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Allergic rhinitis affects between 20 million and 40 million people in the United States annually, including 10 to 30% of adults and up to 40% of children.1,2 Moreover, the prevalence appears to be increasing.² Several recent reviews regarding the pathogenesis, diagnosis, and treatment of allergic rhinitis have been published.^2–5 This section will summarize clinically relevant information about this common entity.

Etiology/Pathogenesis

Allergic rhinitis is caused by an intranasal IgE-mediated reaction to inhalant antigens. Recent concepts of pathogenesis suggest that IgE-mediated reactions are promoted by Th2 helper lymphocytes, which synthesize interleukins (IL) 4, 5, 6, and 13.⁶ In contrast, Th1 helper lymphocytes, which promote delayed-type hypersensitivity, produce IL-2, interferon γ, tumor necrosis β, and IL-12,^6,7 while both Th1 and Th2 cells express IL-3, -10, and granulocyte-macrophage colony–stimulating factor (GM-CSF).^6,7

The combination of antigen with nasal mast cell–or basophil-fixed specific IgE leads to the release of vasoactive and pro-inflammatory mediators and cytokines. The effects of these mediators and cytokines on blood vessels, mucus-secreting cells, nerves, and inflammatory cells lead to the eosinophilic inflammation, typical symptoms, and nasal hyperreactivity associated with allergic rhinitis. Histamine, the most well known mediator derived from mast cell degranulation, accounts for approximately half of the symptoms of allergic rhinitis.³

Allergic rhinitis may be perennial or seasonal, depending on the primary antigens involved. Perennial allergic rhinitis is caused by inhalant allergens such as house dust mites, animal dander, and indoor molds. Such perennial allergic rhinitis may be worse in the winter when the home is closed up and forced air heating systems are operating. Seasonal allergic rhinitis is usually due to tree pollen (early spring), grass pollen (late spring), or weed pollen (fall). In addition, outdoor mold spores may cause seasonal allergic rhinitis, especially during the spring and fall. Although grass pollen may be more perennial in subtropical climates, springtime exacerbations are usually still present.

Recently, an alternative clinical classification for allergic rhinitis has been proposed.⁵ Intermittent allergic rhinitis was suggested to describe symptoms that are present less than 4 days per week for less than 4 weeks per year, and persistent allergic rhinitis was suggested to describe symptoms that are present more than 4 days a week for more than 4 weeks per year. Moderate-severe (vs. mild) allergic rhinitis was considered to be present when one or more of the following symptoms occur due to the untreated illness: sleep disturbance, impairment of daily activities (leisure and/or sport), impairment of school or work, or troublesome symptoms.

Potential management of allergic rhinitis involves antigen avoidance, pharmacological therapy, and immunotherapy. More complete antigen avoidance information may be found elsewhere.2 The most important aspects of dust mite control involve obtaining plastic or synthetic encasings for the pillows, mattress, and box springs and washing the bedclothes in hot water weekly. Mold avoidance involves reduction of the conditions that promote mold growth (moisture, warmth, and darkness) and the use of a fungicide where mold is growing. Although elimination of an animal from the home is the best form of avoidance for dander-induced disease, washing the pet weekly and an air purifier with a high-energy particulate air (HEPA) filter may provide some reduction in airborne animal dander antigen. Avoidance of outdoor pollen and mold spore exposure when the patient is outdoors is difficult, although air-conditioning and HEPA filters may minimize the indoor concentrations of these outdoor allergens.

Antihistamines are particularly helpful for the sneezing, itching, and runny nose associated with allergic rhinitis. The second-generation antihistamines (Table 5–1) generally may be preferred due to the absence or reduction of important side effects, such as anticholinergic effects, sedation, and performance impairment. Desloratadine, fexofenadine, and loratadine are classified by the U.S. Food and Drug Administration (FDA) as nonsedating because standard doses result in no greater incidence of sedation than that seen with placebo. The incidence of sedation with cetirizine at a standard adult dose of 10 mg is higher than with placebo, although it is significantly less sedating than most first-generation antihistamines.² Azelastine is a topical antihistamine with efficacy that appears comparable to oral antihistamines. However, ~20% of patients in clinical trials complain of bitter taste, and 11.5% report somnolence.²

Although earlier second-generation antihistamines (terfenadine, astemizole) were rarely associated with serious cardiovascular effects (ventricular tachyarrythmias, cardiac arrest, or sudden death associated with prolonged QT interval), cetirizine, desloratadine, fexofenadine, and loratadine have not been shown to be associated with QT interval changes or rhythm disturbances.²

Oral decongestants (pseudoephedrine, phenylpropanolamine, phenylephrine) are adrenergic agonists that may be used as a supplement to antihistamines when nasal congestion is prominent. These drugs may be administered alone or as combination products with several antihistamines. Side effects from oral decongestants may include insomnia, loss of appetite, and excessive nervousness. In addition, because of their pharmacological effects, these drugs should be avoided or used with caution in patients with cardiac arrythmias, angina pectoris, hypertension, hyperthyroidism, glaucoma, and urinary dysfunction. Pseudoephedrine appears to be less likely than phenylpropanolamine to cause elevated blood pressure.² Antihistamines and/or decongestants may be used as needed for intermittent symptoms and regularly for mild to moderate daily symptoms.

Nasal cromolyn has an excellent safety profile and may be considered, especially for children and pregnant women with mild to moderate daily symptoms. Nasal cromolyn may also be used 15 minutes prior to predictable intermittent allergen exposure (e.g., going to a house with a pet) to prevent allergy symptoms. The disadvantages of nasal cromolyn include its frequent dosing requirements (qid) and its lack of efficacy in 30 to 40% of the population, despite strict adherence to the frequent dosing regimen.5

Intranasal corticosteroids are the single most effective medication for the treatment of allergic rhinitis. A recent meta-analysis confirms that they are more effective than oral antihistamines in the treatment of allergic rhinitis.⁸ Several intranasal corticosteroid preparations are available (Table 5–2). They are particularly useful in patients with daily moderate or severe symptoms, and they work best when administered regularly. The available data suggest that intranasal steroids (except for dexamethasone) are not associated with clinically significant systemic effects in adults.² However, the FDA has recently presented data suggesting that some nasal corticosteroids may slightly (but statistically significantly) reduce the growth rate in children, although the overall significance of these observations, especially regarding an effect on ultimate height, is unclear.² Because of this concern, the FDA recommends that (1) intranasal steroids should be used in children at the lowest effective dose, (2) height should be monitored routinely, and (3) other therapeutic approaches should be appropriately used so that intranasal steroid doses may be minimized.

Montelukast, a leukotriene receptor antagonist, was approved by the FDA for the treatment of seasonal allergic rhinitis. The use of leukotriene receptor antagonists for the pharmacotherapy of allergic rhinitis has been reviewed.⁹ The studies published to date demonstrate that leukotriene receptor antagonists are sometimes more effective than placebo, are no more effective than second-generation antihistamines, and are less effective than intranasal steroids in the treatment of allergic rhinitis.⁹ The exact role for leukotriene receptor antagonists in the treatment of allergic rhinitis remains to be determined.

Intranasal ipratropium may be useful for patients with allergic rhinitis who experience prominent watery rhinorrhea. Finally, regarding pharmacological therapy, a short (5–7 days) course of oral corticosteroids may be required occasionally for severe allergic rhinitis. Intraturbinate injection of corticosteroids is not recommended for treatment of rhinitis because the possible benefits do not outweigh the potentially serious side effects of cavernous vein thrombosis and blindness, especially because alternatives such as intranasal or oral steroids are available.²

Allergen immunotherapy may be considered for patients with clear-cut allergic rhinitis that is not adequately controlled by other means.² Because of potentially life-threatening allergic reactions, it should be performed only by specialists trained in its use. Immunotherapy should be given for a 12-month trial, and, if effective, continued for 3 to 5 years and then evaluated for trial discontinuation. The clinical benefit derived from immunotherapy can be measured in symptom and/or medication reduction, but not usually eradication or cure.

Allergy and Sinus Disease

Sinus disease has been reported to occur in 53 to 63% of allergic subjects,10–13 and allergy has been reported to be present in 20 to 56% of patients with sinusitis.^11,14–23 However, whether this represents a true association between allergy and sinus disease or just the frequent coexistence of two common conditions is not totally clear. Savolainen¹⁴ studied 225 patients with documented acute maxillary sinusitis and 103 age-matched controls. Allergy was diagnosed on the basis of history, skin tests, and nasal smear. A statistically significant increase in definite (25% vs. 16.5%) or probable (6.5% vs. 3%) allergy was found in the subjects with sinusitis compared with controls. In a national survey of chronic sinusitis in Korea,²⁴ in which chronic sinusitis was diagnosed based on symptoms and endoscopic examination, symptoms of allergic rhinitis (not specifically defined in the article) were 10 times more likely in patients with chronic sinusitis than in subjects without chronic sinusitis (p < 0.05). Berrettini et al²⁵ found abnormal sinus CTs in 67.5% of 40 mite-sensitive patients with perennial allergic rhinitis, compared with 33.4% of controls undergoing cranial CTs for dizziness. In contrast, the incidence of radiologically diagnosed sinusitis was not increased in allergic versus nonallergic subjects in 91 children with chronic respiratory symptoms,¹¹ 445 children and adults with chronic nasal symptoms,¹³ or 270 patients with asthma and/or rhinitis.¹⁰

One longitudinal study has also provided evidence against a specific association between allergy and sinusitis. In this study,²⁶ 64 patients with allergic rhinitis and 23 nonallergic individuals were followed for 11 months. During the period of observation, the subjects with allergic rhinitis did not experience more frequent or longer lasting upper respiratory infections or sinusitis than did nonallergic subjects.

Although the above studies have not supported a clear-cut relationship between the frequency of sinusitis and the presence of allergy, several studies have noted a relationship between the severity of sinusitis and the presence of allergy. In these studies^15,16,27 correlations were reported between the extent of sinus disease, as determined by sinus CT scan, and the presence of specific IgE, as determined by RAST testing. Extensive disease in these studies was also correlated with the presence of asthma, peripheral eosinophilia, sinus tissue eosinophilia, and total serum IgE level.

Mechanistic Considerations

If allergy predisposes to more severe sinusitis, if not more frequent disease, what might the mechanism (s) be? Three potential mechanisms have been considered: (1) an IgE-mediated reaction occurring in the sinuses themselves, (2) allergic rhinitis-induced ostial obstruction, and (3) a constitutional predisposition to sinus mucosal inflammation in allergic patients.

Pelikan et al²⁸ evaluated sinus radiology at baseline and then either 6 or 12 hours after allergen challenge in 37 patients with chronic sinusitis who were studied at a time of minimal symptoms. Forty-one positive nasal allergen challenges were observed in 29 of 37 patients. In 32 of the 41 positive nasal responses, a positive maxillary sinus response was also observed (>3.0 mm increased thickening and/or increased opacification or decreased aeration). In contrast, a positive sinus response occurred in only 3 of 21 negative nasal challenges (p < .01). These data would be consistent with either a local sinus IgE-mediated reaction occurring coincident with the nasal allergic response or sinus changes occurring secondary to allergy-induced ostial obstruction. However, this study is weakened by the fact that the radiographs were apparently not interpreted in a blinded fashion and definitive criteria for a positive sinus response were apparently not established a priori.

Three studies argue against a local IgE-mediated reaction occurring in the sinus. In the first study,²⁹ five nonatopic subjects inhaled technetium-labeled ragweed. Intense reactivity was detected in the nasal cavity, but none was detected in the sinuses, suggesting that the antigen does not penetrate into sinus tissue. In the second study, Liu et al³⁰ evaluated tissue-specific mite IgE in the sinus mucosa and nasal turbinates of 60 patients with sinusitis. Although specific mite IgE was elevated in the turbinate tissue of atopic patients, mite IgE was not found to be elevated in sinus mucosa. Finally, Slavin et al³¹ studied five highly symptomatic ragweed-sensitive adults during the ragweed season. Using three different sinus imaging modalities, no sinus inflammation was demonstrated in these patients.

Melen et al³² evaluated ostial diameter on entry and during the peak of the pollen season in 20 patients with seasonal allergic rhinitis treated with intranasal budesonide or placebo. Ostial diameters were normal at both time periods and were not different in budesonide-versus placebo-treated subjects, even though budesonide-treated patients reported significant symptomatic improvement. Consistent with these observations, sinus CT scan–defined ostiomeatal unit abnormalities did not correlate with sinus mucosal changes or with clinical status in 10 patients with ragweed allergic rhinitis.³³ These data do not support the concept that allergy-induced ostial obstruction leads to sinusitis in allergic subjects.

Finally, several studies have evaluated immunohisto-chemical markers of inflammation in sinus biopsies from allergic versus nonallergic subjects with chronic sinusitis. Although tissue eosinophilia appears to be prominent in both allergic and nonallergic subjects,34–36 it may be more prominent in allergic subjects.^15,37–39 An increase in macrophages³⁴ and polymorphonuclear leukocytes^38,39 has also been reported in the sinuses of both allergic and nonallergic patients with chronic sinusitis.

Cells expressing receptors for IL-5, GM-CSF, IL-6, and IL-13 appear to be increased in both allergic and nonallergic subjects with sinusitis compared with controls,^36,40–43 although IL-5 appears to be more prominent in allergic subjects,^39,41,44,45 whereas GM-CSF appears to be more prominent in nonallergic subjects.^40,41 Both allergic and nonallergic patients have been reported to manifest increased total (CD3)³⁶ and helper (CD4)^36,46 sinus T cells, and suppressor/cytotoxic (CD8) T cells have been reported to be decreased in allergic subjects but increased in nonallergic subjects compared with controls.³⁶ In addition, only allergic subjects have been reported to have increased mast cells,³⁴ CD20+ B cells,⁴⁷ and IgE-producing B cell precursors in sinus biopsies,⁴⁷ and allergic subjects exhibited a higher proportion of CD30 positive mononuclear cells (presumably Th2 cells) in sinus mucosa than nonallergic subjects.⁴³ These data suggest that Th2 cytokines and their receptors are important in the eosinophilic inflammation of sinusitis in both allergic and nonallergic subjects, but that involvement of somewhat different cytokine pathways and effector cells may lead to increased inflammation in allergic subjects.⁴⁰ The putative antigen that is stimulating the apparent immunological inflammatory response in the sinuses remains unknown, but microbial superantigens appear to be one possibility.⁴⁸

Diagnostic Considerations

Regardless of the mechanisms involved, the frequent coexistence of allergy and sinus disease demands a high index of suspicion for the presence of allergy in patients with sinus disease and for sinus disease in patients with allergic rhinitis. In patients with chronic sinusitis, the presence of asthma,¹⁵ increased total serum IgE level,^15,37,49 and more prominent nasal eosinophilia⁴⁹ may suggest an allergic component. However, as discussed above, the definitive diagnosis of allergic rhinitis in patients with chronic sinusitis entails identification of antigen-specific IgE that correlates with symptoms upon exposure to the antigen(s).

The presence of sinus disease in patients with allergic rhinitis may be difficult to predict on clinical ground alone. However, the following findings have been reported to correlate with significant radiologic sinus abnormalities in patients with underlying allergic rhinitis: cough,^12,50 purulent mucus,⁵⁰ thick posterior nasal drainage,¹² and a negative nasal smear for eosinophils.^12,50 In addition, in a study of 91 children with chronic respiratory symptoms, 59% of whom were atopic, the triad of rhinorrhea, cough, and the absence of sneezing was strongly correlated (r = 0.49) with abnormal sinus CT scans.¹¹

Therapeutic Considerations

The diagnosis of sinusitis in patients with known allergic rhinitis has obvious treatment implications. Antibiotics are often effective,^45,50 and other appropriate medical and surgical management would be dictated by the severity and responsiveness of the sinus disease. The implications of a diagnosis of allergy in patients with chronic sinusitis are less certain. Avoidance of antigens to which the patient is sensitive would be recommended, although there are no studies that evaluate the response of sinus disease to antigen avoidance in allergic individuals.

There are some data regarding the effects of nasal steroids in allergic patients with sinusitis. Two studies^36,41 report decreased expression of interleukins (IL-4, IL-5, IL-13) in the sinus biopsies of allergic subjects with chronic sinusitis treated with intranasal steroids in comparison to allergic subjects with sinusitis not receiving intranasal steroids. The exact clinical significance of these findings is not clear. However, in conjunction with observations that intranasal steroids are the most effective pharmacological agents for the management of allergic rhinitis,² these data suggest that patients with allergic rhinitis and chronic sinusitis generally should receive intranasal steroids. In addition, two studies^51,52 suggest that the addition of intranasal steroids to antibiotic treatment of acute sinusitis in patients with a history of recurrent sinusitis or chronic rhinitis reduces symptoms of acute sinusitis and improves clinical success rates. In one of these studies,⁵¹ patients were excluded for “active seasonal allergic rhinitis,” and atopic status (any RAST score >3), which was present in 38% of subjects, did not predict responsiveness to nasal steroid therapy.

Inhalant antigen immunotherapy has been clearly shown to be effective in patients with allergic rhinitis.² However, its efficacy specifically for sinus manifestations in allergic patients with chronic sinusitis is less well documented. Schlenter and Mann⁵³ reported an improved prognosis in 15 allergic patients with relapsing sinusitis treated with immunotherapy compared with 16 atopic patients with sinusitis not so treated. However, only the abstract of this study is in English, and we cannot therefore evaluate the details of this study. Lehrer et al⁵⁴ reported a decrease in sinusitis episodes during 12 to 27 months of follow-up in four allergic subjects treated with immunotherapy, but these observations in this small sample are uncontrolled.

The largest study of immunotherapy in allergic patients with sinusitis was reported by Asakura et al.⁵⁵ These authors studied 37 allergic subjects with sinusitis. Skin tests were positive to Candida,9 dust,³² and bacterial vaccine⁵

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