis are found more frequently.6

The diagnosis of AR 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, as it is associated with reduced cost, is more sensitive, and entails no delay in obtaining results.2,12 Individuals 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 and Outcomes

Once a diagnosis of AR is confirmed, 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. Avoidance of clinically relevant allergens can lead to substantial reduction of symptoms and medication reliance,2 and is arguably the most important aspect of AR management. The inhalant allergens that may account for AR are listed in Table 2. Individuals with AR are frequently sensitive to more than one allergen.

Table 2: Inhalant Allergens
Cockroaches
Dust mites
Grasses
Mold spores
Pets (e.g., dogs, cats)
Trees
Weeds

The occurrence and severity of symptoms among patients with seasonal AR due to outdoor pollens and mold spores will parallel exposure to and levels of these factors in ambient air. For this reason, monitoring pollen and mold counts in one’s vicinity is frequently of benefit, as the knowledge of these counts can be useful for planning outdoor activities. For example, 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, along with counts of pollen grains, recorded simultaneously for 3 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 can be regarded as “more efficient” aeroallergens, as grass counts in single digits may be sufficient to provoke symptoms in sensitized individuals who are exposed, while mold counts of several thousand are still considered “low.”

For individuals who are allergic to outdoor pollens, air conditioning can be associated with dramatic symptom relief.2 By reducing indoor relative humidity, air conditioning also leads to significant reductions in mold spore and dust mite allergen levels.13 We now spend the majority of our time indoors14; for this reason, the utility of air conditioning for reducing symptoms should not be underestimated.

Dust mites are a major source of allergen in house dust.2,13 Dust mites have been isolated in dust samples taken from all five major continents. They are microscopic and rely on heat and humidity to survive and proliferate.2 Allergy to dust mites is common in patients with AR. Recommended avoidance measures to reduce exposures to dust mites include the encasement of mattress/box spring and pillow in impermeable covers, reducing indoor relative humidity, washing bedding weekly in hot cycle (≥130° F), and if possible, removal of carpets in favor of tiled or hardwood flooring.13

For individuals allergic to cat or dog dander who are themselves pet owners, no avoidance strategy can approach the benefit that will be gained with elimination of the pet from the home.15 In view of emotional attachments that commonly occur with pet ownership, as well as the potential therapeutic value of pets that may exist,16 the decision to advise removal of a pet from the home must be discussed openly with allergic patients and considered carefully from an individualized risk/benefit standpoint. If a cat or dog is removed from the home, it must be recognized that due to persistence of the allergen for periods of several months, clinical benefit may not occur promptly. When elimination of pets from the home is not possible, second best measures include restricting the pet from the allergic person’s bedroom, use of high efficiency particulate or electrostatic air cleaners, and removal of carpets and other upholstered items which otherwise serve as a reservoir for allergen.15 Although allergen reduction may be transient and the potential for clinical benefit has not been clearly established, bathing the pet (cat or dog) may also be attempted as a “second best” alternative to elimination of the pet from the home.

Pharmacotherapy

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

The most common medications taken by patients for AR are H1 antihistamines.2 These drugs antagonize the action of histamine by blocking receptor sites on target cells. Antihistamines were introduced more than 60 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 individuals 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 mouth and eyes, constipation, inhibition of micturition, and potential provocation of narrow angle glaucoma, may occur. Because of concomitant comorbid conditions (e.g., increased intraocular pressure, benign prostatic hypertrophy, preexisting cognitive impairment, etc.) that may increase the potential risk associated with regular or even intermittent use, first generation antihistamines should be prescribed or recommended cautiously in older adults.

Use of second-generation antihistamines, which lack the prominent central nervous system or anti-cholinergic properties of conventional antihistamines, are generally preferred.2 Second-generation antihistamines available over-the-counter include oral cetirizine, oral fexofenadine, and oral loratidine. Oral desloratidine, oral levocetirizine, intranasal azelastine, and intranasal olopatadine are available by prescription. Intranasal antihistamines are as or more efficacious compared with oral second-generation antihistamines, particularly for congestion and drainage.

Oral decongestants primarily reduce nasal congestion and may attenuate drainage, but do not affect sneezing or itching; they are frequently helpful taken in combination with an antihistamine. These agents are available over-the-counter. Use of these medications may be problematic,2 especially in older adults,6 in view of their propensity for promoting central nervous system (e.g., tremor, irritability, insomnia, nervousness) and cardiovascular (palpitations, blood pressure elevation) adverse effects. These medications may also raise intraocular pressure and provoke obstructive urinary symptoms.

Topical decongestants are highly efficacious for relief of congestion. Benefit is usually prompt and dramatic; however, rebound congestion may follow as the vasoconstrictive action of these agents diminishes. A paradoxical effect then tends to occur with continuing use: the decongestive action lessens, while the sense of nasal obstruction increases. The pathophysiology of this condition, rhinitis medicamentosus, is not fully understood but is thought to entail development of down-regulation of alpha adrenoreceptors, making them less responsive to endogenously released noradrenalin and exogenously applied vasoconstrictors. As rebound congestion may occur as soon as 3 days of treatment,18 use of these agents is most favorable from a risk/benefit standpoint for this period, and it is prudent for patients to be advised to suspend topical decongestant use after 3 days. Treatment of rhinitis medicamentosus consists of suspending topical decongestant use to permit the nasal mucosa to recover.

Intranasal corticosteroids (INS) are the most efficacious agents for management of AR.2 Given the understanding that symptoms of AR reflect an inflammatory response promoted by aeroallergen exposure (see above), 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 AR symptoms compared with other agents.

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

Intranasal ipratropium is efficacious for rhinorrhea, but has little benefit with respect to other AR symptoms.2 This medication may be helpful if rhinorrhea is refractory to other medications listed above, or for persons with vasomotor/irritant rhinitis.2 Adverse effects include the potential for local irritation or epistaxis.

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

Oral antileukotrienes have been associated with statistically significant improvement in symptom scores and quality of life compared with placebo in patients with AR.19The degree of therapeutic benefit is equivalent to loratdine (a second-generation antihistamine). Therapeutic benefit with INS is statistically superior.20 As many patients with AR will have concomitant asthma, antileukotriene agents offer the option of providing efficacy for both of these conditions in a single agent.21

Table 33,22 displays the therapeutic utility of the above agents for addressing the four major symptoms of AR in addition to ocular symptoms.2,11,18 In clinical practice, combination treatment with more than one of these agents is frequently required to achieve and maintain control of AR.

Table 3: Medications for Allergic Rhinitis
Symptoms
Medication Sneezing Rhinorrhea Congestion Pruritus Ocular NNT NNH
Antihistamine, oral ++ ++ + +++ ++ 15.2 51
Antihistamine, intranasal ++ ++ + ++ 0 5 22
Intranasal steroid +++ +++ +++ ++ ++ 4.4 48
Intranasal cromolyn + + + + 0
Decongestant, oral 0 0 + 0 0
Decongestant, intranasal 0 0 ++++ 0 0
Anticholinergic, intranasal 0 ++ 0 0 0
Antileukotriene 0 + ++ 0 ++ 14.3 167

Evidence-based medicine has been increasingly utilized to aid 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 AR.22 NNT is the average number of patients who need to receive a treatment for one to benefit, while NNH is the average number of patients who need to receive a treatment for one to be harmed. The lower the NNT and higher the NNH, respectively, the more effective and favorable a treatment is regarded. NNT and NNH calculations for the above medications are also displayed in Table 3.

Allergen Immunotherapy

Allergen immunotherapy is commonly administered for patients with AR (and/or asthma). Its efficacy is well established for patients with AR2,23 and for patients with asthma (see the chapter “Asthma,” elsewhere in this section).24

Allergen immunotherapy entails the incremental administration of inhalant allergens for the purpose of inducing immune system changes in host response with natural exposure to these allergens.23 Numerous randomized, double-blinded, placebo-controlled trials have shown that allergen immunotherapy is associated with benefit, for reducing symptoms and medication reliance.23,25 The rate of systemic reaction from allergen immunotherapy is approximately 2 to 3 per thousand injections.26,27 Using a published trial of allergen immunotherapy in which 37 of 44 patients randomized to injections of timothy grass pollen or placebo completed a 3-year study,28 in which statistically significant 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 one person to experience a systemic reaction. Because of the risk for anaphylaxis with administration of 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 30 minutes after immunotherapy administration is also recommended23 to be certain a systemic reaction has not occurred.

A trial of immunotherapy merits consideration for AR patients who have secondary complications (e.g., sinusitis, otitis), who have concomitant (mild-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.2,23,25Allergen immunotherapy also may be desirable for patients with AR 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 benefit with pharmacotherapy, and whether comorbid conditions such as cardiovascular disease or beta-blocker exposure are present.29 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 (and/or asthma), allergen immunotherapy is efficacious, and can promote benefit consisting of reduced symptoms and medication reliance.
  • Much of the morbidity associated with untreated or undertreated allergic rhinitis can be prevented with proper diagnosis and management.

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References

  1. Bostock J. Case of periodical affection of the eyes and chest. Med Chir Trans 1819; 10:161–165.
  2. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 2008; 122(suppl 2):S1–S84.
  3. Bousquet J, van Cauwenberge P, Khaltaev N, et al. Allergic rhinitis and its impact on asthma (ARIA) in collaboration with the World Health Organization. Allergy2002; 57:841–855.
  4. Meltzer EO. The prevalence and medical and economic impact of allergic rhinitis in the United States. J Allergy Clin Immunol 1997; 99:S805–S828.
  5. Linneberg A, Nielsen NH, Madsen F, Frølund L, Dirksen A, Jørgensen T. Increasing prevalence of specific IgE to aeroallergens in an adult population: two cross-sectional surveys 8 years apart: the Copenhagen Allergy Study. J Allergy Clin Immunol 2000; 106:247–252.
  6. Lang DM. Management of allergic rhinitis. Geriatric Times 2002; 3:41–48.
  7. Naclerio R. Pathophysiology of perennial allergic rhinitis. Allergy 1997; 52(suppl 36):7–13.
  8. Pelikan Z. Late and delayed responses of the nasal mucosa to allergen challenge. Ann Allergy 1978; 41:37–47.
  9. Okuda M, Watase T, Mezawa A, Liu CM. The role of leukotriene D4 in allergic rhinitis. Ann Allergy 1988; 60:537–540.
  10. Donnelly A, Glass M, Minkwitz MC, Casale TB. The leukotriene D4-receptor antagonist ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Resp Crit Care Med 1995; 151:1734–1739.
  11. Spector SL, Nicklas RA, Chapman JA, et al. Symptom severity assessment of allergic rhinitis: part 1. Ann Allergy Asthma Immunol 2003; 91:105–114.
  12. Bernstein IL, Li JT, Bernstein DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008; 100(3 suppl 3):S1–S148.
  13. Arlian LG, Platts-Mills TA. The biology of dust mites and the remediation of mite allergens in allergic disease. J Allergy Clin Immunol 2001; 107(suppl 3):S406–S413.
  14. Samet JM, Marbury MC, Spengler JD. Health effects and sources of indoor air pollution: part I. Am Rev Respir Dis 1987; 136:1486–1508.
  15. Chapman MD, Wood RA. The role and remediation of animal allergens in allergic diseases. J Allergy Clin Immunol 2001; 107(suppl 3):S414–S421.
  16. Fitzgerald FT. The therapeutic value of pets. West J Med 1986; 144:103–105.
  17. O’Hanlon JF, Ramaekers JG. Antihistamine effects on actual driving performance in a standard test: a summary of the Dutch experience, 1989-94. Allergy 1995; 50:234–242.
  18. Morris S, Eccles R, Martez SJ, Riker DK, Witek TJ. An evaluation of nasal response following different treatment regimes of oxymetazoline with reference to rebound congestion. Am J Rhinol 1997; 11:109–115.
  19. Rodrigo GJ, Yañez A. The role of antileukotriene therapy in seasonal allergic rhinitis: a systematic review of randomized trials. Ann Allergy Asthma Immunol2006; 96:779–786.
  20. Martin BG, Andrews CP, van Bavel JH, et al. Comparison of fluticasone propionate aqueous nasal spray and oral montelukast for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol 2006; 96:851–857.
  21. Philip G, Nayak AS, Berger WE, et al. The effect of montelukast on rhinitis symptoms in patients with asthma and seasonal allergic rhinitis. Curr Med Res Opin2004; 20:1549–1558.
  22. Portnoy J, Van Osdol T, Williams PB. Evidence-based strategies for treatment of allergic rhinitis. Curr Allergy Asthma Rep 2004; 4:439–446.
  23. Cox L, Nelson H, Lockey R, et al. Allergen immunotherapy: a practice parameter third update [published online ahead of print December 3, 2010]. J Allergy Clin Immunol 2011; 127(suppl 1): S1–S55.
  24. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev 2007; (1):CD001936.
  25. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst Rev 2003; (4):CD001186.
  26. DaVeiga SP, Liu X, Caruso K, Golubski S, Xu M, Lang DM. Systemic reactions associated with subcutaneous allergen immunotherapy: timing and risk assessment [published online ahead of print April 14, 2011]. Ann Allergy Asthma Immunol 2011; 106:533–537.
  27. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System [published online ahead of print February 7, 2010]. J Allergy Clin Immunol 2010; 125:569–574.
  28. Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 2001; 107:87–93.
  29. Lang DM. Do beta-blockers really enhance the risk of anaphylaxis during immunotherapy? Curr Allergy and Asthma Rep 2008; 8:37–44.