Principles of Treatment of Allergic Disease

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Chapter 136 Principles of Treatment of Allergic Disease

The basic principles of the treatment of allergic disease include the avoidance of exposure to allergens and irritants that trigger symptoms and the pharmacologic management of symptoms caused by unavoidable acute and chronic allergen exposures. In selected patients with allergic disease refractory to avoidance measures and optimal pharmacologic management, allergen immunotherapy may be considered.

Environmental Control Measures

Children spend the majority of their time in indoor environments, including the home. In an effort to save energy, houses and buildings have been built more tightly and with more insulation with fewer air exchanges. These factors have led to an increase in indoor humidity and higher concentrations of allergens and irritants in indoor air. Examination of indoor environments suggests that house dust mite, cat, and cockroach allergens are the most common significant triggers of allergic disease in these settings; exposures to allergens from other pets, pests, fungi, and respiratory irritants such as cigarette smoke are also a problem.

More than 30,000 species of mites have been identified, but the term dust mites usually refers to the pyroglyphid mites Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Euroglyphus maynei, which are the major sources of allergen in house dust. Respiration and water vapor exchange occur through the skin of dust mites, rendering them sensitive to decreases in humidity and temperature extremes. The regular use of humidifiers and swamp coolers promotes dust mite survival. Mites do not survive with relative humidity <50%. They feed on animal and human skin scales and other debris, which is why they exist in large numbers in mattresses and bedding, carpet, and upholstered furniture. They are also found in flour and mixes for baked goods. Anaphylaxis has been reported following the ingestion of baked goods such as waffles and pancakes prepared with flour infested with dust mites. Dust mite fecal pellets are a major source of allergens. They consist of partially digested food combined with digestive enzymes encased in a permeable membrane, which keeps the fecal pellets intact. These fecal pellets have been likened to pollen grains, given their similarities in size (10-40 µm), the amount of allergen they contain, and their ability to release allergens rapidly on contact with moist mucous membranes. Mites can persist in imported furnishings for at least 2 yr; mite allergens have been shown to remain stable under domestic conditions for periods of at least 4 yr. Dust mite allergens become airborne during normal household activities; a vigorous disturbance such as vacuuming without a vacuum bag or shaking a bed sheet can launch significant amounts of dust mite allergens into the air. Once airborne, dust mite allergen particles settle out of the air relatively rapidly because of their size and weight. Nonetheless, dust mite allergen exposure likely occurs during sleep on mite-infested pillows and mattresses and during normal household activities when dust mite concentrations in the home are high enough. Levels of dust mite allergens as low as 2 µg/g of house dust can lead to sensitization, whereas levels of 10 µg/g of house dust are associated with symptoms.

Appropriate environmental control measures can significantly reduce exposure to dust mite allergens (Table 136-1). Major emphasis should be placed on reducing exposure to dust mite allergens in the bedroom and the bed because of the large amount of time the child spends there. Encasements impermeable to dust mite allergens should be placed on all pillows, the mattress, and the box spring. Dust should be removed from the surfaces of these covers and the bed frame by vacuuming weekly. The sheets and mattress pad should be washed weekly in hot water at a temperature of >130°F. Minimizing the number of items in the room that collect dust, such as books, drapes, toys, stuffed animals, and any clutter, is recommended. Major reservoirs of dust mite allergen that are often more difficult to deal with include the carpet and upholstered furniture, which should be vacuumed weekly with an efficient double-thickness-bagged vacuum cleaner. Although the application of acaricides or denaturing agents to carpets and upholstered furniture has been advised, the actual benefit remains unclear, and the amount of effort required may be more than most families are willing to invest. If possible, carpet removal, at least in the bedroom, may prove a better choice for eliminating a large reservoir of dust mite allergen. Other measures for dust mite allergen control include maintaining the indoor relative humidity at <50% and keeping the air conditioning set at the lowest level during the warmer months.

Table 136-1 ENVIRONMENTAL CONTROL OF ALLERGEN EXPOSURE

ALLERGEN	CONTROL MEASURES
Dust mites	Encase bedding in airtight, allergen-impermeable covers Wash bedding weekly in water at temperatures >130°F Remove wall-to-wall carpeting Replace curtains with blinds Remove upholstered furniture Reduce indoor humidity

Animal dander

Avoid furred pets

Keep animals out of patient’s bedroom

Cockroaches

Control available food and water sources

Keep kitchen/bathroom surfaces dry and free of standing water

Seal cracks in walls

Use professionally extermination services; safe pesticide should be used in baits

Mold

Repair moisture-prone areas

Avoid high humidity in patient’s bedroom

Use high-efficiency particulate air (HEPA) filters in living areas

Repair water leaks

Replace carpets with hardwood floors

Regularly check basements, attics, and crawl spaces for standing water and mold

Pollen

Keep automobile and house windows closed

Control timing of outdoor exposure

Restrict camping, hiking, and leaf raking

Drive in an air-conditioned automobile

Air-condition the home

Install portable HEPA filters

Modified from Leung DYM, Sampson HA, Geha RS, et al: Pediatric allergy principles and practice, St Louis, 2003, Mosby, p 294.

In many countries, more than half of the households have pets, the most common of which are cats and dogs. The major sources of allergens from cats, dogs, horses, and cattle are hair, dander, and saliva, whereas the major source of allergens from rodents is urine. Studies of airborne cat allergen have shown that a significant portion is found on small particles that behave aerodynamically like spheres <7 µm in diameter. As much as 30% of airborne cat allergen may reside on particles <5 µm. Particles this small may not be adequately filtered by the nose and could potentially be deposited in the airways. Their small size enables these particles to remain airborne for longer periods and to be suspended repeatedly by air currents from heating and ventilation systems or just by walking across the carpet or sitting in an upholstered chair. Fel d 1, the major cat allergen, is a highly charged protein that readily sticks to a variety of surfaces, including walls, carpeting, and upholstered furniture. Owing to this adhesiveness, cat allergens bind to the cat owner’s clothing and are routinely transported to public buildings, including schools, where they have been measured in moderately high amounts. From these sites, significant amounts of cat allergen can subsequently be carried into homes without cats. Analysis of house dust from homes with cats reveals levels of Fel d 1 ranging from 8 µg to 1.5 mg/g of house dust. Levels of Fel d 1 in homes without cats vary from 0.2 to 80 µg/g of house dust. Sensitization to cat allergen has been associated with levels ranging from 1 to 8 µg/g of house dust. Carpets, upholstered furniture, and bedding serve as reservoirs of cat allergens, resulting in the persistence of significant amounts in the home for months after a cat has been removed. Complete avoidance of cat allergen is virtually impossible, although significant reduction in exposure to cat allergens is achievable.

Removing the pet from the home is obviously the most effective means of reducing exposure to animal allergens, although it has been demonstrated that without other interventions, such as removing carpeting and upholstered furniture and wiping down walls, it takes 6 months or more for the levels of cat allergen to drop to a level found in houses without a cat. As a result, cat owners who remove their pets from their homes should be informed not to expect immediate results. Unfortunately, advice to remove a pet from the home or keep it outdoors is often ignored. In contrast to dust mite allergens, cat allergen is light and remains suspended in the air for long periods. As a result, air cleaners with high-efficiency particulate air (HEPA) filters are helpful in reducing the amount of airborne cat allergen. Other suggested methods include washing the cat regularly and maintaining a cat allergen–free bedroom from which the cat is excluded and where mattress covers and air-filtering devices are used. The cat should also be restricted from other living areas where the sensitized child spends large amounts of time, such as the family room and other play areas (see Table 136-1). Regular vacuuming with a HEPA-filtered and double–thickness bag vacuum cleaner is also encouraged. Similar measures are suggested for the control of exposure to other animal allergens, although whether these measures reduce exposure to levels resulting in clinical improvement as demonstrated by decreased symptoms, improved peak flows, or decreases in bronchial hyperreactivity remains to be documented by appropriately controlled studies.

Infestation of the home by insects and other pests such as mice and rats is another potential source of significant allergen exposure in the indoor environment. Studies have identified the importance of exposure to cockroach allergens as a major risk factor for the development of asthma in inner-city children. Once sensitized, inner-city cockroach-sensitive asthmatic children with continued exposure to high levels of cockroach allergens in their bedrooms are at higher risk for urgent care visits and hospitalization than inner-city asthmatic children who are not allergic to cockroaches. Recommended methods to decrease cockroach allergen exposure include reducing cockroaches’ access to the home by sealing cracks in the flooring and walls and removing sources of food and water by repairing leaky pipes, putting away food, and frequent cleaning (see Table 136-1). Regular extermination using baits or chemical treatment of infested areas is also advised.

Efforts to improve indoor air quality should also encompass reducing exposure to respiratory irritants. Passive exposure to environmental tobacco smoke worsens asthma and increases nasal symptoms in patients with allergic nasal disease. Smoking cessation should be repeatedly encouraged, and smoking indoors should never be permitted. The use of wood-burning stoves and fireplaces and of kerosene heaters should be discouraged.

Although exposure to pollens and fungi occurs primarily outdoors, these allergens are detectable indoors during the warmer months, when their indoor levels often reflect their prevalence in the outdoor environment. During the winter, when the outdoor levels of other fungi are lowest, the indoor fungi Aspergillus and Penicillium are the most prevalent. Fungi are often found in damp basements and thrive in conditions associated with increased moisture in the home, such as water leaks, flooding, and increased humidity promoted by the excessive use of humidifiers or swamp coolers. Exposure to indoor fungal allergens can be reduced by maintaining the indoor relative humidity at < 50%, removing contaminated carpets, and wiping down washable surfaces prone to fungal growth, such as shower stalls, shower curtains, sinks, drip trays, and garbage pails, with the use of solutions of detergent and 5% bleach (see Table 136-1). Dehumidifiers should be placed in damp basements. Standing water at any site in the home should be eliminated, and the cause addressed. Removing all items from the home that are prone to fungal contamination and growth is also encouraged. Keeping the windows and doors closed and using air conditioning to filter outdoor air can keep both indoor pollen and fungi levels to a minimum during the warmer months, when outdoor levels of these allergens are at their peak. The use of window or attic fans is to be avoided. Laundry should be dried in a dryer rather than on a clothesline. Measures to avoid pollens and fungal spores when out of the house include closing the windows and using the air conditioner when traveling in the car, avoiding moldy vegetation, and wearing a mask when these materials cannot be avoided. Outdoor activities during periods of high pollen counts should be kept to a minimum. Someone other than the sensitized patient should mow the lawn and rake leaves. Frequent handwashing after outdoor play is suggested to avoid transferring pollens from the hands to the eyes and nose. At the end of the day, showering and shampooing are suggested to avoid contamination of the bed with allergens. During the day, the bed should remain covered with a bedspread.

Pharmacologic Therapy

Adrenergic Agents

Adrenergic agents exert their effects through the stimulation of cell surface α- and β-adrenergic receptors in a variety of target tissues. These receptors belong to the G protein–coupled superfamily of receptors. In general, α-adrenergic receptor stimulation results in excitatory responses such as vasoconstriction, whereas β-adrenergic stimulation leads to inhibitory responses such as bronchodilation. The α-adrenergic receptors have been classified into α₁– and α₂-adrenergic receptors. Further studies of these receptors in humans have identified 3 subtypes of α₁-adrenergic receptors and 3 subtypes of α₂-adrenergic receptors. The β-adrenergic receptors are further divided into 3 subtypes: β₁, β₂, and β₃. Each of these adrenergic receptors exhibits a distinctive tissue distribution. The physiologic response in a given tissue to the administration of an adrenergic agent depends on the specific receptor-binding characteristics of the drug as well as the numbers and distribution of the various types of adrenergic receptors in the tissue. Epinephrine remains the drug of choice for the treatment of anaphylaxis because of its combined α- and β-adrenergic effects.

The α-adrenergic agents are effective in the treatment of allergic nasal disease because of their decongestant effects (see Tables 137-2 and 137-4). In the nose, stimulation of α₁-adrenergic receptors on postcapillary venules and of α₂-adrenergic receptors on precapillary arterioles leads to vasoconstriction, resulting in a reduction in nasal congestion. The oral decongestants currently in clinical use include pseudoephedrine and phenylephrine. These medications are available individually or in combination with antihistamines in liquid and tablet forms, including sustained-release preparations. Phenylpropanolamine and all combination products containing this sympathomimetic amine similar in structure to pseudoephedrine have been taken off the market in the USA by the U.S. Food and Drug Administration (FDA) because of concerns about the risk of hemorrhagic stroke and the inability to predict who is at risk. Pseudoephedrine is rapidly and thoroughly absorbed, whereas phenylephrine, the less effective of the two drugs, is incompletely absorbed, resulting in a significantly lower bioavailability of ≈ 38%. Peak plasma concentrations of these drugs are reached between 30 min and 2 hr of administration, but the decongestant effect has not been directly correlated to the plasma concentration. Pseudoephedrine is excreted essentially unchanged by the kidney. The use of oral decongestants should be avoided in patients with hypertension, coronary artery disease, glaucoma, or metabolic disorders such as diabetes and hyperthyroidism. Reported adverse effects of oral decongestants include excitability, headache, nervousness, palpitations, tachycardia, arrhythmias, hypertension, nausea, vomiting, and urinary retention. Decongestants available as topical nasal sprays include phenylephrine, oxymetazoline, naphthazoline, tetrahydrozoline, and xylometazoline. Given their efficacy and rapid onset of action, the potential for excessive use of topical nasal decongestants resulting in rebound nasal congestion is high. When this occurs, refraining from the use of these sprays for 2-3 days is necessary for recovery.

Drugs that stimulate β-adrenergic receptors have been used for years in the treatment of asthma because of their potent bronchodilator effects (see Table 138-11). The subclassification of β-adrenergic receptors into β₁ and β₂ subtypes led to the development of drugs selective for the β₂-adrenergic receptor, such as albuterol, that have the advantage of producing significant bronchodilation with less cardiac stimulation. The long-acting inhaled β₂-adrenergic agonists (LABAs) salmeterol and formoterol, with a 12-hr duration of action, are approved for use in children ≥ 4 yr of age. LABAs are not recommended for the treatment of acute asthma exacerbations because of their relatively slow onset of action. Concern about an apparent increased risk of asthma-related adverse events is why LABAs are not recommended as monotherapy for the long-term control of persistent asthma but are promoted as best used in conjunction with an inhaled steroid. Dry powder inhaled and metered-dose inhaler preparations combining a LABA with an inhaled corticosteroid have had significant impact on the treatment of children with moderate persistent asthma. In addition to their bronchodilating effects, β₂-adrenergic agonists have been reported to improve mucociliary clearance, decrease microvascular permeability, inhibit cholinergic nerve transmission, and reduce mediator release in mast cells, basophils, and eosinophils. The β-adrenergic agonists can be delivered orally, by inhalation, or by injection. The inhaled route is preferred because of the rapid onset of action and fewer adverse effects. Reported adverse effects of β-adrenergic agents include tremor, palpitations, tachycardia, arrhythmias, central nervous system stimulation, hyperglycemia, hypokalemia, hypomagnesemia, and a transient increase in hypoxia, which is attributed to an increase in perfusion to inadequately ventilated areas of the asthmatic lung. In some studies, levalbuterol, a single isomer of albuterol developed to reduce the adverse effects of short-acting β-agonists, has been reported to exhibit a bronchodilatory effect clinically comparable to that of racemic albuterol at a lower dose and with a preferable safety profile. Levalbuterol is available as a nebulized preparation and a metered-dose inhaler preparation.

Anticholinergic Agents

Anticholinergic drugs inhibit vagally mediated reflexes by antagonizing the action of acetylcholine at muscarinic receptors. Of the available anticholinergic agents, ipratropium bromide is the most commonly used. It is a quaternary amine that is poorly absorbed across mucosal surfaces and does not readily cross the blood-brain barrier. As a bronchodilator, it has a slower onset of action than short-acting inhaled β₂-agonists and takes longer to reach maximal effect, making it less effective as a rescue medication. Ipratropium is available by prescription as a metered-dose inhaler delivering 17 µg/spray and as a 0.02% nebulized solution (500 µg/2.5 mL). Inhaled anticholinergics have very few adverse effects, although they occasionally trigger coughing.

Ipratropium given as a nasal spray (0.03-0.06%) has been shown to be effective in the reduction of rhinorrhea resulting from perennial nonallergic rhinitis, the common cold, and other triggers such as exposure to irritants or cold air. The use of ipratropium is limited in the treatment of moderate to severe allergic rhinitis because it does not alter other common allergic nasal symptoms, such as sneezing, nasal congestion, and pruritus. Nasal dryness and epistaxis are occasionally encountered with use of the nasal spray.

Antihistamines

The release of histamine and its effects on surrounding tissues is central to the development of symptoms classically associated with the allergic response. As a result, antihistamines are frequently used for the treatment of allergic disease. Histamine exerts its effects through binding with one of its four receptors, as H₁-, H₂-, H₃-, or H₄-receptor. Histamine effects triggered through H₁-receptor binding are those most relevant to allergic inflammation, and include pain, pruritus, vasodilation, increased vascular permeability, smooth muscle contraction, mucus production, and the stimulation of parasympathetic nerve endings and reflexes. The human H₁-receptor gene has been mapped to the distal short arm of chromosome 3. The antimuscarinic effect of some of the early H₁-type antihistamines may be explained by the reported 45% homology of the H₁-receptor with the human muscarinic receptor. The H₁-type antihistamines prevent the effects of H₁-receptor activation through reversible, competitive inhibition of histamine by binding to the H₁-receptor. As a result, antihistamines work best in preventing rather than reversing the actions of histamine and are most effective when given at doses and dosing intervals resulting in the persistent saturation of target organ tissue histamine receptors.

The H₁-type antihistamines are traditionally divided into six classes on the basis of differences in their chemical structures (Tables 136-2 and 137-2). These antihistamines are further divided into first-generation antihistamines, which, because of their lipophilicity, cross the blood-brain barrier to exert effects on the central nervous system, and second-generation antihistamines, which exert minimal, if any, central nervous system effects because of their inability to cross the blood-brain barrier owing to their size, charge, and lipophilicity. The sedative effects and cognitive impairment associated with the use of first-generation antihistamines are well documented. Thus, one of the primary advantages of second-generation antihistamines is that they are nonsedating or much less sedating than first-generation antihistamines. Both first- and second-generation antihistamines are available in oral preparations. A number of first-generation antihistamines are available over the counter, whereas loratadine and cetirizine are currently the second-generation antihistamines available without a prescription. Other first-generation and second-generation antihistamines require a prescription. The only antihistamines available as an intranasal spray are azelastine and olopatadine, which is also a mast cell stabilizer. The benefit of this form of administration is the potential for a rapid onset of action, within 15-30 min. Azelastine, which is systemically absorbed and can cross the blood-brain barrier, has central nervous system effects in some patients and is not currently approved for use in children <12 yr of age.

Table 136-2 CLASSIFICATION OF ANTIHISTAMINES (H₁-ANTAGONISTS)

CLASS	EXAMPLES
ETHYLENEDIAMINES
First-generation	Antazoline, pyrilamine, tripelennamine
TYPE II ETHANOLAMINES
First-generation	Carbinoxamine, clemastine, diphenhydramine
TYPE III ALKYLAMINES
First-generation	Brompheniramine, chlorpheniramine, triprolidine
Second-generation	Acrivastine
TYPE IV PIPERAZINES
First-generation	Cyclizine, hydroxyzine, meclizine
Second-generation	Cetirizine
TYPE V PIPERIDINES
First-generation	Azatadine, cyproheptadine
Second-generation	Fexofenadine, loratadine
TYPE VI PHENOTHIAZINES
First-generation	Methdilazine, promethazine

Orally administered antihistamines are well absorbed and reach peak serum concentrations within ∼2 hr. High tissue concentrations of antihistamines are usually achieved, likely accounting for the sustained suppression of wheal and flare reactions even after serum levels have significantly declined. Most antihistamines are metabolized by the hepatic cytochrome P450 enzyme system. Elimination of antihistamines may be reduced in patients with hepatic impairment or by the simultaneous ingestion of inhibitors of this pathway, such as erythromycin and other macrolide antibiotics, ciprofloxacin, ketoconazole, itraconazole, and certain antidepressants, such as nefazodone and fluvoxamine. Some antihistamines, such as hydroxyzine and loratadine, are converted to clinically active metabolites. Clearance of fexofenadine and cetirizine is reduced in patients with impaired renal function. Cetirizine clearance is also reduced in patients with hepatic dysfunction.

The efficacy of antihistamines in the treatment of seasonal and perennial allergic rhinoconjunctivitis is well documented (Chapter 137). Compared with other medications in regard to the relief of allergic nasal symptoms, antihistamines are more effective than cromolyn sodium but significantly less effective than intranasal corticosteroids. Improvement in symptom relief in patients with allergic rhinitis has been reported when an antihistamine is given in combination with a decongestant or with an intranasal steroid. Numerous formulations combining antihistamines and decongestants are available. Antihistamines have also been shown to be beneficial in the treatment of acute and chronic urticaria/angioedema. With regard to asthma, a significant clinical effect of antihistamines at conventional doses is difficult to document, other than the possible improvement offered by better control of allergic nasal symptoms.

The second-generation antihistamines are preferable for the treatment of allergic disease in children because of negligible sedative and anticholinergic effects in comparison with first-generation antihistamines without a sacrifice in efficacy. Most second-generation antihistamines are effective with once-daily dosing, which, because of the convenience, may improve therapy adherence. The widespread availability of first-generation antihistamines and their lower cost account for their continued use. The adverse effects most often encountered with second-generation agents include the performance impairment and anticholinergic effects noted with first-generation antihistamines. The anticholinergic adverse effects encountered may include drying of the mouth and eyes, urinary retention, constipation, excitation, nervousness, palpitations, and tachycardia. Prolongation of the QT interval and ventricular tachycardia (Torsades de pointes) were reported in association with the use of two second-generation antihistamines that have since been removed from the market; those currently in use have not been associated with concerning cardiac effects.

Chromones

Cromolyn sodium, the disodium salt of 1,3-bis (2-carboxychromon-5-yloxy)-2-hydroxypropane, and nedocromil sodium, a pyranoquinoline dicarboxylic acid, are the two chromones used to treat allergic disorders. Neither cromolyn nor nedocromil is absorbed well orally, with only 1% of the swallowed dose absorbed. Absorbed drug is not metabolized but is rapidly eliminated in approximately equal amounts by the kidneys and liver. These drugs must be applied topically to the mucosal surface of the target organ to be effective. Both drugs inhibit mast cell degranulation and mediator release. They suppress the activation of a variety of cells, such as eosinophils, neutrophils, macrophages, and epithelial cells. They also suppress the activity of afferent C-type sensory nerve fibers of the nonadrenergic, noncholinergic nervous system. Both drugs inhibit the intracellular increase in free calcium after mast cell activation and phosphorylate a mast cell protein resembling moesin, which is thought to be involved in terminating mediator release. Despite these findings, the molecular mechanism of action of these drugs remains to be completely defined.

Cromolyn and nedocromil prevent early- and late-phase allergic responses when administered before allergen exposure. They block allergen-induced increases in bronchial hyperresponsiveness as well as seasonal increases in nonspecific bronchial hyperresponsiveness. With prolonged use, both drugs are capable of reducing bronchial hyperresponsiveness. These drugs have no bronchodilator properties but can inhibit the bronchoconstrictive effects of a variety of stimuli, such as allergen challenge, exercise, hyperventilation with cold air, ultrasonically nebulized distilled water, and exposure to atmospheric and industrial pollutants.

Cromolyn and nedocromil are used as alternative, but not preferred, therapy for the treatment of mild persistent asthma. Because of their lack of bronchodilator properties, neither drug is useful for the treatment of acute asthma, although both may be used as preventive treatment before vigorous exercise or unavoidable known allergen exposure. Nedocromil is the more potent of the two. Cromolyn is available for the treatment of asthma by prescription as a 1% solution (20 mg/2 mL) for nebulization and in a metered-dose inhaler (800 µg/actuation). The suggested dose for the treatment of asthma is 20 mg of cromolyn 2 to 4 times/24 hr by nebulization or 1.6 mg 2 to 4 times/24 hr by metered-dose inhaler. In numerous studies, cromolyn has been found useful in the treatment of allergic rhinitis and allergic conjunctivitis. Preparations for the nasal and ocular administration of cromolyn are available without a prescription. The suggested dose for the treatment of allergic rhinitis is one spray in each nostril 3 to 4 times daily of a nasal spray containing 5.2 mg of cromolyn per spray (see Table 137-4). For the treatment of allergic conjunctivitis, the suggested dose is 1 drop in each eye 4 to 6 times a day of a 4% ophthalmic solution. Nedocromil is not available in a nebulized form but is available in a metered-dose inhaler. The recommended dose for the treatment of asthma is 3.5 mg (1.75 mg/puff) 2 to 4 times/24 hr. A 2% solution of nedocromil is available by prescription for the treatment of allergic conjunctivitis at a suggested dose of 1-2 drops in each eye twice daily.

The safety of these drugs, even with prolonged administration, is well documented. Dry throat and transient bronchoconstriction have been the most frequently reported adverse effects of cromolyn use for the treatment of asthma, with only rare reports of patients becoming sensitized to the drug. Some patients using nedocromil complain about its taste. Infrequently reported adverse effects of nedocromil include coughing, sore throat, rhinitis, headache, and nausea.

Glucocorticoids

Glucocorticoids are widely used in the treatment of allergic disorders because of their potent anti-inflammatory properties. The diverse anti-inflammatory actions of glucocorticoids are mediated via the glucocorticoid receptor, which is present in all inflammatory effector cells, as well as by direct inhibition of cytokines and mediators. Glucocorticoids are administered topically in ophthalmic preparations, nasal sprays, creams and ointments, metered-dose inhalers, and as a solution for nebulization. Systemic administration is accomplished orally or parenterally. The proper use and efficacy of glucocorticoids in the treatment of allergic disease along with the adverse effects associated with their use are presented in discussions of individual allergic diseases (Chapters 137–146).

Leukotriene-Modifying Agents

Drugs that alter the leukotriene pathway exert their clinical effects either by inhibiting leukotriene production or by blocking receptor binding. These agents possess mild anti-inflammatory properties and exhibit bronchodilator effects. In addition to inhibiting the early- and late-phase allergic responses to inhaled allergen, they diminish bronchoconstriction induced by exercise and exposure to allergen, aspirin, and cold air. These agents have some use in the treatment of asthma (Chapter 138) and are modestly effective in the treatment of allergic rhinitis (Chapter 137).

Theophylline

Because of its bronchodilating effects, theophylline (1,3-dimethyxanthine) has been used for years for the treatment of acute and chronic asthma. Nonspecific inhibition of phosphodiesterase isozymes and antagonism of adenosine receptors occur at achievable serum concentrations of the drug. The bronchodilator effect of theophylline is likely caused by its action as a phosphodiesterase inhibitor, whereas its ability to antagonize adenosine receptors may play a role in other effects, such as the attenuation of diaphragmatic muscle fatigue and diminishing adenosine-enhanced mast cell mediator release. Theophylline inhibits the immediate- and late-phase pulmonary responses to allergen challenge and exhibits modest protective effects. Selected anti-inflammatory and immunomodulatory effects of this drug are also documented. Theophylline is available by prescription as both rapidly absorbed and slow-release formulations. It is often administered intravenously when used for the treatment of severe acute asthma. The therapeutic and toxic effects of theophylline are related to the serum concentration, with the incidence of toxic effects significantly increasing as the serum levels approach and exceed 20 µg/mL. A variety of conditions and medications are capable of increasing or decreasing theophylline metabolism. The toxic effects of theophylline, ranging from mild nausea, insomnia, irritability, tremors, and headache to cardiac arrhythmias, seizures, and death, necessitate the routine monitoring of theophylline serum levels. Because of the introduction of other effective therapies for the treatment of acute and chronic asthma, the need to monitor drug serum levels routinely, and the potential for significant toxicity, the role of theophylline in the treatment of asthma has contracted significantly (Chapter 138).

Lodoxamide Tromethamine

A mast cell stabilizer, lodoxamide tromethamine is more effective than topical cromolyn sodium in alleviating signs and symptoms of allergic ocular disease (Chapter 141). It is used in children >2 yr of age for vernal keratoconjunctivitis, vernal conjunctivitis, and vernal keratitis. Occasional adverse effects have included transient burning or stinging after instillation.

Olopatadine Hydrochloride

Olopatadine hydrochloride is both a mast cell stabilizer and an H₁-receptor antagonist effective in relieving signs and symptoms of allergic conjunctivitis after topical instillation. It is labeled for use in children at least 3 yr of age. Headaches have occurred in 7% of patients treated; burning and stinging have occurred in <5%.

Anti–Immunoglobulin E

Monoclonal anti–immunoglobulin E antibodies (anti-IgE) bind to circulating IgE at a site that prevents its subsequent attachment to the high-affinity receptors for IgE on the mast cell surface. The parenteral administration of anti-IgE reduces free serum IgE concentrations, inhibits skin test responses in allergic patients, suppresses early- and late-phase responses to allergens, and decreases sputum eosinophilia in asthmatic persons. Anti-IgE has a beneficial effect in the treatment of patients with allergic rhinitis and asthma. An anti-IgE preparation (omalizumab) is available for the treatment of children ≥12 yr of age with documented allergen-induced asthma that is inadequately controlled by inhaled corticosteroids. Although this agent is usually well tolerated, local reactions at the injection site and rare episodes of anaphylaxis have been reported. Anti-IgE may also be beneficial in the treatment of other allergic disorders, such as anaphylaxis and food allergy. One monoclonal antibody preparation of anti-IgE used in the treatment of adults with peanut allergy resulted in a significant increase in the symptom threshold dose of peanuts. The cost of anti-IgE therapy requires careful patient selection, special consideration being given to those patients with persistent symptoms despite aggressive pharmacotherapy, significant adverse effects of current therapy, and more than one allergic disorder.

New Therapies

Several strategies for inhibiting the actions of proinflammatory cytokines are under investigation. Approaches include the use of recombinant soluble receptors that attach to a specific cytokine and inhibit subsequent binding to cell surface receptors, the development of specific cytokine receptor antagonists, and the administration of humanized monoclonal anti-cytokine antibodies. Recombinant soluble interleukin-4 (IL-4) receptor antagonists exert their effects by binding to and inactivating IL-4 before it can attach to its cell surface receptor. Although initial studies of an inhaled soluble IL-4 receptor in patients with moderate asthma requiring inhaled corticosteroids suggested a beneficial clinical effect, subsequent clinical studies of the effects of anti–IL-4 drugs in the treatment of asthma revealed these therapies to be safe, but clinical efficacy was lacking. Clinical trials of humanized monoclonal anti–IL-5 antibodies administered by injection to asthmatic patients revealed a decrease in circulating eosinophils and sputum eosinophilia, but a lesser reduction of eosinophils from the bronchial submucosa, and this effect was unaccompanied by a reduction in methacholine reactivity or a suppression of the early- or late-phase response to allergen.

The use of cytokines with anti-inflammatory effects in the treatment of allergic disorders is under investigation. Unfortunately, initial studies have not demonstrated a beneficial effect of IL-10 or interferons in the treatment of asthma. Although studies have documented that IL-12 administration is associated with a decrease in eosinophil accumulation in response to allergen challenge, inhibition of early- and late-phase responses to allergen and decreases in bronchial hyperreactivity have not been observed. In addition, the high incidence of significant adverse effects encountered with IL-12 administration limits its potential as a viable therapeutic option.

Allergen Immunotherapy

Allergen immunotherapy involves administering gradually increasing doses of allergens to a person with allergic disease for the purpose of reducing or eliminating the patient’s adverse clinical response to subsequent natural exposure to those allergens. When properly administered to an appropriate candidate, allergen immunotherapy is a safe, effective form of therapy capable not only of reducing or preventing symptoms but also of potentially altering the natural history of the disease by minimizing disease duration and preventing disease progression. Conventional allergen immunotherapy is given subcutaneously under the direction of an experienced allergist.

Indications and Contraindications

Allergen immunotherapy is reserved for patients with an allergic disease demonstrated to respond to this form of therapy, such as seasonal or perennial allergic rhinoconjunctivitis, asthma triggered by allergen exposures, and insect venom sensitivity. Proof of the efficacy of conventional allergen immunotherapy for the treatment of food allergy, atopic dermatitis, latex allergy, and acute or chronic urticaria is lacking and, therefore, allergen immunotherapy is not recommended for the treatment of these disorders. Before allergen immunotherapy is considered, sensitivity of the patient to the allergens to be administered should be documented by a positive skin test result or an in vitro test revealing an increased serum level of allergen-specific IgE. The clinical relevance of these allergens should be supported by a history of symptoms upon known exposure or a timing of symptoms that correlates well with suspected allergen exposure, such as the presence of allergic nasal and ocular symptoms throughout the late summer and fall in a child with a large positive ragweed skin test response. The duration and severity of the patient’s symptoms should warrant the expense, effort, and risk associated with the administration of allergen immunotherapy. The presence of disabling symptoms in spite of a trial of allergen avoidance and appropriate medications at a suitable dose should be documented. For patients sensitized to seasonal allergens, more than two consecutive seasons of symptoms are usually required before allergen immunotherapy is recommended, unless the symptoms are unusually severe or the adverse effects of medication are unacceptable. The obvious exception to this rule is the child with insect sting anaphylaxis, who should be started on venom immunotherapy once the sensitivity is correctly diagnosed (Chapter 140).

Other factors that may affect the decision to institute allergen immunotherapy include quality of life issues, such as the amount of school missed or medical resource utilization, the age of the patient, and other logistical factors. With the exception of venom immunotherapy, few data for the efficacy of allergen immunotherapy in children <5 yr of age are available. Allergen immunotherapy is not recommended for children <5 yr of age because of their increased risk of systemic reactions, the special expertise required to treat anaphylaxis in this age group, their potential inability to communicate clearly with the physician in the event of an allergic reaction, and their age-related potential for emotional distress with frequent injections. Other important logistic factors include the willingness of the patient to comply with a schedule of frequent injections over the course of several years, cost considerations, and the availability of an appropriate setting for administering allergen immunotherapy.

Allergen immunotherapy is contraindicated in children undergoing β-blocker therapy as well as those with certain immunologic or autoimmune disorders, allergic bronchopulmonary aspergillosis, hypersensitivity pneumonitis, severe psychiatric disturbance, or a medical condition that would impair the ability to survive an allergic reaction. Pregnancy is a contraindication to the initiation of allergen immunotherapy or dosing increases, although a pregnant adolescent can continue to receive her usual maintenance dose. Patients with unstable asthma should not be started on allergen immunotherapy because of their increased risk for fatal anaphylaxis. Allergen immunotherapy is not used for the treatment of allergic bronchopulmonary aspergillosis or hypersensitivity pneumonitis because it has no benefit. Children receiving β-blockers should be switched to another form of therapy before allergen immunotherapy is considered, because of an increased intensity of allergic reactions and a poor response of conventional therapy to these reactions with β-blocker therapy. Allergen immunotherapy is usually avoided in patients with autoimmune disorders because of the potential for unanticipated stimulation of the immune system, which might result in disease activation.

Allergen Extracts

The potency of the aqueous extracts used in allergen immunotherapy is affected by numerous factors. Allergens from weed and grass pollens are more easily extracted in aqueous solutions and, as a result, are more potent than extracts obtained from other sources, such as molds, tree pollens, and dust mites. Owing to their complexity, allergen extracts from fungal allergens are more variable than extracts from pollen allergens. Refrigeration and appropriate handling of allergen extracts used in allergen immunotherapy are important, because degradation of many allergen extracts, such as those from tree, grass, and weed pollens and dust mites, may occur at higher temperatures. Dilute extracts are more susceptible to loss of potency resulting from adherence of allergen to the glass vial than are more concentrated extracts. To combat this effect, human serum albumin is sometimes added to dilute allergen extracts. Some allergen extracts, such as those from cockroaches, dust mites, and fungi, contain proteases capable of degrading other allergens in the extract. As a result, it is often recommended that these allergens not be mixed with those from tree, grass, and weed pollens. Insect venoms are never mixed with other allergens. When available, the use of standardized allergen extracts is preferred to ensure consistency in dosing and to avoid the variability in allergen content encountered with nonstandardized allergen extracts.

Allergen Extract Administration

The goal of allergen immunotherapy is to increase gradually the dose of allergen extract administered until the injection of an “optimal” maintenance dose containing 4-12 µg of each major allergen in the extract is reached. The mixture of allergen extracts administered during the course of allergen immunotherapy is individually formulated for each patient on the basis of his or her documented sensitivities. Although various dosing schedules are used, initial injections are most often given at 5- to 10-day intervals year-round. Schedules of allergen administration are selected according to the sensitivity of the patient to the allergens in the extract. The most sensitive patients are advanced to a maintenance dose more gradually. Doses of allergen immunotherapy are increased according to a set schedule, although the reaction to the previous injection is also taken into account. A systemic reaction to the previous dose would result in a significant reduction in the next dose, whereas reducing the dose solely on the basis of a local reaction does not reduce the rate of systemic reactions. Usually 5-6 mo of weekly injections is required to reach the maintenance dose, although it may take longer in patients with marked sensitivity. Unique schedules for the administration of insect venoms, which differ from those for the administration of other allergens (Chapter 140), are used. Once the maintenance dose is reached and well tolerated, the interval between injections is increased to a few weeks or a month. Because allergen extracts gradually lose potency, the first dose from a fresh replacement vial of maintenance allergen extract is reduced by 25-75% and is then increased in increments weekly until the usual maintenance dose is reached. The recommended length for a course of allergen immunotherapy is 3-5 yr. Insect venom immunotherapy may be continued longer in patients with a history of life-threatening anaphylaxis. Patients who have not shown improvement after 1 yr of receiving maintenance doses of an appropriate allergen extract are unlikely to benefit, and their allergen immunotherapy should be discontinued. Most patients enjoy a sustained improvement after allergen immunotherapy, whereas others experience a gradual return of symptoms. Those who experience a relapse may have response to another course of treatment.

Rush immunotherapy is the administration of multiple injections either in a single day or over several days in an attempt to reach maintenance dose more rapidly. The risk of adverse reactions, including systemic reactions, is higher than with traditional allergen immunotherapy schedules. Patients to undergo rush immunotherapy are often pretreated with antihistamines and corticosteroids. Children are at even greater risk for adverse reactions with rush immunotherapy, so the benefits and risks should be fully considered. Pre-administration of omalizumab has been shown to reduce the incidence of systemic reactions associated with the use of this form of immunotherapy.

Although allergen immunotherapy is regarded as safe, the potential for anaphylaxis always exists when patients are injected with extracts containing allergens to which they are sensitized. Allergen immunotherapy should be offered in only medical settings where a physician with access to emergency equipment and medications required for the treatment of anaphylaxis is available (Chapter 143). Allergy shots should never be given at home or by untrained personnel. The patient should remain in the office for 30 min after the injection because most reactions to allergen immunotherapy begin within this time frame. Fatal anaphylaxis triggered by allergen immunotherapy, although rare, is estimated to occur at an incidence of 1 per 2 million injections. The risk of an adverse reaction is increased by dosage errors and the use of rush immunotherapy schedules. Particular caution is warranted when injections from a new vial are given. Patients with exquisite sensitivity or unstable asthma and those experiencing exacerbations of allergic rhinitis or asthma are also at increased risk for adverse reactions to allergen immunotherapy. Precautions to reduce significant adverse reactions include using standardized extracts, allowing only trained personnel to administer injections, paying careful attention to detail when giving injections, ensuring beforehand that the patient is medically stable, having appropriate medications and equipment available, and requiring the patient to remain in the office for 30 min after each injection. Checking peak flow or spirometry values before an injection is advisable for some asthmatic patients.

A desire to decrease the likelihood of allergic reactions induced by the administration of aqueous allergens led to the development of alum-precipitated extracts, in which the proteins are precipitated with aluminum hydroxide and alum-precipitated, pyridine-extracted extracts. Because of the smaller number of available extracts, the use of this type of extract remains limited. Another method developed to reduce allergenicity while maintaining immunogenicity is the polymerization of allergen extracts with glutaraldehyde. When polymerized extracts are used, the maintenance dose can be reached within 2 mo with a markedly reduced incidence of systemic reactions. Polymerized allergen extracts have not yet been approved for use in the USA. Other approaches to immunotherapy are under investigation; they include chemical or genetic manipulation of the allergen and linking of the principle allergenic moiety of a relevant allergen to a highly active adjuvant, such as an immunostimulatory sequence mimicking patterns of bacterial DNA.

Local nasal immunotherapy is administered by having the patient spray allergen solutions into the nose at scheduled intervals. Although symptom amelioration has been noted, a lack of a significant systemic immunologic response has decreased interest in pursuing this form of therapy. Sublingual immunotherapy (SLIT) involves the sublingual administration of high-dose allergen, which is then swallowed. The use of SLIT is expected to increase significantly because of its favorable safety profile and convenience of administration.