Introduction

Essentials of Diagnosis

• Seasonal or perennial occurrence of nasal pruritus, congestion, rhinorrhea, or paroxysms of sneezing, which may be associated with lower respiratory symptoms, eye erythema, pruritus, irritation, tearing, or eczematous dermatitis.
• Environmental aeroallergen exposure.
• Presence of specific-IgE antibody to tested aeroallergens.

Clinical Findings
In addition to the symptoms listed above, up to 40% of patients with allergic rhinitis also manifest lower respiratory symptoms: cough, wheezing, chest tightness, or dyspnea. The physical examination may reveal edematous or inflamed nasal mucosa. In severe cases, the affected mucosa may be pale, boggy, or blue-tinged from vascular engorgement and venous congestion. Nasal symptoms can be nonspecific, however, and the differential diagnosis can include viral rhinitis, bacterial sinusitis, vasomotor rhinitis, nasal polyposis, drug-induced rhinitis, hormonal rhinitis, rhinitis medicamentosa, atrophic rhinitis, gastroesophageal reflux, and systemic disorders such as thyroid disease or Wegener’s granulomatosis. Even a basic understanding of regional aeroallergen patterns and seasons can aid the clinician during the evaluation of patients presenting with acute or chronic rhinitis.

Patients with moderate to severe disease, those who are potential candidates for allergen immunotherapy, and those with strong predisposing factors for atopic diatheses (eg, a strong family history of atopy or ongoing exposure to potential sources of allergen) should undergo testing. Since the development of rhinitis precedes the presentation of asthma in over 50% of cases, early intervention may decrease the risk of more severe clinical allergic disease. Patients with comorbidities or associated complications such as allergic asthma, allergic conjunctivitis, chronic cough, sinusitis, polyposis, eczema, or otitis media may also benefit from evaluation by a subspecialist.

Treatment

The three basic principles of allergy management are avoidance of the allergen, symptomatic pharmacologic therapy, and specific allergen immunotherapy. Patients with suboptimal responses to reasonable therapeutic interventions benefit from diagnostic allergy skin testing.

A. Avoidance Therapy
Avoidance is the most effective treatment for any allergic condition but may be limited in its applicability. It cures the clinical manifestations but does not reduce the sensitivity to the allergen.

1. Pollens
Airborne allergens can travel significant distances, but concentrations are highest near their source. Pollen release occurs in the early morning, and airborne levels depend on temperature and wind velocity. Closing windows and remaining in air-conditioned environments can decrease exposure when pollen counts are high.

2. Animal danders
If the allergy is slight, the patient may benefit from merely keeping the animal out of the bedroom; usually, however, it is necessary to remove the animal from the home altogether. Hypersensitivity to animal dander can be exquisite, and passively transferred dander can accumulate to significant levels in “off-limits” areas. Washing or otherwise treating the fur of a live animal has not been proved to reduce allergenicity.

3. House dust and dust mites
The mattress and pillows should be encased in dust mite-proof material, and all other bedding should be washed weekly and dried at high temperature. The bedroom floor should be uncarpeted. The room should be dusted frequently. Electronic air purifiers are of unproved effectiveness for dust mite reduction since the primary source of exposure is the bed. Acaricides are currently not recommended. Dust mite reduction interventions can be successful adjunctive measures to medical therapy, can significantly reduce symptoms, and can reduce bronchial hyperreactivity and medication requirements in sensitized patients.

4. Mold spores
Out of doors, mold spores are unavoidable during certain seasons. Nevertheless, activities such as gardening and farming can be associated with acute high levels of exposure and should be avoided. Indoor mold contamination can be controlled by repairing leaks, by preventing mold buildup in bathrooms and around windows, and by replacement of mold-contaminated carpeting.

B. Drug Therapy
Three classes of pharmacotherapy are useful for IgE-mediated diseases, based on (1) inhibition of release of mediators from mast cells, (2) inhibition of the action of mediators on their target cells, and (3) reversal of the vascular and inflammatory responses in the target tissues (Table 19-1).

1. Antihistamines
Antihistamine drugs competitively inhibit the binding of histamine to H₁ receptors and are useful for the treatment of IgE-mediated allergy. There are a number of such drugs, but the use of first-generation antihistamines (chlorpheniramine, brompheniramine, diphenhydramine, clemastine, hydroxyzine) are limited by sedation, neurocognitive impairment, and dry mucous membranes. Rare complications include seizures and tachyarrhythmias. Second-generation nonsedating histamine H₁-receptor-blocking drugs, loratadine, fexofenadine, and desloratadine appear not to be associated with arrhythmias and, along with cetirizine, are the systemic drugs of choice. Cetirizine is mildly sedating, but the incidence of side effects is markedly lower than that of its parent compound, hydroxyzine. Azelastine is a topical antihistamine preparation that is applied intranasally to decrease its systemic side effects. Because of methodologic issues, publication bias, and inability to generalize findings, providing a rank order of potency and clinical efficacy for the available antihistamines is difficult. Although some patients with allergic rhinitis may respond better to one compound over another, an incomplete response to antihistamine therapy often indicates the need for combined treatment with a corticosteroid nasal spray. This highlights the necessity to control both the early phase and late phase of the allergic response for optimal symptom control.

Antihistamine therapy is helpful in allergic rhinitis and in urticaria but not in all patients. It rarely alleviates symptoms of asthma, though it is not contraindicated when used to treat concomitant rhinitis or pruritus. The antipruritic effect of antihistamines may be a useful adjunct in treatment of eczematous diseases. Intramuscular or intravenous antihistamines are used in systemic anaphylaxis as adjunctive treatment only. They relieve cutaneous and gastrointestinal symptoms but have no effect on vascular collapse or airway obstruction.

2. Sympathomimetic drugs
Adrenergic agonists are used for both a-adrenergic (vasoconstricting) and ß-adrenergic (bronchodilating) properties. a-Adrenergic agonists can be used orally (pseudoephedrine) or topically (phenylephrine, naphazoline, oxymetazoline) as nasal decongestants and topically as conjunctival vasoconstrictors. Daily use of topical preparations can lead to rapid development of rebound vasodilation (rhinitis medicamentosa). The main side effects of oral decongestants are insomnia, tremor, and tachycardia.

3. Glucocorticoids
These drugs have a therapeutic role in virtually all types of allergic diseases because of their anti-inflammatory action rather than by their immunosuppressive effects. Corticosteroids reduce accumulation of immune cells at sites of inflammation by suppressing cytokine synthesis, inducing apoptosis of eosinophils, reducing adhesion molecule expression, and reducing vascular and airway permeability. Systemic use for the treatment of allergic disease, however, requires close attention to toxicity. Steroids are available in oral, intramuscular, intravenous, intranasal, and bronchial inhalation forms; as eye drops; and in topical formulations for dermatologic use. Short-term systemic burst therapy can be used for treatment of severe asthma, allergic contact dermatitis, marked allergic rhinitis, acute exacerbations of hypersensitivity pneumonitis, and allergic bronchopulmonary aspergillosis. Because of complications, including cataracts, corneal ulceration, keratitis, and glaucoma, the prescription of steroid eye drops should be reserved for ophthalmologists.

Topical corticosteroid nasal sprays are effective and appear safe for long-term use, but epistaxis can occur and nasal septum perforation is a rare complication. Although the dosages and formulations available for the treatment of asthma vary greatly in terms of dosage and clinical potency, intranasal preparations of flunisolide, fluticasone, beclomethasone, mometasone, budesonide, and triamcinolone are similarly efficacious for the treatment of allergic rhinitis. Long-term topical corticosteroid therapy for allergic rhinitis is an essential aspect of management of the inflammatory phase of the disease. It may take several days of consistent use before optimal responses are seen, but these compounds have consistently proved superior to antihistamine monotherapy for control of nasal pruritus, sneezing, and nasal congestion. Surprisingly, they may also provide some relief from concomitant eye pruritus and have shown positive effects on sleep, which can be adversely affected in patients with allergic rhinitis. Topical corticosteroids may also be effective for treatment of vasomotor rhinitis and may be employed as adjunctive treatment for sinusitis in combination with antibiotic therapy.

4. Cromolyn sodium and sodium nedocromil
Pretreatment with these drugs prevents the response to allergen by stabilizing the mast cell, though the specific molecular mechanisms of action are unknown. Although unrelated, they have similar effects and, because of poor bioavailability, are effective only when applied directly to the involved organ. Their action is short-lived, so that they must be given three or four times a day. Cromolyn is available as a bronchial inhaler, nasal spray, and ophthalmologic preparation; nedocromil is available in metered-dose inhalers. In comparison with topical corticosteroids they appear to be much less potent, but the drugs have very few side effects and wide margins of safety. A high-dose oral form of cromolyn is available to treat systemic mastocytosis, but poor oral absorption limits its effectiveness.

5. Anticholinergic agents
Ipratropium bromide is effective as a nasal topical agent for use in rhinitis. Mucous membrane glandular secretion is under cholinergic control and can be inhibited by anticholinergic agents. First-generation antihistamines have systemic anticholinergic activity, but ipratropium is preferred as adjunctive treatment of allergic rhinitis or as primary treatment for many types of nonallergic rhinitis. Ipratropium does not alleviate sneezing, pruritus, or nasal congestion but can be useful for treatment of postnasal drip and rhinorrhea.

6. Leukotriene antagonists
Montelukast is an effective drug for the treatment of asthma. To a much more limited degree, leukotriene antagonists can be efficacious for the treatment of allergic rhinitis, either as monotherapy or combined with an antihistamine. By inhibiting leukotriene-mediated vasodilation vascular permeability and by potentially reducing eosinophilic inflammation, orally administered montelukast can provide symptomatic relief, especially for nasal congestion. It is less effective than intranasal corticosteroids, however.

C. Immunotherapy
Treatment of atopy -  especially allergic rhinitis -  by the repeated long-term injection of allergen has been shown in many controlled clinical trials to be an effective method for reducing or eliminating symptoms and signs of the allergic disorder.

1. Indications
This treatment is recommended for patients with severe allergic rhinitis who respond poorly to drug therapy and whose allergens are not avoidable. Immunotherapy is unequivocally effective in patients with allergic rhinitis and allergic conjunctivitis who react to pollens, mold, and house dust mites. It reduces immunologic hypersensitivity, symptoms, and medication requirements. In children with documented allergic rhinitis, immunotherapy may reduce the risk of subsequent development of asthma. Efficacy in allergic asthma is debated. The lower clinical response rates observed in asthma have been attributed to the multifactorial nature of the disease. Immunotherapy is of no value in atopic dermatitis. Food or drug hypersensitivity is treated by avoidance only, since immunotherapy is not available.

2. Immunologic effects
“Allergen immunotherapy” is preferable to “desensitization” because the immunologic basis for this treatment has not been clearly elucidated. Nevertheless, certain immunologic changes can be induced by these injections. Circulating levels of IgE antibodies specific to the injected allergens increase slightly during the first few months, then decrease, eventually to substantially lower levels than before treatment. Seasonal rises in IgE antibodies to pollens are blunted or eliminated. IgG blocking antibody is produced. Changes in regulatory T cells favoring suppression of IgE antibody production and apoptosis of antigen-specific T cell clones have been noted. TH2 cytokine responses may be shifted toward TH1 responses in peripheral blood mononuclear cells. Higher thresholds for release of inflammatory mediators and decreases in late-phase allergic reactions might also be related to the reduction in biologic sensitivity of end-organ systems (eyes, nose, bronchi, and skin).

3. Clinical effects
Most patients with allergic rhinitis caused by aeroallergens become more tolerant to natural pollen exposure during successive seasons while on immunotherapy. A small minority becomes completely asymptomatic, but most patients enjoy a significant decrease in symptoms and medication usage. In a study of children, ages 7-13, treated for allergic rhinitis with allergen immunotherapy, the risk of developing asthma appears to be decreased by half. Only high-dose injected immunotherapy has been demonstrated to be effective. A beneficial response may persist for years after treatment is stopped. The clinical effects and immunologic responses are antigen-specific, but the treatment may also decrease the risk of developing new environmental sensitivities.

4. Procedure
A sterile aqueous solution of the allergen or allergens responsible for the patient’s disease is administered by subcutaneous injection in increasing doses once or twice a week until a maintenance dose is reached, at which time the interval is advanced to every 4 weeks. The maintenance dose is typically one to ten thousand times the starting dose. Ascending doses are used to minimize the risk of systemic allergic reactions during initial stages of immunotherapy. Three to 5 years is a typical course of therapy. Oral immunotherapy remains experimental in the United States, and sublingual or low-dose immunotherapy is unconventional and of unproved efficacy.

5. Adverse effects
Reactions to treatment may be local or systemic. Localized immediate and late-phase skin reactions occur at injection sites. These are not harmful, but the dose must be adjusted to avoid excessively large or prolonged local reactions. Immediate systemic reactions or anaphylaxis is a potential problem with each injection and must be prevented by monitoring of dosage. The patient remains at the treatment facility for at least 20 minutes after each injection so that drugs and equipment for treating anaphylaxis will be available if needed. No long-term adverse consequences of aqueous allergen extract immunotherapy are known to have occurred in immunocompetent individuals.

Preferences
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Moller C et al: Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251.