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Chapter 42 –  ALLERGIC RHINITIS Richard L. Mabry   Bradley F. Marple INTRODUCTION

Although not as glamorous as its surgical counterparts, the management of allergic rhinitis constitutes a large proportion of the day-to-day practice of the general otolaryngologist. In addition to its primary effect, inhalant allergy of the upper respiratory tract might affect the development and clinical course of other disease states such as sinusitis, otitis media, and asthma. Indeed, it has been said that (excluding trauma and malignancies) allergy might represent a primary or secondary factor in up to half the patients encountered in an otolaryngology practice. In 1996,[21] it was estimated that almost 36 million individuals in the United States were afflicted with allergic rhinitis. Other statistics are equally impressive: a cost of $1.3 billion per year in medical and drug expenses in 1994, with almost 2 million days per year lost from work or school because of allergic rhinitis.[16] Thus, the importance of allergic rhinitis should not be minimized, either by the patient or the treating physician.

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SYMPTOMS AND SIGNS OF ALLERGIC RHINITIS

The characteristic symptoms and signs of allergic rhinitis are easily understood if one keeps in mind the effects of the mediators released by mast cells and basophils as a result of a Gell and Coombs type I reaction. These include glandular stimulation, vasodilation, increased vascular permeability, and irritation, changes that are responsible for the typical symptoms of itching, sneezing, rhinorrhea, and nasal congestion.

An allergy history includes information about the seasons or circumstances that trigger symptoms, the types of symptoms that predominate, the results of any previous allergy testing, and the effect of previous treatment, as well as the presence of complicating problems such as sinusitis, asthma, otitis media, and so forth. Although an allergic history begins at the time of the first visit, it is a constantly evolving process.

The signs of allergic rhinitis include the "allergic salute," which is characterized as follows: the hand lifts the nasal tip to respond to itching temporarily opening the airway, a transverse nasal crease seems to be caused by repetition of this maneuver, and facial grimacing and twitching are present because of itching membranes. The nasal turbinates are generally pale to bluish. Another characteristic sign is clear rhinorrhea. The presence of polyps does not necessarily indicate allergy.[28] Obligate mouth-breathing might result in a typical open-mouthed countenance and "adenoid facies."[17]

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ADJUNCTIVE TESTS

A number of adjunctive tests have traditionally been used to confirm the clinical diagnosis of allergic rhinitis. Among these are a differential count of peripheral leukocytes or the examination of smears of nasal secretions for the presence of eosinophils.[12] These measures have generally given way to specific diagnostic techniques that measure levels of IgE for various antigens.

The diagnosis of allergic rhinitis is made by history, and the novice rhinologist must realize that the presence of a positive test is just that: a positive test. Clinical correlation between the patient's symptoms and any postulated sensitivity to the incriminated antigens is necessary to confirm a diagnosis of clinically relevant "allergy."

Confirmatory Skin Testing for Allergy

The "gold standard" of allergy testing is generally considered to be skin testing. The basis of this procedure is the reaction between antigen and sensitized mast cells in the skin, producing the classic wheal and flare skin response. This reaction begins with an acute phase that starts within 2 to 5 minutes, reaches a maximum at 10 to 20 minutes, and is characterized by vasodilation (producing erythema) and local edema (producing a wheal). It might be followed by a late phase, with further whealing and induration occurring 4 to 6 hours or more later.

A number of factors affect skin tests. In addition to the volume and potency of antigen introduced, the degree of sensitization of cutaneous mast cells and reactivity of the skin also are modified by drugs, the age and race of the patient, the area of the body injected, the distance separating individual skin tests, and the time of day of testing.[22] Skin test responses are suppressed by antihistamines. All forms of antihistamines must be avoided for at least 48 to 72 hours before skin testing. Although tricyclic antidepressants are no longer commonly used, patients taking them must omit them for up to 96 hours before skin testing, because they suppress whealing responses. Decongestants, systemic steroids, and leukotriene modifiers do not significantly affect skin test results.

To ensure that skin reactivity is normal, both positive and negative controls are necessary with all skin tests. A positive whealing response to the positive control (histamine) indicates an intact wheal and flare response (and is a fail safe against unrecognized antihistamine ingestion before testing). A positive response to the negative control suggests the presence of dermatographia, in which skin trauma results in a wheal and flare response, making skin testing in these patients unreliable.[15]

Skin tests are generally classified as epicutaneous or intracutaneous. The former group includes scratch tests and prick-puncture testing, and the latter group includes both single-dilution and multiple-dilution intradermal tests.

In 1865, Blackley performed a crude scratch test on himself to show his sensitivity to rye grass, and in the early 1900s, scratch tests were commonly used to diagnose immediate-type allergy. Unfortunately, these tests produced numerous false-positive reactions, and the results were highly variable and difficult to interpret, because neither the amount of antigen nor the scratch through which it was introduced were standardized. In 1987, the American Medical Association Council on Scientific Affairs pronounced scratch testing "less reproducible than prick and puncture tests," stating that they were "no longer recommended."[1]

The most commonly applied epicutaneous test is the prick or puncture method, which was developed by Lewis and Grant in 1924 but did not gain widespread acceptance until its modification by Pepys in 1975. In this test, a drop of test extract (or control solution) is placed on the skin, then a needle or similar instrument is passed at an angle through the liquid and the skin is pricked by lifting to elevate the dermis without producing bleeding or is punctured by perpendicular pressure with a needle. In interpreting the test, both the wheal and surrounding erythema are evaluated and measured and are compared with positive and negative controls, with the results graded from 0 to 4+. Positive prick-test reactions are generally noted in patients with higher levels of allergen-specific IgE, and the test might be negative in patients with lower (but significant) degrees of atopy. Thus, prick tests are often used as a screening test and followed by intradermal testing when indicated.

A number of variants of the prick-puncture method have been developed in an effort to standardize the test and make it more sensitive. These include standardized test instruments such as the Morrow Brown needle, as well as multiple-test devices such as the Multi-test II® and Quintest® tests. These latter tests are not strictly prick tests, because their needles might penetrate the dermis.

The intradermal test was applied to the diagnosis of allergy by Schloss in 1912 and popularized for this purpose by Cooke in 1915. In this test, a measured amount of antigen is injected intracutaneously to form a wheal. An antigenic reaction results in significant enlargement of the wheal. Allergists who use a single-dilution intradermal testing technique measure both the wheal and erythema produced and compare them with positive and negative controls with a grading system of 0 to 4+ in the same way as the prick test.[23] To minimize the risk of systemic reaction, single-dilution intradermal testing should not be performed unless a screening-prick test for the same antigen has shown that the patient is not exquisitely sensitive to it. Although the antigen concentrations used in intradermal testing are from 1000 to 10,000 times weaker than those used for prick testing, a much greater amount of antigen is introduced with this method. Therefore, the risk of a systemic reaction is greater with a single-dilution intradermal test than with a prick test.

Because skin testing with prick and single-dilution intradermal techniques does not permit accurate quantitation of the patient's sensitivity, the technique of intradermal dilution testing (also known as skin-endpoint titration) was developed. Carrying forward the work of Hansel, Herbert Rinkel perfected a system of intradermal testing in the mid-1940s with a series of fivefold dilutions of the same antigen. Testing begins with an anticipated nonreacting dose and progresses to the concentration that initiates positive whealing and then continues with the application of the next stronger concentration. This endpoint of titration indicates the relative sensitivity of the patient to the tested allergen and represents the concentration at which immunotherapy can safely be initiated, thus avoiding prolonged therapy at very low doses while providing a significant safety factor.[25]

Confirmatory In Vitro Testing for Allergy

Skin testing for allergy is subject to a number of drawbacks, including the potential for production of a significant reaction and the discomfort, however minimal, associated with the procedure. These drawbacks have led to a continued search for other diagnostic methods. Shortly after the characterization of IgE as the sensitizing factor in allergy, a radioimmunoassay was developed that could detect specific IgE antibodies in serum. This assay, which was called the radioallergosorbent test (RAST), evolved significantly over the years that followed and has become an important tool in the diagnosis of inhalant allergy.[8]

Although numerous variations of technology exist, the basic principle of the in vitro analysis of allergen-specific IgE is a "sandwich" technique in which allergens on a solid phase (such as a paper disk) are allowed to react with serum from the patient. Any IgE antibodies to that allergen that are present bind to the solid phase. This resultant complex is then incubated with radiolabeled rabbit antibodies to human IgE. After washing, the amount of radioactivity in the resulting sandwich of allergen/antibody/anti-IgE/radioactive marker on the disk is measured with a gamma counter, and the amount of antibody present is calculated.

The modified RAST technique and scoring system of Fadal and Nalebuff (F/N mRAST) significantly improved the usefulness of the RAST, both increasing its clinical sensitivity and bringing the classes that resulted into parallel with results from skin endpoint titration.[30] The major changes since the development of the F/N mRAST have been in the solid phase used (cellulose, plastic, hydrophilic polymer) and in the marker used (various fluorometric techniques). If the process involves enzymatic or fluorometric processes rather than a radioactive marker, it is generally referred to as an enzyme-linked immunosorbent assay (ELISA). Although RAST is often used as a generic term for all of these, each technology has its own characteristics, and the clinician must become familiar with the system in use in his or her practice. The decision to use skin tests or in vitro tests will depend on the individual circumstances of each patient and each practice, and it is best if the clinician is familiar with both methods.[14]

Along with the popularization of the allergen-specific RAST, the measurement of total IgE has been advocated as a means of diagnosing the presence of allergy. However, it has become apparent that in some instances a high total IgE (>100 IU/mL) is not associated with true allergy, whereas in others a low total IgE might be present in patients with significant allergy. The measurement of total IgE might be useful in clarifying otherwise equivocal results but has little value when used alone to diagnose the presence of allergy. Serial measurement of total IgE is useful in the management of patients with allergic fungal sinusitis.[13]

Modern technology exists for the assay of allergen-specific IgE for numerous antigens. However, as a general rule, an assay of 8 to 15 antigens is sufficient to adequately indicate the presence or absence of significant inhalant allergy.[11] Positive responses are followed by additional testing for other relevant antigens.

A further extension of the screening concept occurs in the use of disks that have a number of antigens bound to them. These might give either a "yes/no" response or a semiquantitive indication of the amount of allergen-specific IgE present. A negative response often is sufficient to rule out the presence of significant inhalant allergy. On the other hand, because specific testing for each potentially positive antigen in the screening mix must be carried out

before administering immunotherapy, these tests have little usefulness to the physician equipped to test and treat for specific allergens.

Management by Environmental Control

The best and most desirable management of allergy is avoidance when possible. Although this must often be supplemented by pharmacotherapy, and sometimes with immunotherapy, environmental control remains the most important component of this therapeutic triad.

Printed material about specific control measures aimed at various antigens is readily available from numerous commercial sources but must be supplemented by advice from the physician. The most "avoidable" antigens are the perennial offenders: dust mites, molds, and animals.[29]

House dust mites thrive in warm, moist conditions and feed on human skin scales (such as those found in bedclothes). The antigen is found in the mite feces. Control measures include elimination of reservoirs (upholstered furniture, carpeting, stuffed animals), covering of mattresses and pillows with barrier material, control of relative humidity (<50%), and the use of acaricides (benzyl benzoate) or preparations that denature the dust mite antigen (tannic acid). Unfortunately, no compound yet exists that both kills dust mites and renders their antigen harmless.

The major animal antigen that causes allergic problems is cat allergen, which is secreted by sebaceous glands and borne on light skin scales. Removing the cat is often a suggestion met with resistance (if not active rebellion), and other measures are often necessary. These include keeping the cat out of the bedroom and removal of as much antigen as possible from reservoirs (furniture, carpets) by vacuuming with a high-efficiency particulate arresting (HEPA) filter vacuum. Weekly washing of the cat with copious amounts of warm water, or even wiping with warm water, have been recommended as a preventive measure,[24] although the efficacy of these measures has been challenged.

Mold is found in many areas of the home. It requires circumstances for growth similar to the dust mite (i.e., warmth and humidity), and control of these factors also will help control indoor mold growth. In addition, such sources of indoor mold as refrigerator drip pans, stored material in basements and attics, and the soil around indoor plants should be considered in attempting to remove mold from the patient's environment.

Management by Pharmacotherapy

Antigens are not always avoidable, and immunotherapy modifies the allergic response but does not always afford protection from an overwhelming antigen exposure. Therefore, symptomatic management by means of pharmacotherapy is required to some degree for every patient with allergic rhinitis. Numerous types of drugs are available for this purpose, and each has unique characteristics. The physician must tailor the regimen according to the patient's symptoms and circumstances.

Antihistamines

Antihistamines act to control the "wet" symptoms of allergic rhinitis, such as rhinorrhea, sneezing, and itching membranes. Progressively more sophisticated forms have been developed since the pioneering work of Bovet and Staub in 1937. First-generation

antihistamines (also called "sedating" antihistamines because of their most common side effect) act by competing with histamine for H1 receptor sites on target organs. In addition to sedation, they might produce anticholinergic effects resulting in bladder neck obstruction and prostatism and excessive dryness of secretions. Prolonged use of these preparations results in tachyphylaxis, or tolerance, requiring a change to a different form of antihistamine. Examples of first-generation antihistamines include chlorpheniramine, brompheniramine, triprolidine, and diphenhydramine. All first-generation antihistamines are available over the counter, and most patients consulting the specialist have tried one or more already.

Second-generation, or nonsedating, antihistamines generally have multiple actions, which often include direct effects on allergic mediators. Because they do not readily cross the blood-brain barrier, they either do not produce sedation or do so only in large doses. Their anticholinergic effects are much less pronounced, and they are free of tachyphylaxis. The two earliest such preparations (terfenadine, astemizole) have been removed from the market in the United States (although not in other countries), because they were shown to present an increased risk of cardiac arrhythmias when administered concomitantly with macrolide antibiotics and systemic antifungals. Subsequently developed second-generation antihistamines include loratadine, cetirizine, and acrivastine.

Topical antihistamines have been developed, such as levocabastine and azelastine. Levocabastine is available in Canada and Mexico but not in the United States. Topical azelastine was introduced in the United State in the 1990s and offers the benefits of both antihistamine and antiinflammatory actions, although many patients note a side effect of taste perversion.

The newest antihistamines are metabolites and congeners of existing drugs, offering fewer potential side effects but with equal effectiveness.[26] The first such third-generation preparation to become available was fexofenadine, the active metabolite of terfenadine. The introduction of desloratadine, derived from loratadine, followed shortly thereafter. Tecastemizole (from astemizole) and levocetirizine (from cetirizine) are currently under active development. The benefits sought from these and future antihistamines will be equal or superior potency, enhanced safety profiles, with enhanced onset of action and extended duration of activity.

A decision by the Food and Drug Administration (FDA) to make antihistamines available over the counter will undoubtedly affect the use of these and other antiallergy drugs, primarily for economic reasons.

Decongestants

Decongestants are alpha-adrenergic agonists that produce vasoconstriction in the turbinates, lessening nasal congestion. When topically applied for more than 5 to 7 days, they might produce a rebound rhinitis, and addiction to nose drops and sprays is a commonly encountered phenomenon in patients with chronic rhinitis. Because nasal allergy is a chronic disorder, such patients are more likely to abuse topical nasal decongestants and must be warned of the problem.

The most common orally administered decongestants are pseudoephedrine and phenylephrine. Potential side effects of these drugs are related to their vasopressor actions (which might cause elevated blood pressure, especially in patients with preexisting labile

hypertension), and their central nervous system (CNS) stimulatory effects (producing insomnia and jitteriness). These stimulatory side effects are potentiated in patients taking tricyclic antidepressants or monoamine oxidase (MAO). The decongestant phenylpropanolamine was removed from use in the United States[18] after a suggested linkage between its use and the incidence of hemorrhagic strokes in some women.

For the management of allergic rhinitis, decongestants are often combined with antihistamines. Because newer antihistamines, unlike first-generation preparations, do not cause sedation, their combination with decongestants might produce undesirable stimulatory side effects unless an effective timed-release form is used.

Mast Cell Stabilizers

The prototype of mast cell stabilizers, cromolyn, has been available in the United States as a topical nasal solution since 1983. In laboratory animals, cromolyn was found to stabilize mast cells, preventing the allergic reaction. Additional work has shown that in human subjects this is only one of the effects of this class of drugs, which have numerous other actions. Nevertheless, by convention, they are still referred to as mast cell stabilizers.

Cromolyn is most beneficial when used before an anticipated allergen exposure but must be administered at least four times daily for maximum effect. Patients with severe allergic rhinitis might not respond adequately to this medication, but it is an extremely safe and often effective initial therapeutic measure. Because it is available without a prescription, it is an excellent preparation to be recommended for patients seeking over-the-counter relief.

Other topical mast cell stabilizers that remain in development for intranasal use include olopatadine, oxatomide, and quazolast. The intranasal mast cell stabilizer nedocromil is available in Europe but not in the United States.

Corticosteroids

Corticosteroid preparations are potent antiinflammatory agents that do not prevent an antigen-antibody allergic reaction but diminish the effects of vasoactive kinins and other mediators by decreasing capillary permeability, stabilizing lysosomal membranes, blocking the action of migratory inhibitory factor, and directly affecting phospholipase. Systemically administered corticosteroids primarily affect the late-phase allergic reaction, whereas topical preparations also might act on the acute phase after pretreatment for a week or longer.

Systemic administration of corticosteroids must be done with the full realization of their potential for suppression of endogenous cortisol production, as well as their possible adverse effects on many organ systems. Significant hypothalamic-pituitary-adrenal suppression might occur after approximately 5 to 7 days of the daily administration of 20 to 30 mg of prednisone or its equivalent, or occur in up to 30 days with lower doses. Adrenal recovery might occur within 1 week of discontinuing short-term, high-dose therapy, whereas up to 1 year or more might be required after prolonged, high-dose therapy.

Potential adverse effects of systemically administered corticosteroids might be major or minor. Systemic corticosteroids in the management of allergic rhinitis might be administered orally as a tapered-dosage program (either tailored by the physician or as a commercially available item) or in the form of a repository injection. The latter should be administered with

caution, because although the corticosteroid effect provides relief for up to 6 weeks, virtually total hypothalamic-pituitary-adrenal suppression might occur for this same period.[20]

The popularization of topical nasal corticosteroid preparations during the past two decades has greatly diminished the systemic administration of these preparations. The tendency has been for newer forms to require less frequent administration (improving patient compliance) and to have less likelihood of systemic effect (diminishing the possibility of complications associated with prolonged use at high doses). Up to one-half of all nasally administered steroids might be absorbed from the nasal mucosa. A portion of the material also is swallowed and is absorbed from the gastrointestinal tract. However, with the exception of dexamethasone, all nasal corticosteroids undergo extensive first-pass hepatic metabolism to either inactive or less active compounds. This metabolism, plus the pharmacodynamics of the individual preparation, prevents significant systemic effects from topical administration unless they are administered for prolonged periods and at higher than recommended doses (or if the patient is also using an inhaled corticosteroid preparation for lower airway disease). Attention is now being focused on the relative lipophilicity of various inhaled steroids and their potential buildup in fatty tissues. Although hypothalamic-pituitary axis suppression has been shown when large doses of a number of nasal steroids are administered, most clinical evidence indicates that these preparations are safe when administered at normal doses. The possible exception is beclomethasone, which has a narrow margin of safety between therapeutic doses and those causing systemic effect.

The FDA has issued a "black box warning" for respiratory steroid use in children because of the potential risk of growth inhibition reported in studies involving beclomethasone,[27] even though other studies have indicated that any temporary growth inhibition is overcome in later years and that other nasal steroids might be free of this risk. Nevertheless, steroid use in children (as in all patients) should be monitored to use the lowest effective dose, and potential side effects should always be kept in mind.

Nasal corticosteroids are administered as either a pump spray (generally in an aqueous vehicle) or as a suspension dispensed in a powered fashion by a propellant. All topical nasal corticosteroids might cause side effects such as local nasal irritation, crusting, epistaxis, or even nasal septal perforation. The development of better-pressurized delivery systems and devices, and a trend toward the use of aqueous preparations, has improved this problem somewhat, as has the emphasis on advising patients of the proper way to use these sprays. This advice includes directing the tip of the nozzle toward the corner of the eye (away from the septum) and using sprays only for the duration recommended, with regular examinations to watch for signs of local damage.

Anticholinergics

Because rhinorrhea is such a prominent feature of allergic rhinitis, combination preparations that contain anticholinergic drugs were introduced many years ago. Unfortunately, many of these had a profound overdrying effect, provoking nasal crusting and thickened nasal and sinus secretions. Only a few such preparations are still marketed, and these should be avoided if possible because of their potential side effects.

Early efforts to administer topical anticholinergics included atropine in saline, compounded and administered in a spray bottle. Although often effective for up to 4 hours, a variable amount of drug was administered in each dose by this technique. In 1996, the FDA approved

the marketing of the topical anticholinergic, ipratropium bromide, as an aqueous nasal pump spray formulation. The 0.03% strength of this drug, administered in a dose of two sprays in each nostril three times daily, produces a significant decrease in the rhinorrhea associated with symptomatic allergic rhinitis. The preparation is generally free of systemic anticholinergic effects but offers no relief of congestion, sneezing, or itching that accompanies allergic rhinitis. It is primarily an adjunctive treatment, but a very effective one, in selected patients.

Leukotriene Modifiers

In addition to "designer" antihistamines and more potent yet safer topical nasal corticosteroids, attention has been directed to modulating the allergic reaction by inhibiting the formation of leukotrienes or blocking their effects. Zileuton is the best-known 5-lipoxygenase inhibitor, whereas common cysteinyl-leukotriene inhibitors include zafirlukast and montelukast. Monitoring of liver function is recommended in patients receiving zileuton. The original role of leukotriene modifiers was in the treatment of asthma and polyposis (especially Samter's triad patients), and only recently have they been investigated as adjuncts to antihistamine and/or corticosteroid therapy or as stand-alone treatments for allergic rhinitis.[19] In 2003, montelukast received approval by the FDA for use in the treatment of seasonal allergic rhinitis.

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HYGIENE HYPOTHESIS

Epidemiologic data provide strong evidence of a steady rise in the incidence of allergic (asthma,[277] rhinitis,[258] and atopic dermatitis[275]) and autoimmune diseases (multiple sclerosis,[209] insulin-dependent diabetes mellitus,[81] and Crohn's disease[248]) in developed countries since the beginning of the 1970s. Concomitantly, an obvious decrease in the incidence of many infectious diseases in developed countries has occurred as a result of antibiotics, vaccination, or more simply improved hygiene and better socioeconomic conditions. A hypothesis has thus emerged that the decrease in infectious diseases is causally linked to the increase in the incidence of allergic and autoimmune diseases, the "hygiene hypothesis." This is not a new concept as Leibowitz and others, suggested in 1966[149] that the risk of multiple sclerosis is increased among persons who spent their childhood in a home with a high level of sanitation. Almost 20 years later, Strachan observed that the risk of allergic rhinitis was inversely linked to birth order and the size of the family.[246] He proposed that infections within households in early childhood have a role in preventing allergic rhinitis.

The geographical distribution of allergic and autoimmune diseases in the world also shows interesting patterns. The incidence of disease decreases from north to south in the Northern Hemisphere and reciprocally from south to north in the Southern Hemisphere. Under diagnosis of allergic and autoimmune diseases in underdeveloped countries could explain these geographical differences, but this is not likely. Although this explanation might be proposed for allergic rhinitis and atopic dermatitis, relatively benign diseases, it is not likely to apply to type I diabetes and multiple sclerosis, which lead to significant symptoms and are not likely to go undiagnosed. Environment seems to play an important role in this gradient. This is well illustrated by the fact that the rate of development of type I diabetes among the children of Pakistanis who migrated to the United Kingdom is the same as the rate among nonimmigrants in that country and about 10 times as high as the incidence of type I diabetes in Pakistan.[41][244] An obvious factor in the north-south gradient is socioeconomic differences. Several studies have found a lower frequency of immunologic diseases in populations with a low socioeconomic status. Some infections have been found to be distributed according to a south-north gradient in European countries that mirrors the gradient for autoimmune diseases. Low socioeconomic levels and high temperatures, two common features of southern countries, may predispose to infections in a number of ways: less stringent control of microbial contamination of water and food, an increased risk of bacterial proliferation with higher ambient temperatures, and poorer housing conditions may all affect the risk of contamination between persons.

When infections are an incriminating factor, they often occur in childhood. In Yorkshire, a case-control study demonstrated an inverse correlation between the incidence of type I diabetes and the degree of social mixing, including day-care attendance and the number of infections that occur before 1 year of age.[165] Furthermore, young children with older brothers and sisters at home and those who attend a day-care center during the first 6 months of life

subsequently have a lower incidence of asthma[15] and type I diabetes[165] than children who do not attend a day-care center and have no older siblings.

The administration of antibiotics to children has been suspected to increase the risk of asthma and allergy. Droste and others observed that the use of antibiotics in the first year of life increased the risk of asthma or other allergic diseases in children with a genetic predisposition to atopy.[71] Antibiotics might act by decreasing the number of infections or by modifying intestinal flora.

Differences in disease incidence between urban and suburban dwellers have been observed, and factors other than air pollution have been implicated. In 1999, Braun-Fahrländer and colleagues found that children whose parents were farmers and who lived on the farm were less likely to become allergic than children from the same rural region who were not raised on a farm.[47] Another study confirmed these findings and showed that allergies were less frequent when the children were exposed early and for a prolonged period to farm animals and cow's milk.[216] An inverse correlation between endotoxin levels in bedding and the incidence of atopic diseases among children living in rural areas was also found, suggesting that a subject's environmental exposure to endotoxin may have a crucial role in the development of tolerance to ubiquitous allergens found in natural environments.[48]

Animal studies support the above epidemiologic observations, because autoimmune diseases in susceptible strains of mice or rats develop earlier and at a higher rate among animals bred in a specific pathogen-free environment than among animals bred in a conventional environment. The same has been observed relating to allergic diseases. Administration of Mycobacterium bovis and M. vaccae can attenuate the late-phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma.[120]

Several mechanisms might explain these relationships. The development of most autoimmune diseases depends on the TH1 cytokines IL-2 and IFN-γ, whereas the development of allergic diseases requires the TH2 cytokines IL-4 and IL-5. Initial reports that suggested an inverse relationship between the incidence of autoimmune and allergic diseases[253] led to speculation that the reciprocal down-regulation of TH1 cytokines by TH2 cytokines, and the reverse, might account for these observations. However more recent evidence supports an association between the incidence of allergic and autoimmune diseases.[131][238] These observations would fit with the concept of common mechanisms underlying infection-mediated protection against autoimmunity and allergy.

Another potential mechanism involves regulatory T cells and cytokines. The decrease in antigenic stimulation related to the decreased frequency of childhood infections has resulted in a decrease in the levels of regulatory cytokines, specifically IL-10, and possible transforming growth factor-β (TGF-β). CD25+ T cells and other regulatory T cells produce these two cytokines which, in turn, act to down-regulate both TH1 and TH2-mediated responses. Data from humans and animal models tend to support the concept that infectious agents stimulate the production of regulatory cells whose effects extend beyond the responses to the invading microbe.[11][269] IL-10 and TGF-β, which may be produced by CD25+ and other regulatory T cells,[105] can inhibit both TH1 and TH2 responses, and thus are plausible candidates as mediators of the inverse relationship between infections on the one hand and allergic and autoimmune diseases on the other.

Another hypothesized mechanism relates to stimulation of the innate immune system by viruses and bacteria and their components (such as endotoxin), which may be important in the ontogeny of the normal immune system. This is likely to be mediated by TLRs, which are receptors for various bacterial components. When TLRs bind to bacterial ligands, they stimulate mononuclear cells to produce cytokines, some of which could down-regulate allergic and autoimmune responses.

Another interesting observation relates to the presence of pets in the house and the risk of asthma. Farm animals have not been common in big European and American cities, but domestic pets are extremely common. They are a prolific source of allergen, and sensitization to these allergens is strongly associated with asthma.[158] Reports from Europe suggest that the presence of a cat in the home decreases the risk of sensitization to cat allergens.[218] Because of studies that suggest that the same effect occurs in countries where domestic animals are equally common in the homes of families with a history of asthma as in the homes of families without such history, the initially proposed explanation that this effect could be secondary to decisions by families with allergic disease not to have pets is unlikely. Ownby, Johnson, and Peterson strengthened these initial observations.[196] They report that children in a birth cohort raised in a house with two or more dogs or cats in the first year of life have not only less allergic sensitization to dog and cat as determined by skin prick tests and allergen specific IgE levels, but also less sensitization to allergens in general at age 6 to 7 years. Because domestic animals can be a source of endotoxin, this finding suggests the possibility that the effects of pets as described by Ownby, Johnson, and Peterson in the United States could be comparable to that of cows and farm animals in Europe. Mechanisms similar to those discussed earlier in this chapter involving regulatory T cells and inhibitory cytokines are being investigated to explain these findings.

Therefore, the interesting relationships between infections and immune mediated diseases, such as allergic and autoimmune diseases, and between early exposure to some allergens and the lowered risk of future allergic sensitization, potentially create new therapeutic strategies. The challenge will be to elucidate the responsible immune mechanisms involved and to determine the extent of exposure that will ensure safety and the desired outcome—the development of healthy children with a very low risk of allergic and autoimmune disease.

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OFFENDERS AND SEASONS

The allergens that generally produce allergic rhinitis have traditionally been classed as "seasonal" or "perennial" offenders. The former group consists primarily of pollens (grasses, weeds, trees), whereas the latter includes dust mites, molds, animal danders, and cockroaches. In addition to these, some patients demonstrate allergy to other unusual plants, animals, and fibers. However, in most patients, testing may be confined to a small and well-defined group of antigens.

Seasonal Antigens

Seasonal antigens are pollens, and the pollinating seasons for these offenders will vary significantly with the geographic area involved. As a general rule, the sequence proceeds from grasses (in the spring) to trees (in the spring, with the exception of mountain cedar in the winter), to weeds (generally pollinating in the fall). In some temperate climates, offenders elsewhere classed as seasonal might be essentially perennial offenders.

All allergens are not equipotent in their ability to produce symptoms. On a milligram-for-milligram basis, the most potent seasonal antigens are grasses, followed by weeds, then trees (angiosperms being more potent than gymnosperms).

Perennial Antigens

As the term implies, perennial antigens are those that might be present regardless of season. These include molds, dust mites, and animal danders. This group is sometimes expanded to include "dust." The composition of commercial dust antigen is highly variable (dust mites, animal danders, kapok and other fibers, insect parts, and molds) and is therefore not readily standardized between lots and manufacturers.

Despite the designation, some perennial antigens are more prevalent during certain times of year. Dust and dust mites, for instance, have a "season" that is the converse of the baseball season, with symptoms beginning in the fall, peaking during the winter, and declining in early spring.

The primary dust mites in the United State are Dermatophagoides pteronyssinus and Dermatophagoides farinae. These tiny mites live on skin scales and other debris and thrive in warm (65° to 80°F) and humid (at least 50%–70% relative humidity) circumstances. Their allergen is found in the fecal pellets they deposit. Significant reservoirs of dust mites include bedding, mattresses and pillows, carpets, upholstered furniture, and stuffed toys.

Molds (members of the fungi imperfecta) might be an indoor or outdoor allergen. Although outdoor mold levels drop precipitously with freezing weather, indoor mold levels remain fairly constant and might actually increase indoors when conditions of warmth and moisture are present. Significant reservoirs of mold include indoor houseplants, compost piles, leaves, and refrigerator drip pans.

It is not necessary to come in direct contact with animals to be exposed to their danders. The prime example is cat dander, which is extremely light and clings stubbornly to reservoirs such as clothing, bedding, and upholstered furniture. Studies have shown cat dander in homes and offices where no cat has ever been because of dander carried on the clothes of individuals exposed to cats.[4] Similar problems might occur with horse dander on the clothing of trainers or riders, as well as on horse blankets.

The cockroach is an often-overlooked perennial allergen. Decomposing body parts of this insect are frequently found in older homes, schools, and other buildings (even those that are clean and well maintained). Cockroach sensitivity might be a significant contributor to asthma and rhinitis.

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Cummings: Otolaryngology: Head & Neck Surgery, 4th ed.Copyright © 2005 Mosby, Inc.

IMMUNOTHERAPY INNOVATIONS

Specific immunotherapy requires testing to determine the exact antigens responsible for allergy and the administration of those antigens in doses sufficient to elicit an immune response without producing an adverse (anaphylactic) reaction. Because of the complexities involved, attention has focused on the potential for administering human, recombinant anti-IgE that would complex the specific IgE responsible for allergic symptoms, regardless of the antigens involved and without the risk of anaphylaxis. This compound, omalizumab, was initially thought to be best suited for treatment of allergic asthma but will undoubtedly find use in the management of allergic rhinitis as well.[3]

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Cummings: Otolaryngology: Head & Neck Surgery, 4th ed.Copyright © 2005 Mosby, Inc.

CONCLUSION

Allergic rhinitis might present as a distinct clinical entity or might coexist with (and contribute to) other disease states such as sinusitis, polyposis, asthma, and laryngitis. The otorhinolaryngologist should be able to suspect the presence of nasal allergy on the basis of typical history and physical examination, administer appropriate pharmacotherapy, and advise patients in proper environmental control. Testing to confirm specific inciting antigens and the administration of definitive immunotherapy might require referral but should not be outside the abilities of the properly trained otolaryngologist.

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