J. Russell May and Philip H. Smith
KEY CONCEPTS
Allergic rhinitis is a common disease. Prevention measures and treatment are justified in most cases because of the potential for complications.
Because an immune response to allergens results in release of inflammatory mediators that cause allergic rhinitis symptoms, patients must understand the rationale for proper timing and administration of prophylactic regimens.
Avoidance of allergens is difficult and it may be impractical to expect full success.
Antihistamines offer an effective option for treating both seasonal and persistent allergic rhinitis.
Intranasal steroids are highly effective in patients who use them properly.
While immunotherapy is the only disease-modifying treatment of allergic rhinitis, expense, potential risks, and the major time commitment required make patient selection critical.
Allergic rhinitis involves inflammation of the nasal mucous membrane. In a sensitized individual, allergic rhinitis occurs when inhaled allergenic particles contact mucous membranes and elicit a specific response mediated by immunoglobulin E (IgE). This acute response involves the release of inflammatory mediators and is characterized by sneezing, nasal itching, and watery rhinorrhea, often associated with nasal congestion. Itching of the throat, eyes, and ears frequently accompanies allergic rhinitis.
Allergic rhinitis may be regarded as seasonal allergic rhinitis, commonly known as hay fever, or persistent allergic rhinitis (formerly known as perennial rhinitis). Seasonal rhinitis occurs in response to specific allergens usually present at predictable times of the year, during plants’ pollination (typically the spring or fall). Seasonal allergens include pollen from trees, grasses, and weeds. Persistent allergic rhinitis is a year-round disease caused by nonseasonal allergens, such as house dust mites, animal dander, and molds, or multiple allergic sensitivities. It typically results in less variable, chronic symptoms. Many patients have a combination of these two types of allergic rhinitis, with symptoms year-round and seasonal exacerbations.
EPIDEMIOLOGY
Allergic rhinitis is one of the most common medical disorders found in humans, affecting 400 million people worldwide.1 It is the second leading cause of chronic disease in the United States, affecting one person in every four households.2 In the populations of Europe, United States, Australia, and New Zealand, the prevalence of an IgE sensitization to aeroallergens measured by allergen-specific IgE in serum or skin tests is more than 40% to 50%.3Patients may be limited in their ability to carry out normal daily functions; higher levels of general fatigue, mental fatigue, anxiety, depressive disorders, and learning disabilities (secondary to sleep loss and fatigue) are possible.
In addition, the impact of allergic rhinitis goes well beyond these CNS issues. Allergic rhinitis is associated with several other serious medical conditions, including asthma, chronic rhinosinusitis, otitis media, nasal polyposis, respiratory infections, and orthodontic malocclusions.
ETIOLOGY
The development of allergic rhinitis is determined by genetics, allergen exposure, and the presence of other risk factors. A family history of allergic rhinitis, atopic dermatitis, or asthma suggests that rhinitis is allergic. The risk of developing allergic disease appears to increase if one parent is atopic and further increases if two are allergic; however, small sample sizes and the lack of reproducibility prevent generalization.3
Allergen exposure is another necessary factor. For allergic rhinitis to occur, an individual must be exposed over time to a protein that elicits the allergic response in that individual. Many potential sufferers never develop symptoms because they do not come into contact with the allergen that would produce symptoms in them.
Evidence suggests microbial exposure in the first years of life could help prevent allergic disease by stimulating a nonatopic immune response.4 Farm children are exposed to higher concentrations of endotoxin, derived from cell walls of gram-negative bacteria, in barns and dust around the farmhouse. Consumption of nonpasteurized farm milk may cause further exposure. These observations have led to the idea that allergic disease could be prevented by proactively increasing exposure to harmless bacteria early in life (see Alternative Treatment Options below). This could explain why positive skin tests indicating allergen sensitization have been observed more frequently for people in higher socioeconomic classes and for people who live in suburban areas.
Other predisposing factors include an elevated serum IgE (>100 international units/mL [>100 kIU/L]) before the age of 6 years, eczema, and heavy exposure to secondhand cigarette smoke.5
Allergens
Allergens that produce seasonal rhinitis include protein components of airborne pollen grains, often enzymes, from a variety of trees, grasses, and weeds. Ragweed and grass pollen are the most common offenders in the United States; however, this varies with the geographic region. In general, tree pollens cause symptoms in the spring, grass pollens cause symptoms in the late spring and summer, and weed pollens are the culprits from late summer through fall. Patients who are hypersensitive to all three may have overlapping problem periods and may be described as having perennial rhinitis when they are actually experiencing prolonged seasonal rhinitis. For this reason and the fact that most patients with seasonal problems are sensitive to at least some of the perennial allergens, there is little practical difference between the two types of allergic rhinitis. To complicate matters further, the antigenic components of many grasses—including fescue, Kentucky bluegrass, orchard, redtop, and timothy—cross-react extensively. By contrast, most tree allergens are antigenically distinct. Trees with allergenic pollen include ash, beech, birch, cedar, hickory, maple, oak, poplar, and sycamore. Flowering plants that depend on insect pollination do not cause allergic rhinitis because their pollen is too heavy and sticky and is not carried in the air.
Smaller mold spores are also important but cause allergy much less frequently. Various spores are present year-round; however, mold growth on decaying vegetation increases seasonally. Just walking through uncut fields or raking leaves can increase exposure. Thus, mold spores can be responsible for both perennial and seasonal allergies.
Indoor allergens are always present. Most important among these are house-dust mite fecal proteins, animal dander, cockroaches, and certain mold species. Dust mite levels are on the rise, possibly because of the construction of energy-efficient homes and offices with reduced ventilation and increased humidity, use of wall-to-wall carpeting, and the popularity of cool-water detergents and cold-water washing.3
PATHOPHYSIOLOGY
Knowledge of nasal physiology aids in the understanding of allergic rhinitis. The nose performs three “air conditioning” functions to prepare incoming gases for the lungs. During the fraction of a second that air is in the nose, it is heated, humidified, and cleaned. The cleaning process plays a role in the development of allergic rhinitis. As the air passes through the nose, the turbulence throws particulate matter against a mucous blanket. The rhythmic movements of the nasal cilia cause the mucous blanket to move posteriorly at approximately 9 mm/min, where it is eventually swallowed; thus, trapped foreign particles are removed via the GI tract and do not reach the lungs. It also concentrates foreign protein material into the posterior nasopharynx, where lymph tissues identify them and produce most of the allergic antibody that drives allergic rhinitis.
The vascular tissue in the nose is erectile. Stimulation of sympathetic fibers causes vasoconstriction, reduction in erectile tissue size and the size of the membranes and turbinates, and airway widening. Parasympathetic stimulation causes opposite effects.
Mast cells, in the nasal membranes, participate in the regulation of nasal patency by releasing mediators such as histamine. These are described below.
Immune Response to Allergens
Allergic reactions in the nose are mediated by antigen–antibody responses when allergens interact with specific IgE molecules bound to nasal mast cells and basophils. In allergic people, these cells are increased in both number and reactivity. During inhalation, airborne allergens enter the nose and are processed by lymphocytes, which produce antigen-specific IgE, thereby sensitizing genetically predisposed hosts to those agents. Upon nasal reexposure, IgE bound to mast cells interacts with airborne allergen, triggering release of inflammatory mediators in vastly increased quantities (Fig. 76–1).6
FIGURE 76-1 Allergen sensitization and the allergic response. A. Exposure to antigen stimulates IgE production and sensitization of mast cells with antigen-specific IgE antibodies. B. Subsequent exposure to the same antigen produces an allergic reaction when mast cell mediators are released.
Both immediate and late-phase reactions are observed after allergen exposure. The immediate reaction occurs within seconds to minutes, resulting in the rapid release of preformed mediators and newly generated mediators from the arachidonic acid cascade as the mast cell membrane is disturbed (Table 76–1). These mediators of immediate hypersensitivity include histamine, some leukotrienes, prostaglandin D2, tryptase, and kinins.6 In addition, the mast cell has been found to be a source of several cytokines that probably are relevant to the chronicity of the mucosal inflammation that characterizes allergic rhinitis.7 Sensory nerve stimulation produces itching, and sneezing occurs via reflex stimulation of efferent vagal pathways. Neuropeptides substance P and calcitonin gene-related peptide from nonadrenergic, noncholinergic nerves affect vascular engorgement directly and via modulation of sympathetic tone. Histamine produces rhinorrhea, itching, sneezing, and obstruction, with the obstruction only partially blocked by H1- or H2-blocking agents.8 Nasal obstruction is also caused by kinins, prostaglandin D2, and leukotrienes C4/D4. Kinins, when directly administered, produce pain rather than itching.9 These inflammatory mediators also produce vasodilation, increased vascular permeability, and production of increased nasal secretions.10
TABLE 76-1 Mast Cell Mediators
Four to 8 hours after the initial exposure to an allergen, a late-phase reaction occurs symptomatically in 50% of allergic rhinitis patients.11 This response, thought to be caused by cytokines released primarily by mast cells and thymus-derived helper lymphocytes, is characterized by profound infiltration and activation of migrating cells. This inflammatory response likely is responsible for the persistent, chronic symptoms of allergic rhinitis, including nasal congestion. The inflamed mucosa becomes hyperresponsive, a state characterized by exacerbation of nasal reactions to non-specific or irritant triggers. In this state, the patient also reacts to increasingly lower amounts of the same allergen.12 The process also causes significant increases in non-specific irritability (as seen in asthma) and the notion among patients that they have become “allergic to everything.”
CLINICAL PRESENTATION
The patient with allergic rhinitis typically complains of clear rhinorrhea, paroxysms of sneezing, nasal congestion, postnasal drip, and pruritic eyes, ears, nose, or palate. Symptoms of allergic conjunctivitis are associated more frequently with seasonal than perennial allergic rhinitis, because a majority of the perennial allergens, such as dust mites and molds, are indoors, where air velocity is too low for substantial deposition of allergenic particles on the conjunctivae. However, with heavy exposure from animal or mold allergens, allergic conjunctivitis can be pronounced.
Symptoms secondary to the late-phase reaction, predominantly nasal congestion, begin 3 to 5 hours after antigen exposure and peak at 12 to 24 hours. Subsequent symptoms, both allergic and irritant, are elicited more easily because of the priming effect. For instance, a ragweed-sensitive patient, when exposed to ragweed pollen out of season, responds with modest symptoms and may be very tolerant of irritants such as air pollution or tobacco smoke. During the ragweed season, however, when the nasal mucosa is already inflamed, exposure to small doses of pollen or to irritants to which the patient is usually tolerant elicits a response clinically indistinguishable from the patient’s allergy.
Diagnostic Considerations
Allergic rhinitis is distinguished from other causes of rhinitis by a thorough history, physical examination, and certain diagnostic tests. The medical history consists of a careful description of symptoms, environmental factors and exposures, results of previous therapy, use of other medications, previous nasal injuries, previous nasal or sinus surgery, family history, and the presence of other medical problems and medications. Historical identification of specific causative allergens may be difficult. For example, a reaction induced by mowing the lawn may not be caused by grass pollens but may be caused by the disturbance of various weeds, molds, or other plants in the lawn. With perennial allergic rhinitis, the cause–effect and temporal relationships are less clear, making the diagnosis of specific causes more difficult, especially with such covert allergens as house dust mites and molds.
In children, physical examination may reveal allergic shiners—a transverse nasal crease caused by repeated rubbing of the nose—and adenoidal breathing. Pale, bluish, edematous nasal turbinates coated with thin, clear secretions are characteristic of a purely allergic reaction. Tearing, conjunctival injection and edema, and periorbital swelling may be present. Physical findings are generally less clear-cut for adults.
Nasal scrapings will provide a representative sample of cells infiltrating the nasal mucosa and can be helpful in supporting the diagnosis.13 Microscopic examination of the nasal smear from an allergic individual typically will show numerous eosinophils. The blood eosinophil count may be elevated in allergic rhinitis, but it is nonspecific and has limited usefulness.14
Allergy testing can help determine whether a patient’s rhinitis is caused by an allergen. Immediate-type hypersensitivity skin tests are used for the diagnosis of allergic rhinitis. These include skin tests performed by the percutaneous route, where the diluted allergen is pricked or scratched into the skin surface, or by the intradermal route, where a small volume (0.01 to 0.05 mL) of diluted allergen is injected between the layers of skin. Percutaneous tests are more commonly performed and are safer and more generally accepted, with intradermal tests reserved for patients requiring confirmation in special circumstances.
In all allergy testing, a positive control (histamine) and a negative control are essential for correct interpretation. After 15 minutes of the application of the allergen, the site is examined for a positive reaction (defined as a wheal-and-flare reaction). Because correct testing is done with extremely minute doses, undetectable by nonsensitized individuals, this reaction is evidence of the presence of mast cell-bound IgE specific to the allergen tested. Many, but not all, common allergens are available as standardized allergenic extracts.
Antihistamines and a few other medications interfere with the wheal-and-flare reaction. First-generation antihistamines should be stopped at least 3 to 5 days before testing, and second-generation, nonsedating antihistamines should be stopped for 10 days before testing.15 Medications with antihistamine properties (e.g., sympathomimetic agents, phenothiazines, and tricyclic antidepressants) should be discontinued if possible before skin testing.
The radioallergosorbent test (RAST) was the first commonly used method for detecting IgE antibodies in the blood that are specific for a given allergen. Several other quantitative assays that include a reference curve calculated against standardized IgE are available. These tests are highly specific but may be slightly less sensitive than percutaneous tests.
Complications
Not only is allergic rhinitis aggravating, it frequently leads to further complications, particularly if the patient does not receive adequate treatment. Symptoms of untreated rhinitis may lead to disturbed sleep, chronic malaise, fatigue, and poor work or school performance. Patients often are plagued by loss of smell or taste, with sinusitis or polyps underlying many cases of allergy-related hyposmia. Postnasal drip with cough, hoarseness, and even vocal polyps also can be bothersome.
The role of allergic rhinitis in the development of acute otitis media or chronic middle ear effusion is often less clear. Children with allergic rhinitis appear to be at greater risk of these conditions because of nasal obstruction and negative middle ear pressure. Hearing problems in children related to middle ear effusion may lead to delayed development of language in young children or to school problems in older children.
Permanent facial disfigurement can result from chronic allergic rhinitis.16 The chronic edema and venous stasis may contribute to the development of a high-arched, V-shaped palate. Mouth breathing caused by nasal obstruction can be responsible for dental malocclusion and orthodontic problems. Constant upward rubbing of the nose (allergic salute) can cause a transverse crease across the lower nose; nasal congestion often leads to venous pooling and dark circles under the eyes known as allergic shiners.
Allergic rhinitis is clearly associated with asthma. The prevalence of asthma in patients without rhinitis is <2%, while the prevalence of asthma in patients with rhinitis is 10% to 40%.17 It is not known if allergic rhinitis is an early clinical manifestation of asthma or if the nasal disease itself is causative for asthma.
Recurrent sinusitis and chronic sinusitis are relatively common complications of allergic rhinitis. The structure of the mucus blanket breaks down, with decreased water production by serous glands, leaving hair cells trapped in the thicker mucus layer. This greatly reduces the clearance of trapped bacteria and offers ideal breeding grounds for the bacteria. Nasal polyps are less common but nonetheless bothersome; they require specific therapy but may improve with management of the underlying allergic state. Epistaxis also can be a problem; it is related to mucosal hyperemia and inflammation.
TREATMENT
A number of options exist for the treatment of allergic rhinitis, both nonpharmacologic and pharmacologic. Many of the pharmacologic options are available over-the-counter requiring that patients receive guidance in the selection process by a healthcare professional to obtain the most appropriate therapy. Both over-the-counter and prescription choices must be guided by patient-specific symptomatology and patient characteristics as described in this chapter.
Desired Outcomes
The therapeutic goal for patients with allergic rhinitis is to minimize or prevent symptoms and prevent long-term complications. This goal should be accomplished with no or minimal adverse medication effects and reasonable medication expenses. The patient should be able to maintain a normal lifestyle, including participating in outdoor activities, yard work, and playing with pets as desired.
General Approach to Treatment
Once the causative allergens and the specific symptoms are identified, management consists of three possible approaches: (a) allergen avoidance, (b) pharmacotherapy for prevention or treatment of symptoms, and (c) specific immunotherapy. The pharmacotherapy for symptoms approach includes several options that are based on patient-specific information (Table 76–2). Figure 76–2 depicts an algorithm for treatment options.
TABLE 76-2 Pharmacotherapeutic Options for Allergic Rhinitis
FIGURE 76-2 Treatment algorithm for allergic rhinitis.
Nonpharmacologic Therapy
Avoidance of offending allergens is the most direct method of preventing allergic rhinitis, but it is often the most difficult to accomplish, especially for perennial allergens. Mold growth can be reduced by maintaining household humidity below 50% and removing obvious growth with bleach or disinfectant. Patients sensitive to animals will benefit most by removing pets from the home18; however, most animal lovers are reluctant to comply with this approach. Dog and cat allergens may produce symptoms in sensitized individuals.7 After removing a cat from the home, it may take as long as 20 weeks for the home to reach allergen levels of a pet-free home. Washing cats weekly may reduce allergens but studies are inconclusive.7 Some dogs display antigens more profusely than do others; clinically, a sensitized person may tolerate one animal better than another.
Evidence to support avoidance measures for house dust mites suggests that accepted notions for reducing exposure have little practical effect.18 While some evidence shows allergen levels can be reduced by washing bedding on a hot cycle, replacing carpets with hard flooring and using vacuum cleaners with HEPA filters, there is no documented evidence for a clinical benefit. Only encasing bedding in impermeable covers has some clinical benefit in children but not adults. Future studies are needed to determine if environmental control of allergens may be helpful in forestalling further rhinitis and preventing later asthma.
General recommendations have been made to prevent poor air quality in homes.19 Steps include avoiding wall-to-wall carpeting, using moisture control to prevent the accumulation of molds, and controlling sources of pollution such as cigarette smoke. Patients with seasonal allergic rhinitis should keep windows closed and minimize time spent outdoors during pollen seasons. Immediate hair washing and change of clothes are recommended upon returning indoors. Use of fans that direct outside air into the house should be avoided. Filter masks can be worn while gardening or mowing the lawn. Avoidance of upholstery and stuffed toys in the bedroom are easy steps to accomplish. Table 76–3 summarizes recommendations for environmental control. While these steps are logical, there is little existing evidence that environmental control measures provide clinical benefit. These measures are intended to be a part of a comprehensive treatment strategy that will likely include pharmacotherapy and, in selected cases, immunotherapy.
TABLE 76-3 Environmental Controls to Prevent Allergic Rhinitis
Other suggested measures for preventing allergic rhinitis include breastfeeding infants and avoidance of exposure to tobacco smoke.18 Exclusive breastfeeding for the first 3 months of life may help prevent allergies. Avoidance of environmental tobacco smoke (i.e., passive smoking) by children and pregnant woman may also reduce the development of allergies and has been strongly recommended. However, the evidence for both these recommendations is minimal.
Pharmacologic Therapy
First-line therapeutic modalities for treating allergic rhinitis are directed at relief of symptoms (see Table 76–2). Antihistamines and decongestants (both oral and topical) generally are used first in treating allergic rhinitis with medications. Several options in these two categories are available without a prescription, but patients will need sound advice to make appropriate choices. Knowledge of pathophysiology and the inflammatory state has led to prophylactic therapy for those with more severe disease using agents such as cromolyn and topical steroids. However, in attempting to assess the evidence supporting any particular therapy, clinicians have difficulty interpreting the medical literature for a variety of reasons, including lack of uniformity in the research methodologies, inappropriate drug controls, and failure to identify types of rhinitis in study subjects (perennial vs. seasonal and allergic vs. nonallergic).
Antihistamines
Histamine (H1)-receptor antagonists are competitive antagonists to histamine. They bind to H1 receptors without activating them, preventing histamine binding and action. Second-generation antihistamines may also affect components of the inflammatory response such as histamine release, generation of adhesion molecules, and influx of inflammatory cells. Although it was once thought that the older antihistamines had no antiinflammatory action, some were shown to have these effects as early as the 1950s.20 Antihistamines are available in oral, ophthalmic, and intranasal dosage forms.
The oral antihistamines are the most commonly used and can be divided into two major categories: nonselective (first generation) and peripherally selective (second generation). Nonselective agents are commonly referred to as sedating antihistamines, and peripherally selective agents are referred to as nonsedating antihistamines. These generalizing terms can be misleading. Individual agents should be judged on their specific characteristics because variation within these broad categories exists. Also, the nonsedating claim is only valid when the agents are used at recommended doses.21 This is of particular concern as some of these antihistamines are available without a prescription. The mechanism for sedation is not well understood, but its central effect depends on the drugs’ ability to cross the blood–brain barrier. Most older antihistamines are lipid soluble and cross this barrier easily. The peripherally selective agents have little or no central or autonomic nervous system effects. Table 76–4 lists common antihistamines, their chemical classifications, their relative potential for causing sedation, and their relative anticholinergic effects.
TABLE 76-4 Relative Adverse-Effect Profiles of Antihistamines
Antihistamines are much more effective in preventing the actions of histamines and essentially do not reverse these actions once they have taken place. Reversal of symptoms is largely caused by the anticholinergic properties of these drugs. This activity is responsible for the drying effect of antihistamines, which reduces the problem of nasal, salivary, and lacrimal gland hypersecretion. Antihistamines antagonize increased capillary permeability, wheal-and-flare formation, and itching.
In general, the antihistamines are well absorbed, have large volumes of distribution, and are metabolized by the liver. Serum half-lives vary considerably between patients. In addition, the therapeutic effects of these agents are more prolonged than might be predicted by their half-lives.
Drowsiness is usually the chief complaint of patients who take antihistamines. It can interfere with a patient’s ability to drive a car or operate machinery and may interfere with the patient’s ability to function adequately at the workplace. Remember that these problems can also be a reflection of the disease itself. For this reason, many recommend the use of peripherally selective agents as first-line treatment for any patient who is at high risk for the development of adverse events. This includes patients with renal or hepatic impairment, those with small weights (for whom adult doses may provide larger-than-recommended doses on a milligram-per-kilogram basis), patients with preexisting CNS or cardiac disorders, patients who require higher doses, and patients who have shown a tendency to overuse nonprescription or prescription medications.20
The sedative effects of antihistamines can be useful for patients who suffer from sleeplessness caused by the symptoms of allergic rhinitis. In these patients, a bedtime dose may prove beneficial. However, they may cause residual daytime sedation, decreased alertness, and performance impairment.
The logic of preferentially using the second-generation agents is not clear-cut. A meta-analysis of performance-impairment trials did not show a clear and consistent distinction between diphenhydramine and the peripherally selective agents.22 Another study showed that tolerance to sedation secondary to diphenhydramine developed by day 4 of treatment, becoming indistinguishable from placebo,23 but sedation must be distinguished from impairment since the two are not equivalent. Despite this evidence, recent guidelines recommend the nonsedating agents.18
Anticholinergic (drying) effects contribute to the agents’ therapeutic efficacy, but they also cause most adverse effects. Dry mouth, difficulty in voiding urine, constipation, and potential cardiovascular effects may be troublesome. Keep in mind that the differences may be small. Patients with a predisposition to urinary retention (e.g., older men and those on concurrent anticholinergic therapy) should use antihistamines with caution. Caution also should be used for patients with increased intraocular pressure, hyperthyroidism, and cardiovascular disease.
Other adverse effects of oral antihistamines include loss of appetite (and paradoxically, weight gain with increased appetite), nausea, vomiting, and epigastric distress.
Antihistamines are only fully effective when taken approximately 1 to 2 hours before anticipated exposure to the offending allergen. This must be discussed with patients who face exposure daily during a pollen season and with those who have indoor perennial allergens where daily scheduled use is necessary. If tolerance develops to the therapeutic effect, a change to an agent in a different chemical class is usually effective.
Patients should be counseled about the proper use of antihistamines. Adverse effects, especially drowsiness, should be emphasized. Patients should be warned against taking other CNS depressants, including the use of alcohol. Patients should be told not to take a double dose when a dose is missed. Taking the antihistamine with meals or at least a full glass of water will help prevent GI adverse effects such as nausea, vomiting, and epigastric distress. Patients should check with their healthcare professional and read labels before taking nonprescription medications. Many cold products and sleep aids contain antihistamines. Patients should be instructed not to use more than one antihistamine at a time. Table 76–5 lists the recommended dosages of the commonly used agents with their prescription status.
TABLE 76-5 Medication Dosing for Allergic Rhinitis
Many patients respond to and tolerate the older agents quite well. Because many of the older agents are available generically, they are much less expensive. Patient cost for many of the older nonprescription agents is less than $5 for a 30-day supply, compared with more than $20 for some of the nonprescription selective agents and more than $70 dollars for the selective prescription-only products. Although cost is a concern, patient safety should be the first consideration.
The selective agents have moved ahead of the nonselective choices in a recent survey of pharmacist recommended over-the-counter antihistamines.24 Among the 2 million antihistamine recommendations, the top three were loratadine (41%), cetirizine (33%), and fexofenadine (15%) followed by the nonselective agents diphenhydramine (9%) and chlorpheniramine (2%).
For seasonal and persistent allergic rhinitis, the intranasal antihistamine azelastine is available. The 0.1% product can be used in children for seasonal allergies, while the 0.15% product is labeled for adults only for either type of allergic rhinitis. Despite this labeling, recent guidelines favor the use of the intranasal route for seasonal but not persistent allergic rhinitis.18 Azelastine has been used successfully for patients who did not respond to loratadine.25Using the nasal route offers an alternative to switching to another oral antihistamine. Patient satisfaction has been varied because while the product produces rapid symptom relief, patients complain of drying effects, headache, and diminished effectiveness over time. Patients should be warned of the medication’s potential to produce drowsiness, as its systemic availability is approximately 40%.26,27 Olopatadine, another intranasal antihistamine, may cause less drowsiness as it is a selective H1-receptor antagonist.
Clinical Controversy…
Using intranasal antihistamine for seasonal allergic rhinitis is well accepted, but their role in treating persistent allergic rhinitis is not well defined.
Allergic conjunctivitis, often associated with allergic rhinitis, can be treated with ophthalmic antihistamines such as levocabastine or bepotastine. Because systemic antihistamines usually are also effective for allergic conjunctivitis, one of these ophthalmic agents is a logical addition to nasal steroids when ocular symptoms occur, and it is an acceptable approach for patients whose only symptoms involve the eyes or to add for those whose symptoms persist on oral treatment.
Decongestants
Topical and systemic decongestants are sympathomimetic agents that act on adrenergic receptors in the nasal mucosa, producing vasoconstriction. Decongestants shrink swollen mucosa and improve ventilation. When nasal congestion occurs with allergic rhinitis, decongestants work well in combination with antihistamines.
Topical Decongestants
Topical decongestants are applied directly to swollen nasal mucosa via drops or sprays. Table 76–6 lists the common topical decongestants and their durations of action. The use of these agents results in little or no systemic absorption.
TABLE 76-6 Duration of Action of Topical Decongestants
Because these agents are extremely effective and are available to patients without a prescription, they are widely used. However, prolonged use of these agents (for more than 3 to 5 days) can result in a condition known as rhinitis medicamentosa, or rebound vasodilation, with even more severe congestion. Patients who develop this condition use increasingly more spray more often with less response. Although the methods used to treat this “addiction” have not been studied formally, several are used commonly. Abrupt cessation works, but it is difficult because of rebound congestion that may leave the patient congested for several days or weeks. Sleeping may become difficult. Nasal steroids have been used successfully, but they take several days to work. Weaning the patient off topical decongestants can be accomplished by decreasing the dosing frequency or the concentration over several weeks. Combining the weaning process with nasal steroids may prove useful. Ultimately, the success of any plan depends on the patient’s resolve and clear understanding of the importance of stopping the drug to end the problem.
Other adverse effects of topical decongestants include burning, stinging, sneezing, and dryness of the nasal mucosa.
Patients should be counseled on the use of topical decongestants to prevent rhinitis medicamentosa. Patients should be instructed to use as small a dose as possible as infrequently as possible and only when absolutely necessary (e.g., at bedtime to aid in falling asleep). Duration of therapy always should be limited to 5 days or less.
Systemic Decongestants
Oral decongestants are not as effective on an immediate basis as the topical agents, but their effects sometimes last longer and they cause less local irritation. In addition, rhinitis medicamentosa is not a problem with oral agents. The most commonly used agent is pseudoephedrine. Table 76–5 lists the usual doses for the regular and sustained-release versions. The use of phenylephrine is increasing because of regulations related to pseudoephedrine described below.
Concerns of safety have greatly limited the systemic decongestant options. Legal requirements for the sale of pseudoephedrine were put into place to combat the misuse of the drug as a component in making methamphetamine. Pseudoephedrine must now be sold behind the counter, and the monthly amount a patient can purchase is limited. Until this requirement, pseudoephedrine was the most frequently used systemic decongestant, and it was considered the safest. Doses of 180 mg have been shown to produce no measurable change in blood pressure or heart rate.28 In higher doses (210 to 240 mg), pseudoephedrine has raised both blood pressure and heart rate.29 Pseudoephedrine can cause mild CNS stimulation, even at therapeutic doses. Stroke, related to use of oral decongestants such as pseudoephedrine, can occur in patients with hypertension and/or vasospasm.30 Although stroke complications seem to be associated with higher-than-recommended doses, there is also a stroke risk when these agents are taken properly. Severe hypertensive reactions can occur when pseudoephedrine is given concomitantly with monoamine oxidase inhibitors. Hypertensive patients should, unless necessary, avoid systemic decongestants.
Combination Products
Numerous products combine an antihistamine with a decongestant. While the combination may be rational because of the different mechanisms of action, remember that antihistamines must be taken on a regular schedule, but decongestants should only be used when needed. Both nonselective and peripherally selective antihistamines are available in such combinations. As mentioned previously, patients should read labels to avoid therapeutic duplication. Consideration should be given to how often and how severely the patient is congested before recommending these combinations. Only a short course of a combination product should be used.
Nasal Steroids
Nasal steroids are an excellent choice for treating perennial rhinitis, and can be useful in seasonal rhinitis, especially if begun in advance of symptoms. Nasal steroids appear to be effective with minimal adverse effects. Some believe that nasal steroids should be recommended as initial therapy over antihistamines because of their high level of efficacy when used properly and along with avoidance of allergens.18 Multiple mechanisms are involved with the effects of nasal steroids on the nasal mucosa: reducing inflammation by reducing mediator release, suppressing neutrophil chemotaxis, reducing intracellular edema, causing mild vasoconstriction, and inhibiting mast cell-mediated late-phase reactions. Table 76–5 lists the available nasal steroids and their usual doses.
Topical steroids produce only minor adverse effects, most commonly sneezing, stinging, headache, and epistaxis. Despite concerns about safety of systemic steroids, nasal steroids have been found to have no significant association with hypothalamic–pituitary axis suppression, cataract formation, glaucoma, or bone mineral density changes in the doses used for allergic rhinitis. Growth suppression remains a question with some evidence showing that nasal steroids with higher bioavailability (e.g., beclomethasone) may have a greater growth-suppression effect than less bioavailable agents.31 These findings require more study. Most likely, all currently available nasal steroids are safe in the majority of patients, and their clinical benefits outweigh any small growth suppressive effect. Other concerns include local infections with Candida albicans, which occur rarely.
The therapeutic benefits of topical steroids are not immediate, and they are not decongestants. Patients need to understand this to ensure cooperation and continuation of therapy. Some patients notice improvement in a few days, but peak responses may not be observed for 2 to 3 weeks. Once a response is achieved, the dosage may be reduced. Blocked nasal passages should be cleared with a decongestant or saline irrigation before administration to ensure adequate penetration of the spray. Patients should be advised to avoid sneezing or blowing their noses for at least 10 minutes after administration. Topical steroids should not be used for patients with nasal septum ulcers or recent nasal surgery or trauma.
One additional benefit of nasal steroids in treating allergic rhinitis in individuals with asthma and upper airway conditions is that they may confer some protection against exacerbations of asthma, leading to fewer emergency room visits. The overall relative risk for an emergency visit among asthma patients who received intranasal steroids was 0.7.32 No effect was seen for patients receiving antihistamines.
Clinical Controversy…
A recently approved combination of an intranasal steroid with an intranasal antihistamine in fixed doses may provide benefit, but the target patient population has not been well defined.
Other Inhalant Medications
Cromolyn sodium and ipratropium bromide offer two additional approaches for treating allergic rhinitis. Cromolyn sodium is a mast cell stabilizer. Increased interest in this product has resulted from it becoming available without a prescription. Ipratropium bromide is an anticholinergic agent useful in perennial allergic rhinitis.
Cromolyn sodium nasal spray is used for the symptomatic prevention and treatment of allergic rhinitis. It curtails antigen-triggered mast cell degranulation and release of the mediators of allergic reactions, including histamine. Cromolyn sodium has no direct antihistaminic, anticholinergic, or antiinflammatory properties. Similarly to topical steroids, the most common adverse effects—sneezing and nasal stinging—result from local irritation. Dosing information is given in Table 76–5. Cromolyn sodium must cover the entire nasal lining; therefore, patients should be instructed to clear nasal passages before administration. Inhaling gently through the nose during administration aids in this process. Dosing must be repeated at 6-hour intervals to maintain the effect.
For seasonal rhinitis, treatment with cromolyn sodium should be initiated just before the usual start of the offending allergen’s season and continued throughout the season. In perennial rhinitis, the effects may not be seen for 2 to 4 weeks; therefore, antihistamines or decongestants may be needed during this initial phase of therapy. As cromolyn sodium begins to work, the need for these medications should decrease.
Ipratropium nasal spray is an anticholinergic agent that exhibits antisecretory properties when applied locally. It provides symptomatic relief of rhinorrhea associated with allergic and other forms of chronic rhinitis. Dosing information is given in Table 76–5. The optimal dose should be determined based on the specific patient’s symptoms and response. Adverse effects are mild, with the most common being headache, nosebleeds, and nasal dryness.
Immunotherapy
Experience with immunotherapy has reached the one-century mark, as the first report of the successful use of grass pollen extract injections to treat allergic rhinitis was published in 1911.33 The therapy was first called desensitization; however, this did not seem appropriate because skin reactivity sometimes remained. The name was later changed to hyposensitization. Although this term is still used today, immunotherapy is used more commonly and is less confusing.
Immunotherapy is the slow, gradual process of injecting increasing doses of antigens responsible for eliciting allergic symptoms into a patient with the hope of inducing tolerance to the allergen when natural exposure occurs. Several mechanisms have been proposed to explain the beneficial effects of immunotherapy, including induction of IgG-blocking antibodies, reduction in specific IgE (long-term), reduced recruitment of effector cells, altered T-cell cytokine balance (a shift from T-helper type 1 to T-helper type 2), T-cell anergy, and alteration of regulatory T-cell actvitiy.34
Immunotherapy is moderately expensive, has significant potential risks, and requires a major time commitment from the patient. However, the cost of immunotherapy is usually covered by insurance, including Medicaid. Long-term savings can be realized since decades of treatment with medication can be averted through successful immunotherapy. Candidates for immunotherapy should have significant symptoms unsuccessfully controlled by avoidance and pharmacotherapy or should stand to benefit in other significant ways, such as with asthma. Immunotherapy may postpone the onset of asthma or possibly even prevent it.35 Patients who are unable to tolerate the adverse effects of properly managed drug therapy also should be considered. Patients must be committed to the necessary regular office visits required to complete this course of therapy over several years.
The effectiveness of immunotherapy for seasonal allergic rhinitis appears to be better than that seen with perennial rhinitis, in part because it is more difficult to determine which allergen is responsible for perennial symptoms, and it is more often due to multiple sensitizations. Effectiveness has been shown in a number of clinical studies using a variety of pollen extracts, even for patients with severe disease resistant to pharmacotherapy.35 Specific immunotherapy for house dust mites has had good results in appropriately selected patients, but more study is needed. Data indicate that for some patients 3 years of immunotherapy may be sufficient to give lasting benefit36; however, many require longer treatment. Sublingual and local nasal specific immunotherapy may offer acceptable alternatives to the traditional subcutaneous route in some patients.18
The selection of antigens should be based on patient history and skin test results. Numerous regimens for administration of selected allergens have been suggested. In the beginning, very dilute solutions are given initially one to two times per week. The concentration is increased until the maximum tolerated or highest planned or effective dose is achieved. This maintenance dose is continued in slowly increasing intervals over several years, depending on clinical response. In light of the present understanding of the immunologic results of immunotherapy, it should be given year-round rather than seasonally.
Adverse reactions can occur with immunotherapy and range from mild to life threatening. Among the most common are mild local reactions, consisting of induration and swelling at the site of the injection. These may be immediate or delayed. Other more serious reactions (e.g., generalized urticaria, bronchospasm, laryngospasm, and vascular collapse) occur rarely; deaths can result from anaphylactic reactions. Severe reactions are treated with epinephrine as well as other modalities recommended for anaphylaxis. Because of this potential risk, immunotherapy must not be given without adequate direct observation in a medical facility.
Several patient types are poor candidates for immunotherapy, including patients with any medical condition that would compromise the ability to tolerate an anaphylactic-type reaction, patients with impaired immune systems, and patients with a history of nonadherence to therapy.
Leukotriene Receptor Antagonists
Leukotriene receptor antagonists inhibit the cysteinyl leukotriene receptor. The cysteinyl leukotrienes are one type of inflammatory mediators released from mast cells in allergy. Montelukast is approved for the treatment of perennial allergic rhinitis in children as young as 6 months and for seasonal allergic rhinitis in children as young as 2 years. Montelukast is considered a third choice behind antihistamines and nasal steroids.18
Studies published to date show leukotriene receptor antagonists to be no more effective than peripherally selective antihistamines and less effective than intranasal steroids. However, when combined with antihistamines, they are more effective than the antihistamine alone.37 In children with mild persistent asthma and coexisting allergic rhinitis, montelukast as monotherapy has been recommended.38 Table 76–5 lists dosage regimens.
Alternative Treatment Options
The development of a monoclonal antibody directed against the binding site of IgE provides an additional way to treat allergic respiratory diseases. Omalizumab, a recombinant humanized anti-IgE monoclonal antibody, was the first to show efficacy in allergic rhinitis.39 The actual mechanism of how this agent is thought to work is quite complex.40 Anti-IgE antibodies bind to the site on the IgE molecule that recognizes the IgE receptor, thereby preventing the IgE molecule from binding to mast cells or basophils. The half-life of IgE antibodies on the mast cell surface is about 6 weeks, and as the antibodies are freed, they become available for binding to anti-IgE antibodies. By giving repeated doses of omalizumab, the number of IgE antibodies on the mast cell surface can be reduced significantly over time. The drug-bound IgE molecules are not eliminated but remain in circulation as small immune complexes. IgE receptor numbers on basophils and mast cells are decreased as a result of down-regulation. Omalizumab’s role should be limited to patients with allergic rhinitis and asthma with a clear IgE-dependent allergic component uncontrolled despite optimal pharmacologic treatment and allergen avoidance.18
A few other alternative options have been suggested for treatment of allergic rhinitis. As mentioned earlier in this chapter, microbial exposure in the early years of life could help prevent allergic disease by favoring a nonatopic immune response.4 However, the use of probiotics may be limited to treatment or prevention of childhood eczema as available evidence shows little benefit in allergic airway diseases.41Butterbur, with the active ingredient petasin that exhibits antileukotriene and antihistamine activity, has shown some success but is not recommended for most patients.18,42 Other treatments that have been tried but are not recommended are homeopathy, acupuncture, and phototherapy.18
PERSONALIZED PHARMACOTHERAPY
The two primary pharmacotherapy options for the treatment of allergic rhinitis in adults and children are antihistamines and intranasal steroids. Patient preference should play a role when selecting between these two options. While limited evidence supports intranasal steroids over antihistamines, some patients may prefer simple oral therapy. Either choice requires clear patient counseling to ensure appropriate timing of therapy and expectations of effect.
For patients (both adults and children) who are not immunocompromised, have a high likelihood for adherence, and have adequate insurance and/or financial resources, subcutaneous specific immunotherapy is an excellent choice for treatment of seasonal allergic rhinitis and allergic rhinitis secondary to house dust mites. In some children, immunotherapy may prevent development of asthma.
For patients experiencing an exacerbation of nasal congestion as part of their allergic rhinitis picture, decongestants can be used short term.
Leukotriene receptor antagonists are an appropriate option in adults and children with seasonal allergic rhinitis and in preschool children with persistent allergic rhinitis. Other uses are not indicated due to limited efficacy and high cost.
Cromolyn is another alternative that is effective, but many patients may find its frequent daily dosing (up to six times daily) difficult. As previously mentioned, omalizumab’s role should be limited to patients with allergic rhinitis and asthma with a clear IgE-dependent allergic component uncontrolled despite optimal pharmacologic treatment and allergen avoidance.
A drug monitoring summary is shown in Table 76–7. Intranasal and ophthalmic antihistamines may be helpful for specific symptoms not relieved by first-line choices. An intranasal anticholinergic such as ipratropium is specifically useful for rhinorrhea.
TABLE 76-7 Drug Monitoring
More supportive evidence is needed to determine which patients, if any, would benefit from the other alternative options mentioned earlier.
EVALUATION OF THERAPEUTIC OUTCOMES
With allergic rhinitis, major outcomes include the effect of the disease on a patient’s life, the efficacy and tolerability of treatment, and patient satisfaction. Consideration must be given to how the condition is affecting the patient’s job or school performance, family and social interactions, and other aspects of quality of life. Drug therapy should prevent or minimize symptoms with few adverse effects. The patient should not have difficulty obtaining needed medication for financial or other reasons. Patients should be questioned about their satisfaction with the management of their allergic rhinitis. The management should result in minimal disruption to their lives.
Methods for assessing patient-reported outcomes and health-related quality of life in clinical trials related to allergy have been recommended.43 These tools go beyond measuring improvement in symptoms and include such items as sleep quality, nonallergic symptoms (e.g., fatigue, poor concentration, and others), emotions, and participation in a variety of activities. How well each of the current treatment modalities performs and how they compare in improving patient outcomes remain to be determined.
Clinicians caring for allergic rhinitis patients should develop a comprehensive pharmaceutical care plan that addresses several areas. Discuss and agree on therapeutic end points for allergic rhinitis, including the patient’s acceptable level of symptom relief, onset of symptom relief expectations, and seasonal starts and stops. Discuss adverse drug reaction self-monitoring and prevention based on treatment selection. Assess patient attitude toward adherence to and persistence with oral, ocular, intranasal, or immunologic therapies. Ensure proper matching of treatment to symptoms and intervene with the prescriber if necessary. Conduct seasonal or annual review with patient.
The therapeutic goal for all patients with allergic rhinitis is to minimize or prevent symptoms. Evaluation of success is accomplished primarily through the discussions with the patient, in whom both relief of symptoms and tolerance of drug therapy must be discussed.
CONCLUSIONS
Allergic rhinitis is a common disease with symptoms ranging from mild to severe. If avoidance measures are unsuccessful, allergic rhinitis should be treated to improve quality of life and prevent long-term complications. Timing of treating is essential. Treatment regimens should be individualized based on patient symptoms and response. Care should be taken to correctly identify allergy as the cause of the patient’s rhinitis before committing them to chromic treatment.
ABBREVIATION
REFERENCES
1. Greiner AN, Hellings PW, Rotiroti G, Scadding GK. Allergic rhinitis. Lancet 2011;378:2112–2122.
2. Benninger M, Farrar JR, Blaiss M, et al. Evaluating approved medications to treat allergic rhinitis in the United States: An evidenced-based review of efficacy for nasal symptoms by class. Ann Allergy Asthma Immunol 2010;104:13–29.
3. Bousquet J, Khaltaev N, Cruz AA, et al. Allergic rhinitis and its impact on asthma (ARIA) 2008. Allergy 2008; 63(Suppl 86):8–160.
4. von Mutius E, Radon K. Living on a farm: Impact on asthma induction and clinical course. Immunol Allergy Clin North Am 2008;28:631–647.
5. Wallace DV, Dykewicz MS, Bernstein DI, et al. The diagnosis and management of rhinitis: An updated practice parameter. J Allergy Clin Immunol 2008;122:S1–S83.
6. Wilson SJ, Shute JK, Holgate ST, et al. Localization of interleukin (IL)-4 but not 5 to human mast cell secretory granules by immunoelectron microscopy. Clin Exp Allergy 2000;30:493–500.
7. Riccio AAM, Tosco MA, Cosentino C, et al. Cytokine pattern in allergic and nonallergic chronic rhinosinusitis in asthmatic children. Clin Exp Allergy 2002;32:422–426.
8. Wood-Baker R, Lau L, Howarth PH. Histamine and the nasal vasculature: The influence of H1 and H2-histamine receptor antagonism. Clin Otolaryngol 1996;21:348–352.
9. Howarth PH. Mediators of nasal blockage in allergic rhinitis. Allergy 1997;52(40 Suppl):12–18.
10. Howarth PH. Leukotrienes in rhinitis. Am J Respir Crit Care Med 2000;161:S133–S136.
11. Clark RR, Baroody FM. What drives the symptoms of allergic rhinitis? J Respir Dis 1998;19:S6–S15.
12. Gerth van Wijk R. Perennial allergic rhinitis and nasal hyperreactivity. Am J Rhinol 1998;12:33–35.
13. Klaewsongkram J, Ruxrungtham K, Wannakrairot P, et al. Eosinophil count in nasal mucosa is more suitable than the number of ICAM-1-positive nasal epithelial cells to evaluate the severity of house dust mite-sensitive allergic rhinitis: A clinical correlation study. Int Arch Allergy Immunol 2003;132:68–75.
14. Braunstahl GJ, Fokkens WJ, Overbeek SE, et al. Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: A comparison between upper and lower airways. Clin Exp Allergy 2003;33:579–587.
15. Hill SL, Krouse JH. The effects of montelukast on intradermal wheal and flare. Otolarygol Head Neck Surg 2003;129:199–203.
16. Scadding G. Optimal management of nasal congestion caused my allergic rhinitis in children. Pediatr Drugs 2008;10(3):151–162.
17. Bousquet J, Schunemann HJ, Zuberbier T, et al. Development and implementation of guidelines in allergic rhinitis—An ARIA-GA2LEN paper. Allergy 2012;65: 1212–1221.
18. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol 2010;126:466–476.
19. Franchi M, Carrier P, Kotzias D, et al. Working toward healthy air in dwellings in Europe. Allergy 2006;61: 864–868.
20. Casale TB, Blaiss MS, Gelfand E, et al. First do no harm: Managing antihistamine impairment in patients with allergic rhinitis. J Allergy Clin Immunol 2003;111:S835–S842.
21. Sansgiry SS, Shringarpure GS. Springtime confusion: Are consumers getting the right information on how to treat seasonal allergies? J Allergy Clin Immunol 2003;112: 627–628.
22. Bender BG, Berning S, Dudden R, et al. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: A meta-analysis. J Allergy Clin Immunol 2003;111:770–776.
23. Richardson GS, Roehrs TA, Rosenthal L, et al. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;22:511–515.
24. Pharmacy Times OTC Guide 2012. http://www.otcguide.net/conditions/cough-cold-allergy.
25. Berger WE, White MV. Efficacy of azelastine nasal spray in patients with an unsatisfactory response to loratadine. Ann Allergy Asthma Immunol 2003;91:205–211.
26. Astelin. Product Information. Somerset, NJ: Meda Pharmaceuticals, 2011.
27. Astepro. Product Information. Somerset, NJ: Meda Pharmaceuticals, 2010.
28. Empey DE, Young GA, Letley E, et al. Dose response study of the nasal decongestant and cardiovascular effects of pseudoephedrine. Br J Clin Pharmacol 1980;9:351–358.
29. Drew CDM, Knight GT, Hughes DTD, et al. Comparison of the effects of D-(–)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man. Br J Clin Pharmacol 1978;6:221–225.
30. Cantu C, Arauz A, Murilla-Bonilla LM, et al. Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs. Stroke 2003;34:1667–1673.
31. Mehle ME. Are nasal steroids safe? Curr Opin Otolaryngol Head Neck Surg 2003;11:201–205.
32. Adams RJ, Fuhlbrigge AL, Finkelstein JA, Weiss ST. Intranasal steroids and the risk of emergency department visits for asthma. J Allergy Clin Immunol 2002;109: 636–642.
33. Noon L. Prophylactic inoculation against hay fever. Lancet 1911;1:1572–1573.
34. Valenta R, Campana R, Marth K, van Hage M. Allergen-specific immunotherapy: From vaccines to prophylactic approaches. J Intern Med 2012;272:144–157.
35. Incorvaia C, Frati F. One century of allergen-specific immunotherapy for respiratory allergy. Immunotherapy 2011;3(5):629–635.
36. Durham SR, Walker SM, Varga EM, et al. Long-term clinical efficacy of grass pollen immunotherapy. N Engl J Med 1999;341:468–475.
37. Rodrigo GT, Yanez A. The role of antileukotriene therapy in seasonal allergic rhinitis: A systematic review randomized trials. Ann Allergy Asthma Immunol 2006;96:779–786.
38. Polos PG. Montelukast is an effective monotherapy for mild asthma and for asthma with co-morbid allergic rhinitis. Prim Care Respir J 2006;15:310–311.
39. Casale TB, Condemi J, LaForce C, et al. Effect of omalizumab on symptoms of seasonal allergic rhinitis. JAMA 2001;286:2956–2967.
40. Frew AJ. Anti-IgE and asthma. Ann Allergy Asthma Immunol 2003;91:117–118.
41. Boyle RJ, Tang ML. The role of probiotics in the management of allergic disease. Clin Exp Allergy 2006;36:568–576.
42. Gray RD, Haggart K, Lee DK, et al. Effects of butterbur treatment in intermittent allergic rhinitis: A placebo-controlled evaluation. Ann Allergy Asthma Immunol 2004;93(1):56–60.
43. Baiardini I, Bousquet PJ, Brzoza Z, et al. Recommendations for assessing patient reported outcomes and health-related quality of life in clinical trials on allergy: A GA2LEN taskforce position paper. Allergy 2010;65:290–295.