- Email: [email protected]
Allergic rhinitis
0025-7125/92 $0.00
CLINICAL ALLERGY
+ .20
ALLERGIC RHINITIS Anil K. Badhwar, MD, and Howard M. Druce, MD, FACP
Approximately 20% of the United States population, sometime during their lifetime, will sustain chronic rhinitis. 6 The treatment of allergic rhinitis has advanced with increased understanding of its pathophysiology. New medication classes, such as mediator antagonists and biological response modifiers, are under development. In this article, we review some newer concepts of pathophysiology and treatment of allergic rhinitis. INVESTIGATION OF THE PATIENT WITH ALLERGIC RHINITIS History
The history is the major diagnostic tool in recognizing allergy as a cause of rhinitis. The most common symptoms of rhinitis are paroxysms of sneezing, rhinorrhea, pruritus (nasal and palatal), and nasal obstruction. Nasal congestion may be bilateral or may alternate from side to side. Persistent unilateral obstruction suggests the presence of polyps or other structural obstruction. Nasal congestion associated with headache, purulent postnasal discharge, and halitosis suggests chronic sinusitis rather than rhinitis. Nasal itching results in nose rubbing, tickling, and picking in an effort to gain relief. In a characteristic gesture, the patient pushes the tip of the nose upward with the palm of the hand. This has been called the "allergic salute." Some patients make a classical lateral motion across the nostrils using the dorsum of hand or fingers to relieve nasal itching. Excessive mucous secretions may present as rhinorrhea, sniffing, throat clearing, and cough. Patients may complain of poor appetite and nausea due to swallowing excess mucus. If the mucus stagnates and turns yellow, patients often believe that they are infected. From the Division of Allergy and Immunology, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 4· JULY 1992
789
790
BADHW AR & DRUCE
Symptom Patterns It is important to know when the rhinitis symptoms developed. Onset in childhood makes allergic rhinitis more likely. The practitioner should enquire whether the symptoms are seasonal or perennial, daily or episodic. The duration of symptoms should be noted.
Precipitating Factors
Patients should be asked about any change in lifestyle or environment coincident with symptoms and about factors that caused the patient to seek help at this particular time. The precipitating cause may be an allergen, e.g., pollens, dust, molds, and animal-derived proteins, which cause an IgE-mediated reaction. Other irritants, such as perfumes, paint, tobacco smoke, air pollutants, or ammonia, may cause irritant nonallergic responses that mimic allergic disease. 24 Changes in environmental variables, such as temperature, relative humidity, and barometric pressure, may also induce rhinitis symptoms.
Family History
A family history of allergic rhinitis, atopic dermatitis, or asthma suggests that the rhinitis is allergic. Approximately 60% of patients with allergic rhinitis have a positive family history of allergy..,
Environmental History
A detailed history should include information that indicates possible allergic triggers. Questions about the home should include the type of heating, the presence of a basement and potential damp areas, the type of carpet in bedroom, the use of feather pillows or comforters, smokers in the home or work place, exposure to animals or to noxious chemicals, and rural versus suburban location.
Physical Examination
The physical examination should concentrate on the upper respiratory tract but also should include observations of the eyes, ears, mouth, chest, and skin (Table 1). Anterior nasal examination, using a speculum or otoscope with a nasal adapter, is sufficient only if the airway is patent. If the airway is obstructed, the use of a topical vasoconstrictor, such as 1% phenylephrine, will allow better visualization of posterior structures. Decongestion will also give an estimate of the reversibility of mucosal swelling. This can also be measured objectively by rhinomanometry.34 When doubts remain regarding abnormal anatomy or pathology, further detailed examination of the upper respiratory tract is necessary with either head mirrors or a flexible fiberoptic rhinolaryngoscope.
ALLERGIC RHINITIS
791
Table 1. PHYSICAL EXAMINATION
1. Nose a) Mucosal color-pale blue, usually seen in allergic rhinitis; deep red, boggy, usually seen in perennial nona"ergic rhinitis b) Septal deviation, septal spurs c) Nasal polyps, hypertrophy, or atrophy of turbinates d) Color of nasal discharge e) Excoriation of external nose margin, transverse crease over lower portion of the nose due to allergic salute, any external deformity 2. Eyes Conjunctivitis, puffiness, allergic shiners (periorbital cyanosis), increased lacrimation, chemosis 3. Ears Otitis media, middle ear. effusion, hearing deficit 4. Pharynx Tonsillar enlargement, hypertrophy of lymphoid tissue on posterior pharyngeal wall, postnasal discharge, halitosis 5. Sinuses Tenderness 6. Facial appearance Mouth breathing, overbite with high arched palate due to airway obstruction 7. Chest Wheezing, rhonchi
LABORATORY TESTS Nasal Cytology
The popularity of obtaining nasal smears to detect eosinophils has declined. The smears are usually obtained by asking the patient to blow the nose into plastic wrap. Scraping the mucosal surface of the inferior turbinates with a flexible, disposable, plastic probe (Rhinoprobe, 3M Diagnostic, Minneapolis, MN) is a novel and convenient technique that yields useful diagnostic information. 16 Normal nasal mucosal cytology consists of numerous epithelial cells, including ciliated and nonciliated columnar, goblet, and basal cells. There are usually no eosinophilic or basophilic cells. Few neutrophils and bacteria are seen. The main clinical utility of cytology is to differentiate infectious rhinitis (increased number of neutrophils) from allergic rhinitis (eosinophilia). The presence of eosinophilia suggests allergy but is not diagnostic, because it is also found in the nonallergic rhinitis with eosinophilia (NARES) syndrome. 15 The absence of eosinophilia does not rule out an allergic etiology. Patients with nasal eosinophilia usually respond to topical nasal steroids, regardless of etiology. Allergen Skin Testing
Epicutaneous (prick) skin testing with appropriate antigens and positive and negative control substances (histamine and saline) remains the most useful procedure in detecting specific allergic triggers associated with allergic rhinitis. A positive skin test with a wheal and flare reaction is a bioassay of specific IgE on dermal mast cells. Skin testing is rapid, specific, and sensitive. 5 Prick testing
792
BADHWAR & DRUCE
can be simplified by the use of devices or modified needles that permit uniform application of test antigens. liJ We do not advocate routine intradermal testing because of the greater incidence of false-positive tests and the greater risk of systemic reactions. Epicutaneous testing should be done with individual extracts of aeroallergen prevalent for the region where the patient lives. Standardized extracts should be used when available. Food antigens are applied only when the history suggests that certain foods induce symptoms. Positive skin prick tests that correlate with the clinical history are of value in confirming IgE-mediated reactions. In Vitro Tests for Total and Specific IgE
In vitro blood tests measure total serum IgE or specific IgE antibodies directed at defined allergens.' These tests, such as the radioallergosorbent test (RAST) for specific IgE or paper disc radioimmunosorbent test (PRIST) for total IgE, are less sensitive and may be more expensive than skin testing. Because of the wide variation in normal values and overlap in patients with clinical disease, total IgE levels are of limited value in rhinitis. In vitro tests are of use when dermographism and severe dermatitis preclude skin testing, in patients with anaphylactic sensitivity, and in patients who are unable to stop antihistamine therapy. Rhinoscopy: Flexible and Rigid
The flexible fiberoptic rhinoscope permits visualization of the upper respiratory tract, nasopharynx, openings of the Eustachian tubes, and vocal cords. 31 The rigid endoscope is employed to examine the middle meatus and maxillary sinus ostia, which cannot be seen with the flexible endoscope. These instruments are especially useful in investigating causes of nasal obstruction or postnasal drainage in suspected sinusitis but may reveal other pathologic entities, such as polyps or tumors. 36 Nasal Provocation Tests
Nasal provocation testing with suspected allergens has been applied widely in research, but several difficulties limit its usefulness as a routine clinical procedure. There has been no standardization of challenge doses, and the assessment of response varies according to the parameter under study. Techniques developed in one laboratory have generally not been verified in multiple laboratories to ensure comparability. 39 Tests of Mucociliary Clearance
Clearance of upper respiratory secretions by the cilia is critical for preserving the health of the respiratory tract. Impaired ciliary activity is difficult to measure. The best clinical test available is the saccharin transit time. 40 Some saccharin powder on a toothpick is placed on the anterior tip of the inferior turbinate. The time needed by the patient to taste the saccharin is recorded.
ALLERGIC RHINITIS
793
Values greater than 20 minutes are generally abnormal. This test is not precise, but other measurements made by biopsy and specialized microscopic techniques, such as electron or phase-contrast microscopy, are not widely available. Imaging Techniques It is often difficult to distinguish symptoms arIsmg from the paranasal sinuses from primary nasal pathology. Prolonged rhinitis, postnasal discharge, or cough may be the only presenting symptom of chronic sinusitis. Plain films of the sinuses provide useful images of the maxillary sinuses but are a poor test for visualizing the ethmoid sinuses and detecting obstruction in the area of ostiomeatal complex. For this purpose, the coronal eT scan with bone window settings is the preferred test. Other techniques, including A-mode ultrasonography, MRI, and sinus endoscopy, have limited but specialized applications. 9 Radiologic evaluation of the nasopharynx for adenoid size, shape, and position may be indicated to evaluate severe nasal obstruction, snoring, chronic otitis media, and sleep apnea. MAJOR RHINITIS SYNDROMES Seasonal Allergic Rhinitis
Seasonal allergic rhinitis includes nasal and ocular symptoms occurring during well-defined seasons (Table 2). It is caused by an IgE-mediated reaction to inhalant pollen allergens leading to mediator release, which causes mucosal edema and direct and reflex vasodilatation. The mediator release produces sneezing, itching, and rhinorrhea. Seasonal allergic rhinitis affects approximately 10% to 15% of the population. The disease is equally common in both sexes. The incidence is highest between the ages of 15 and 25 years and decreases in middle age, although the symptoms of allergic rhinitis can begin at any age. It occurs rarely in the first year of life. As observed in studies of immigrants to the United States, on average, 2 years of allergen exposure are needed for pollen-induced allergic rhinitis to develop.28 Seasonal allergic rhinitis is most frequently caused by pollens, pollen fragments, and mold spores. The pollens, molds, and their large fragments (2 to 60 f,Lm) are deposited on the nasal mucosa. The airborne allergen has to come in contact with respiratory mucosa to cause rhinitis symptoms. The amount of allergen in the air correlates well with rhinitis symptoms. Ragweed Table 2. MAJOR SYMPTOMS OF SEASONAL ALLERGIC RHINITIS Eye
Nose
Head/Neck
Systemic
Itching Lacrimation Mild soreness Puffiness Chemosis Hyperemia of conjunctiva
Watery rhinorrhea Nasal congestion Itching Allergic salute Sneezing paroxysms Postnasal drip
Sinus headache Earache Less taste/smell Mild sore throat Itching of palate and throat Throat clearing
Malaise Fatigue Poor quality sleep
794
BADHW AR & DRUCE
is the most troublesome cause of seasonal allergic rhinitis in North America. Pollination occurs predominantly between sunrise and 9 AM during the late summer and fall (August through October). The pollen concentration on any day during the season is determined mainly by the weather. In general, rain reduces the pollen amount, and high wind speeds lead to low pollen concentrations. Mold spores are released into the air when lawns are disturbed by the mowing of grass and by the raking of leaves. Damp conditions inside the home encourage the growth of molds, particularly of the genus Cladosporium and Penicillium. Aspergillus fumigatus colonizes decaying vegetation and moldy hay. The pollination seasons for the Midwestern and Eastern seaboard United States are shown in Table 3. More detailed information for selected regions is readily available in reference books and in pollen travel calendars that can be given to patients. 19 When a patient is exposed continuously to pollen, hypersensitivity of the nasal mucosa to histamine and nonspecific irritants develops. This is accompanied by a pronounced hyperreactivity of the nasal glands to parasympathetic stimulation. This nasal priming effect, described by Connell in 1969/ results in the exacerbation of rhinitis symptoms, which may then continue for some time after the peak of pollen season has passed. The priming effect has recently been shown to be due to the accumulation of neutrophils at the site of nasal challenge:s
Perennial Allergic Rhinitis
Chronic nasal symptoms are due to an IgE-mediated reaction to perennial allergens, such as house dust mite, mold, cockroach, animal saliva, urine, and dander. The signs and symptoms resemble those of seasonal allergic rhinitis, but the duration may be year round. The symptoms are present on most days, but episodic exacerbations can occur. For example, if the patient is allergic to mold, the symptoms may get worse when the patient is exposed to a contaminated air-conditioning system or damp basement or when he or she vacations near a lake or stays in a musty cabin. House dust mite-induced perennial allergic rhinitis is worse in a closed house in the winter months. The nasal symptoms are worse when the patient wakes up in the morning. In patients with animal protein-induced allergic rhinitis, symptoms can occur in an explosive manner when the patient encounters the animal sporadically. When the patient has the offending pet in the home, low-grade constant nasal congestion unrelated to handling the pet directly may occur. If the pet is removed from the home and the home is cleaned, the animal protein remains in the house dust for several months:" The persistence of symptoms may cause the patient to question the causal link. If a patient is allergic to many seasonal allergens, it may also mask a history of any seasonality. Table 3. MAJOR POLLINATION SEASONS (FOR MIDWEST AND EASTERN UNITED STATES)
Trees: end of March/April/May Grass: May/June/early July Weeds: August/September Molds: intense from July through November; absent when snow cover is present
ALLERGIC RHINITIS
795
Food-Associated Allergic Rhinitis
In adults, food allergy is a rare cause of rhinitis. In well-documented cases of IgE-mediated reactions to foods, rhinitis may occur, but other symptoms, such as swelling of the lips, urticaria, or wheezing, are often present. Rhinitis occurring after food ingestion may have another etiology, such as the vagal reflex mediating the rhinorrhea produced by ingestion of hot, spicy foods (gustatory rhinitis). Typical allergic nasal symptoms are seen in infants allergic to cow's milk. These symptoms usually start within a few days to weeks after the introduction of cow's milk feedings. The nasal symptoms are associated with nasal eosinophilia and a positive skin test to milk and can be confirmed by a double-blinded food challenge. 4 Milk is a rare cause of chronic rhinitis in patients more than 4 years of age. A negative skin test to milk is predictive of a negative food challenge. The existence of food-induced allergic rhinitis has been confirmed by double-blinded placebo-controlled food challenges to egg, milk, crustacea, peanut, wheat, and carrot in 28 of 106 (24%) subjects aged 8 months to 51 years. 3 Occupational Allergic Rhinitis
Some patients have characteristic allergic nasal symptoms provoked by exposure to allergens during work, with relief when they are away from the workplace. Occupational allergic rhinitis is probably more common than occupational asthma. 26 Okuda et aJ26 documented the existence of occupational allergic rhinitis in factory workers with characteristic work-induced nasal symptoms, pale nasal mucosa with watery rhinorrhoea, nasal eosinophilia (90%), positive immediate skin tests (96%), and nasal provocation to wood dust, red cedar, pyrethrum, cotton, silk, kallikrein, tea, and hog waste. Occupational allergic rhinitis has been seen in workers performing experimental and drug research who may be exposed regularly to rats, mice, guinea pigs, and rabbits. 13 DIFFERENTIAL DIAGNOSIS Perennial Nonallergic Rhinitis
The syndrome of perennial nonallergic rhinitis has also been called vasomotor rhinitis. The patient has persistent nasal symptoms, mainly nasal congestion and rhinorrhea, without correlation with specific allergen exposure. 24 There is no universally accepted definition of perennial nonallergic rhinitis. It may be defined as a syndrome that persists for more than 9 months each year and produces two or more of the following symptoms: serous or seromucous hypersecretion, nasal blockage, and sneezing or postnasal drainage. The onset is usually in adult life. Nasal and ocular itching are usually absent, and anosmia is common. The nasal symptoms are intensified by changes in temperature or relative humidity, alcohol ingestion, odor (perfumes, paints, tobacco, or smoke), bright lights, and hot spicy foods. The nasal congestion shifts from one nostril to the other and is relieved by exercise. Skin tests are usually negative. Episodic rhinitis induced by hot, spicy foods is caused by a vagally mediated reflex and has been called "gustatory rhinitis."3u
796
BADHW AR & DRUCE
Nonallergic Rhinitis with Eosinophilia
In 1981 Jacobs and colleagues!5 described a series of 52 patients with perennial rhinitis and nasal eosinophilia. These patients lacked evidence of allergic disease as determined by skin testing or by IgE levels. This syndrome has been associated with aspirin sensitivity, non-IgE mediated asthma, and Churg-Strauss syndrome.'"
Atrophic Rhinitis
Primary atrophic rhinitis occurs in elderly patients who report nasal congestion and a constant bad smell (ozena) in the nose!9 This condition is characterized by progressive atrophy of the nasal mucosa and underlying bone of the nose. The turbinates are small, and nasal cavities are enlarged. The etiology has not been established. Secondary atrophic rhinitis may result from Wegener's granulomatosis, chronic sinusitis, radical nasal surgery, trauma, and irradiation.
Rhinitis Medicamentosa
Rhinitis medicamentosa is defined as chronic nasal obstruction and inflammatory hypertrophy of nasal mucosa secondary to medication. It is usually caused by the repetitive use of topical alpha-adrenergic nasal decongestant sprays or other intense vasoconstrictors such as cocaine. Tachyphylaxis to nasal decongestant sprays, clinical tolerance, or rebound nasal congestion upon withdrawal may develop. The patient uses the medication more frequently to provide adequate decongestion. The nasal mucosa is very hyperemic and may show areas of punctate bleeding. Some antihypertensive agents (e.g., reserpine, phentolamine, or guanethidine) or, rarely, sympathomimetics (pseudoephedrine, phenylephrine, phenylpropanolamine) may also cause rhinitis medicamentosa.
Rhinitis Induced by Hormones
Rhinitis may be seen in hypothyroidism, pregnancy, menopause, dysautonomia, and in patients taking oral contraceptives. 48
Nasal Mastocytosis
In nasal mastocytosis, patients have symptoms of rhinorrhea and nasal congestion without pruritus. The nasal mucosa is pale and contains increased numbers of mast cells and few eosinophils. Skin tests are negative. The few studies reported suggest that these patients are usually resistant to treatment. The normal mast cell content of the nose is approximately 200 to 400 cells/mm3 of mucosa. 24 Some patients with nasal mastocytosis have more than 2000 cells/ mm3 of mucosa.
ALLERGIC RHINITIS
797
Nasal Neoplasms
Although comparatively rare, both benign and malignant tumors may cause rhinitis symptoms. The patient may present with nasal obstruction, epistaxis, pain, and otalgia. 18 TREATMENT
Treatment can be divided into four parts: (1) pharmacotherapy-symptomatic and prophylactic, (2) nonpharmacologic therapy, including environmental control, (3) immunotherapy, and (4) surgical therapy. Pharmacologic Therapy
H, Antihistamines
Antihistamines are generally used as first-line treatment for allergic rhinitis. Antihistamines are primarily helpful in controlling sneezing, itching, and rhinorrhea but are ineffective in relieving nasal blockage. 38 They are also effective in reducing associated ocular symptoms. Antihistamines are well absorbed after oral administration. The symptomatic relief of allergic symptoms may last up to 12 hours or longer with the newer agents. The antihistamines compete with histamine for binding to H, receptors. They may also inhibit mediator release (azatadine, terfenadine, ketotifen),4' inhibit tissue eosinophil influx (cetirizine)/' and act as a mild bronchodilator (terfenadine, astemizole, cetirizine).l1 Contrary to previous belief, pharmacologic tolerance to antihistamines does not occur, and poor compliance is considered to be a major factor in treatment failures. 17 Thus, there is no rationale for the practice of rotating patients through the various pharmacologic classes of antihistamines. The most common side effects of classical antihistamines are sedation, dryness of mouth, and impaired performance. The sedation can be reduced by combining an antihistamine with a decongestant, starting at a low dose and increasing the dose gradually over several days, using a long-acting classical agent at night only, or by using a new nonsedating second-generation H, antagonist. Second-generation H, Receptor Antagonists
The first-generation H, receptor antagonists produce sedation or other central nervous system symptoms in approximately 20% of patients.'3 The incidence of sedation in patients using a second-generation antihistamine is comparable to that in patients receiving placebo. The efficacy of these drugs is comparable to that of first-generation antihistamines in the treatment of patients with seasonal and perennial allergic rhinitis. They may also cause a decrease in the release of mediators, such as histamine and prostaglandin D,.47 Topical Antihistamines
Intranasally administered azelastine and levocabastine have been shown to be useful for the treatment of allergic rhinitis in preliminary studies. Currently, these agents are investigational.
798
BADHW AR & DRUCE
H2 Antihistamines Some evidence suggests that a combination of H! and H2 receptor antagonists is more effective in reducing histamine-induced nasal congestion than either an H! or H2 antagonist alone. 35 More evidence is required to recommend this combination in clinical practice. Mast Cell Stabilizing Agents
Cromolyn Sodium. Cromolyn sodium inhibits allergen-induced degranulation and mediator release from sensitized mast cells. It prevents the immediate and late onset of allergic reactions following nasal allergen challengeY Cromolyn is more effective in controlling sneezing, rhinorrhea, and nasal itching than nasal congestion. In the United States, it is available as a 4% solution delivered via a metered dose device. For effective topical nasal use, the medication must be used at least four times daily. In a few patients, cromolyn may cause sneezing or nasal stinging. Nedocromil Sodium. Nedocromil sodium is a drug that has significantly greater effects than cromolyn in inhibiting IgE-mediated histamine release from mast cells when studied in vitro. Nedocromil has been shown to be effective in improving not only sneezing and rhinorrhea but also nasal obstruction. 33 This drug has not yet received Food and Drug Administration approval for use in the United States. Decongestants
Oral decongestants are alpha-adrenergic agonists. Preparations available include pseudoephedrine, phenylpropanolamine, and phenylephrine. Their effectiveness has been proved in several controlled clinical studies. 2 The lowest dose needed to induce symptomatic relief of congestion should be used. The principal side effects of decongestants are nervousness, insomnia, irritability, headache, palpitations, and tachycardia. They may interfere with urinary flow in males and are contraindicated in glaucoma and during monoamine oxidase inhibitor therapy. Their effects on blood pressure are still in dispute. Pseudoephedrine appears to be less likely than phenylpropanolamine to elevate blood pressure, but even pseudoephedrine should be used with caution in patients with hypertension.!2 Nasal decongestant sprays and drops, such as phenylephrine, oxymetazoline, xylometazoline, and naphazoline, are also alpha-adrenergic agonists. They are potent vasoconstrictors. When used frequently, tachyphylaxis may develop. When used for more than 5 to 7 consecutive days, patients may show rebound congestion upon withdrawal of the drug. Prolonged regular use may lead to rhinitis medicamentosa. Their use should be reserved for relief in acute conditions, such as upper respiratory tract infections or acute sinusitis. Combination Preparations
The combination of an antihistamine and a decongestant in a single formulation represents a convenient way of counteracting all of the symptoms of allergic rhinitis on a short-term basis but has no effect on the underlying pathophysiology. A wide variety of proprietary combinations exist. The combination drugs have been shown to be superior to either component alone in the management of allergic rhinitis. Until recently, all of the products available in the United States contained a classical antihistamine. The first combination
ALLERGIC RHIr-..;ms
799
of a nonsedating antihistamine and a decongestant has recently been released. This product combines terfenadine with pseudoephedrine. Corticosteroids
Corticosteroids are the most effective medications available for the treatment of allergic rhinitis. They are frequently used intranasally, but, occasionally, systemic steroids are needed to control severe symptoms. Intranasal Corticosteroids. Intranasal steroids inhibit mediator release from mast cells and basophils. They reduce edema of the nasal mucosa. They are topically effective and lack systemic side effects. Nasal steroids also reduce inflammation, suppress neutrophil chemotaxis, and decrease late responses to nasal allergen challenge. 29 The nasal steroids are relatively long acting and can be used once or twice daily. Their regular use results in few symptoms and better quality of life than when the spray is taken only as required. The use of intranasal turbinate injections is not recommended in view of the reported risk of visual loss and suppressed cortisollevels. 20 Some patients may complain of nasal irritation, nasal burning, drying, and epistaxis with use of nasal sprays. Nasal steroids may occasionally cause septal perforation. 32 The epistaxis is usually due to excessive dryness of the nasal mucosa and the action of the applicator. If the patient reports epistaxis, the intranasal steroids should be stopped for a few days. A careful examination of nasal mucosa should be performed on a regular basis, at least every 6 months, in patients receiving long-term nasal steroids. Studies have shown no evidence of mucosal atrophy after several years of continuous use. l4 The therapeutic effect may take several days to develop. Maximal effect is usually seen within 2 to 6 weeks. In patients with severe nasal obstruction, a limited course of topical sympathomimetic nasal sprays, not to exceed 3 to 5 days, should be added to obtain better application and clinical effect. Systemic Steroids. In therapeutic doses, oral steroids usually abolish all nasal symptoms, but with an unacceptable risk of side effects. Systemic steroids are used occasionally in controlling severe seasonal symptoms of short duration or to gain control before using topical treatment. Depot injections of microcrystalline ester methylprednisolone acetate are effective in controlling nasal symptoms but may cause suppression of adrenal function for up to 3 weeks. Anticholinergic Preparations
Atropine is effective in reducing rhinorrhea produced by both allergic and nonallergic causes. Its use is limited by systemic side effects. Ipratropium bromide, a quaternary congener of atropine, is poorly absorbed from mucous membranes. It has been found to reduce rhinorrhea when used intranasally.44 It does not help in relieving sneezing or nasal blockage. It has not yet been approved for nasal administration in the United States. Nonpharmacologic Therapy
Nasal Saline
The application of saline to nasal mucosa acts as a mild decongestant, soothes irritated mucosa, liquefies mucus, and prevents crusting. Saline is usually administered as a nasal spray from two to four times daily in each nostril. Some patients find steam inhalations of symptomatic benefit.
800
BADHWAR & DRUCE
Table 4. ENVIRONMENTAL CONTROL General Measures 1. Keep relative humidity at 50% or less by using air conditioning and dehumidifier. 2. Eliminate irritants. especially cigarette smoke, from home. Specific Measures Pollens: use air conditioner and keep the windows of the house and car closed. Avoid outside activities during the peak of the pollen season. Molds: outdoor molds can be excluded by keeping the windows closed. Use exhaust fan in bathroom and kitchen to keep humidity less than 50%. Dust mite: cover mattresses, box spring, and pillows with an impermeable encasing. All bedding should be washed in hot water (greater than 130°F) once a week. Use synthetic pillows. Remove carpet if possible. Keep the humidity less than 50%. Pets: remove the pet from the home. If the patient does not agree to remove the pet, the pet should not be permitted in the bedroom.
Environmental Control
The patient should minimize exposure to antigens known to exacerbate symptoms as detailed in Table 4. Immunotherapy
Immunotherapy is the subcutaneous administration of increasing doses of the allergens to which the patient is sensitive. Immunotherapy should be considered in patients who cannot control symptoms with environmental control and pharmacotherapy. The patient's clinical symptoms should correlate with skin or in vitro tests. 8 Appropriate immunotherapy increases patient tolerance to natural exposure to a specific aeroallergen. It decreases the severity of symptoms and medication requirements. 25 Immunotherapy produces increases in specific IgG-blocking antibody to allergen, reduces specific IgE antibody levels, blunts the usual seasonal increase in IgE levels, reduces mast cell and basophil degranulation in response to allergen challenge, and stimulates T-Iymphocyte suppression of IgE productionY The immunotherapy is usually discontinued after 4 to 5 years of good compliance with a steady regimen. Approximately 60% of patients maintain clinical improvement after the immunotherapy is discontinued. The patient should be re-evaluated after 1 year for modification or discontinuation of immunotherapy if there is no significant improvement in clinical symptoms. Immunotherapy is not a cure for allergic rhinitis. Approximately 80% to 85% of patients have significant symptomatic relief during immunotherapy. Surgical Therapy
Various surgical procedures can be employed in rhinitis (Table 5). When nasal obstruction is totally resistant to medical therapy, it is occasionally Table 5. SURGICAL PROCEDURES IN RHINITIS
1. Septoplasty 2. Submucous resection of nasal septum 3. Procedures to reduce turbinate bulk
4. Vidian nerve section 5. Rhinoplasty 6. Polypectomy
ALLERGIC RHINITIS
801
Table 6. NOVEL THERAPEUTIC STRATEGIES IN ALLERGIC RHINITIS
Antihistamines with expanded pharmacologic spectrum Combination H, and H2 antihistamines Drugs active against specific chemical mediators Leukotrienes Platelet-activating factor Mast cell stabilizing agents Immunologic manipulation Production of IgG-blocking antibodies Modulation of T-Iymphocyte control of IgE synthesis Inhibition of IgE binding to mast cells and basophils IgE-toxin combinations Synthetic IgE fragments
necessary to perform reduction of hypertrophied turbinates or to correct a deviated nasal septum. The procedure of vidian nerve section for severe rhinorrhea has fallen out of favor, because symptoms tend to recur with nerve regrowth. INITIAL TREATMENT STRATEGY
For symptoms of sneezing, itching, and rhinorrhea, an antihistamine is usually prescribed as first-line therapy. If nasal obstruction is also present, an oral decongestant may be added either separately or in a combined preparation. When symptoms are not adequately controlled, a search should be made for anti genic triggers. If these are detected, appropriate environmental control is indicated. For chronic or severe symptoms, either cromolyn sodium or a topical nasal steroid should be prescribed. Ideally, this should be started 2 weeks before the known seasonal initiation of symptoms and should be continued until the end of the season. Anticholinergic agents can be added in intractable rhinorrhea. In patients who have failed adequate therapy as just detailed or who cannot tolerate these medications, immunotherapy may be considered. Future Directions
Various novel pharmacologic agents are under development that may reverse the pathophysiology of allergic rhinitis. The types of drugs under study are detailed in Table 6. Increased knowledge of the mechanisms involved in allergic rhinitis together with new strategies for intervention make the future bright for those individuals sustaining allergic rhinitis. ACKNOWLEDGMENT The authors thank Maria J. Weingartner for her excellent secretarial support.
References 1. Adkinson NF Jr: Measurement of total serum immunoglobulin E and allergen-specific immunoglobulin E antibody. In Rose NR, Friedman H, Fahey JL (eds): Manual of
802
2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25.
BADHWAR & DRUCE
Clinical Laboratory Immunology, ed 3. Washington, DC, American Society for Microbiology, 1986, pp 664-674 Anggard A, Maim L: Orally administered decongestant drugs in disorders of the upper respiratory passages. Clin Otolaryngol 9:43, 1984 Atkins FM, Steinberg SS, Metcalfe D: Evaluation of immediate adverse reactions to foods in adult patients: A detailed analysis of reactions during oral food challenge. J Allergy Clin Immunol 75:356, 1985 Bock SA, Lee WY, Remigio LK, et al: Studies of hypersensitivity reactions to food in infants and children. J Allergy Clin Immunol 62:327, 1978 Bousquet J: In vivo methods of study of allergy: Skin and mucosal tests, techniques and interpretation. In Middleton E Jr, Reed CE, Ellis EF, et al (eds): Allergy: Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, pp 419-436 Connell J: Nasal hypersensitivity. In Gupta S, Good RA (eds): Comprehensive Immunology: Cellular, Molecular and Clinical Aspects of Allergic Disorders. New York, Plenum Publishing, 1979, p 397 Connell JT: Quantitative intranasal pollen challenges. Ill. The priming effect in allergic rhinitis. J Allergy 43:33, 1969 Connell JT, Sherman WB: Hay fever symptoms related to immunological findings. Ann Allergy 25:239, 1967 Druce HM: Emerging techniques in the diagnosis of sinusitis. Ann Allergy 66:132, 1991 Garibaldi E, Slavin RG: Positive multi-test'" reactions do not cause false positive reactions at adjacent sites. Ann Allergy 65:481, 1990 Gong H Jr, Tashkin DP, Dauphinee B, et al: Effects of oral cetirizine, a selective HI antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol 85:632, 1990 Greening GK: The effect of an antihistamine-pseudoephedrine drug on the blood pressure of moderate hypertensives. Curr Ther Res 11:252, 1969 Gross NJ: Allergy to laboratory animals: Epidemiologic, clinical and physiologic aspects and a trial of cromolyn in its management. J Allergy Clin Immunol 66:158, 1980 Holopainen E, Malmberg H, Binder E: Long-term follow-up of intra-nasal beclomethasone treatment: A clinical and histologic study. Acta Otolaryngol Suppl 386:270, 1982 Jacobs RL, Freedman PM, Boswell RN: Non-allergic rhinitis with eosinophilia (NARES syndrome): Clinical and immunological presentation. J Allergy Clin Immunol 67:253, 1981 Jalowayski AA, Zeiger RS: Examination of nasal and conjunctival epithelial specimens. In Lawlor G}, Fischer GJ (eds): Manual of Allergy and Immunology, Diagnosis and Therapy, ed 2. Boston, Little Brown, 1986, pp 431-434 Kemp JP: Does tolerance develop with prolonged use of antihistamines? J Resp Dis 11:527, 1990 Komisar A: Nasal obstruction due to benign and malignant neoplasms. Otolaryngol Clin North America 22:351, 1989 Lewis WH, Vinay P, Senger VE: Airborne and Allergenic Pollen of North America. Baltimore, Johns Hopkins University Press, 1983 Mabry RL: Practical applications of intranasal corticosteroid injections. Ear Nose Throat J 60:23, 1981 Marks MB: Significance of discoloration in the lower orbitopalpebral grooves in allergic children (allergic shiners). Ann Allergy 21:26, 1963 Massey WA, Lichtenstein LM: The effects of antihistamines beyond HI antagonism in allergic inflammation. J Allergy Clin Immunol 86:1019, 1990 Meltzer EO: Performance effect of antihistamines. J Allergy Clin Immunol 86:613, 1990 Meltzer EO, Schatz M, Zeiger RS: Allergic and nonallergic rhinitis. In Middleton E Jr, Reed CE, Adkinson NF Jr, et al (eds): Allergy, Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, pp 1253-1290 Norman PS, Lichtenstein LM: The clinical and immunologic specificity of immunotherapy. J Allergy Clin Immunol 61:370, 1978
ALLERGIC RHINITIS
803
26. Okuda M, Ohtsuka H, Sakaguchi T, et al: Diagnostic standards for occupational nasal allergy. Rhinology 20:13, 1982 27. Pelikan Z, Pelikan-Filipek M: The effect of disodium cromoglycate and beclomethasone diproprionate on the immediate response of the nasal mucosa to allergen challenge. Ann Allergy 49:283, 1982 28. PhilIips EW: Time required for production of hay fever by a newly encountered pollen. J Allergy 11:28, 1939 29. Pipkorn U, Proud 0, Lichtenstein LM, et al: Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med 316:1506, 1987 30. Raphael GO, Hauptschein-Raphael M, Kaliner M: Gustatory rhinitis: A syndrome of food-induced rhinorrhea. J Allergy CIin Immunol 83:110, 1989 31. Rohr A, Hassner A, Saxon A: Rhinolaryngoscopy for the evaluation of allergicimmunologic disorders. Ann Allergy 50:380, 1983 32. Schoelzel EP, Menzel ML: Nasal sprays and perforation of the nasal septum. JAMA 253:2046, 1985 33. Schuller DE, SeIcow JE, Joos TH, et al: A muIticenter trial of nedocromil sodium, 1% nasal solution, compared with cromolyn sodium and placebo in ragweed seasonal allergic rhinitis. J Allergy Clin Immunol 86:554, 1990 34. Schumacher MJ: Advances in tests for the evaluation of rhinitis. Immunol Allergy Clin North Am 7:15, 1987 35. Secher e, Kirkegaard J, Borum P, et aI: Significance of H J and H2 receptors in the human nose: Rationale for topical use of combined antihistamine preparations. J Allergy Clin Immunol 70:211, 1982 36. Selner Je, Koepke JW: Rhinolaryngoscopy in the allergy office. Ann Allergy 54:479, 1985 37. Settipane GA, Klein DE: Nonallergic rhinitis: Demography of eosinophils, nasal smear, blood total eosinophil counts, and IgE levels. Allergy Proc 6:363, 1985 38. Simons FER, Simons KJ: Second-generation Hcreceptor antagonists. Ann Allergy 66:5, 1991 39. Solomon WR, McLean JA: Nasal provocative testing. In Spector SL (ed): Provocative Challenge Procedures-Background and Methodology. Mt. Kisco, NY, 1989, pp 569626 40. Stanley P, MacWilIiam L, Greenstone M, et al: Efficacy of a saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 78:62, 1984 41. Togias AG, Naclerio RM, Warner J, et al: Demonstration of inhibition of mediator release from human mast cells by azatadine base. JAMA 255:225, 1986 42. Van Arsdel PP Jr, Motulsky AG: Frequency and hereditability of asthma and allergic rhinitis in college students. Acta Genet 9:101, 1959 43. Van Metre TE, Adkinson NF Jr: Immunotherapy for aeroallergen disease. In Middleton E Jr, Reed CE, Adkinson NF Jr, et al (eds): Allergy, Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, p 1327 44. Von Haacke NP, Moore-GilIon V, Capel LH: Double-blind crossover trial of ipratropiu m and placebo in chronic rhinorrhea. Br Med J 287:1258, 1983 45. Wachs M, Proud 0, Lichtenstein LM, et al: Observations on the pathogenesis of nasal priming. J Allergy CIin Immunol 84:492, 1989 46. Wood RA, Chapman MD, Adkinson NE Jr, et al: The effect of cat removal on allergen content in household dust samples. J Allergy CIin Immunol 83:730, 1989 47. Woodward JK: Pharmacology of antihistamines. J Allergy CIin Immunol 86:606, 1990 48. Zeiger RS: Allergic and nonallergic rhinitis: Classification and pathogenesis. Am J Rhinol 3:20, 1989 49. Zohar Y, Talmi YP, Strauss M, et al: Ozaena revisited. J Otolaryngol 19:345, 1990
Address reprint requests to Howard M. Druce, MD, FACP Division of Allergy and Immunology Department of Internal Medicine St. Louis University School of Medicine 1402 S. Grand Boulevard-R209 St. Louis, MO 63104-1028
CLINICAL ALLERGY
+ .20
ALLERGIC RHINITIS Anil K. Badhwar, MD, and Howard M. Druce, MD, FACP
Approximately 20% of the United States population, sometime during their lifetime, will sustain chronic rhinitis. 6 The treatment of allergic rhinitis has advanced with increased understanding of its pathophysiology. New medication classes, such as mediator antagonists and biological response modifiers, are under development. In this article, we review some newer concepts of pathophysiology and treatment of allergic rhinitis. INVESTIGATION OF THE PATIENT WITH ALLERGIC RHINITIS History
The history is the major diagnostic tool in recognizing allergy as a cause of rhinitis. The most common symptoms of rhinitis are paroxysms of sneezing, rhinorrhea, pruritus (nasal and palatal), and nasal obstruction. Nasal congestion may be bilateral or may alternate from side to side. Persistent unilateral obstruction suggests the presence of polyps or other structural obstruction. Nasal congestion associated with headache, purulent postnasal discharge, and halitosis suggests chronic sinusitis rather than rhinitis. Nasal itching results in nose rubbing, tickling, and picking in an effort to gain relief. In a characteristic gesture, the patient pushes the tip of the nose upward with the palm of the hand. This has been called the "allergic salute." Some patients make a classical lateral motion across the nostrils using the dorsum of hand or fingers to relieve nasal itching. Excessive mucous secretions may present as rhinorrhea, sniffing, throat clearing, and cough. Patients may complain of poor appetite and nausea due to swallowing excess mucus. If the mucus stagnates and turns yellow, patients often believe that they are infected. From the Division of Allergy and Immunology, Department of Internal Medicine, St. Louis University School of Medicine, St. Louis, Missouri THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76· NUMBER 4· JULY 1992
789
790
BADHW AR & DRUCE
Symptom Patterns It is important to know when the rhinitis symptoms developed. Onset in childhood makes allergic rhinitis more likely. The practitioner should enquire whether the symptoms are seasonal or perennial, daily or episodic. The duration of symptoms should be noted.
Precipitating Factors
Patients should be asked about any change in lifestyle or environment coincident with symptoms and about factors that caused the patient to seek help at this particular time. The precipitating cause may be an allergen, e.g., pollens, dust, molds, and animal-derived proteins, which cause an IgE-mediated reaction. Other irritants, such as perfumes, paint, tobacco smoke, air pollutants, or ammonia, may cause irritant nonallergic responses that mimic allergic disease. 24 Changes in environmental variables, such as temperature, relative humidity, and barometric pressure, may also induce rhinitis symptoms.
Family History
A family history of allergic rhinitis, atopic dermatitis, or asthma suggests that the rhinitis is allergic. Approximately 60% of patients with allergic rhinitis have a positive family history of allergy..,
Environmental History
A detailed history should include information that indicates possible allergic triggers. Questions about the home should include the type of heating, the presence of a basement and potential damp areas, the type of carpet in bedroom, the use of feather pillows or comforters, smokers in the home or work place, exposure to animals or to noxious chemicals, and rural versus suburban location.
Physical Examination
The physical examination should concentrate on the upper respiratory tract but also should include observations of the eyes, ears, mouth, chest, and skin (Table 1). Anterior nasal examination, using a speculum or otoscope with a nasal adapter, is sufficient only if the airway is patent. If the airway is obstructed, the use of a topical vasoconstrictor, such as 1% phenylephrine, will allow better visualization of posterior structures. Decongestion will also give an estimate of the reversibility of mucosal swelling. This can also be measured objectively by rhinomanometry.34 When doubts remain regarding abnormal anatomy or pathology, further detailed examination of the upper respiratory tract is necessary with either head mirrors or a flexible fiberoptic rhinolaryngoscope.
ALLERGIC RHINITIS
791
Table 1. PHYSICAL EXAMINATION
1. Nose a) Mucosal color-pale blue, usually seen in allergic rhinitis; deep red, boggy, usually seen in perennial nona"ergic rhinitis b) Septal deviation, septal spurs c) Nasal polyps, hypertrophy, or atrophy of turbinates d) Color of nasal discharge e) Excoriation of external nose margin, transverse crease over lower portion of the nose due to allergic salute, any external deformity 2. Eyes Conjunctivitis, puffiness, allergic shiners (periorbital cyanosis), increased lacrimation, chemosis 3. Ears Otitis media, middle ear. effusion, hearing deficit 4. Pharynx Tonsillar enlargement, hypertrophy of lymphoid tissue on posterior pharyngeal wall, postnasal discharge, halitosis 5. Sinuses Tenderness 6. Facial appearance Mouth breathing, overbite with high arched palate due to airway obstruction 7. Chest Wheezing, rhonchi
LABORATORY TESTS Nasal Cytology
The popularity of obtaining nasal smears to detect eosinophils has declined. The smears are usually obtained by asking the patient to blow the nose into plastic wrap. Scraping the mucosal surface of the inferior turbinates with a flexible, disposable, plastic probe (Rhinoprobe, 3M Diagnostic, Minneapolis, MN) is a novel and convenient technique that yields useful diagnostic information. 16 Normal nasal mucosal cytology consists of numerous epithelial cells, including ciliated and nonciliated columnar, goblet, and basal cells. There are usually no eosinophilic or basophilic cells. Few neutrophils and bacteria are seen. The main clinical utility of cytology is to differentiate infectious rhinitis (increased number of neutrophils) from allergic rhinitis (eosinophilia). The presence of eosinophilia suggests allergy but is not diagnostic, because it is also found in the nonallergic rhinitis with eosinophilia (NARES) syndrome. 15 The absence of eosinophilia does not rule out an allergic etiology. Patients with nasal eosinophilia usually respond to topical nasal steroids, regardless of etiology. Allergen Skin Testing
Epicutaneous (prick) skin testing with appropriate antigens and positive and negative control substances (histamine and saline) remains the most useful procedure in detecting specific allergic triggers associated with allergic rhinitis. A positive skin test with a wheal and flare reaction is a bioassay of specific IgE on dermal mast cells. Skin testing is rapid, specific, and sensitive. 5 Prick testing
792
BADHWAR & DRUCE
can be simplified by the use of devices or modified needles that permit uniform application of test antigens. liJ We do not advocate routine intradermal testing because of the greater incidence of false-positive tests and the greater risk of systemic reactions. Epicutaneous testing should be done with individual extracts of aeroallergen prevalent for the region where the patient lives. Standardized extracts should be used when available. Food antigens are applied only when the history suggests that certain foods induce symptoms. Positive skin prick tests that correlate with the clinical history are of value in confirming IgE-mediated reactions. In Vitro Tests for Total and Specific IgE
In vitro blood tests measure total serum IgE or specific IgE antibodies directed at defined allergens.' These tests, such as the radioallergosorbent test (RAST) for specific IgE or paper disc radioimmunosorbent test (PRIST) for total IgE, are less sensitive and may be more expensive than skin testing. Because of the wide variation in normal values and overlap in patients with clinical disease, total IgE levels are of limited value in rhinitis. In vitro tests are of use when dermographism and severe dermatitis preclude skin testing, in patients with anaphylactic sensitivity, and in patients who are unable to stop antihistamine therapy. Rhinoscopy: Flexible and Rigid
The flexible fiberoptic rhinoscope permits visualization of the upper respiratory tract, nasopharynx, openings of the Eustachian tubes, and vocal cords. 31 The rigid endoscope is employed to examine the middle meatus and maxillary sinus ostia, which cannot be seen with the flexible endoscope. These instruments are especially useful in investigating causes of nasal obstruction or postnasal drainage in suspected sinusitis but may reveal other pathologic entities, such as polyps or tumors. 36 Nasal Provocation Tests
Nasal provocation testing with suspected allergens has been applied widely in research, but several difficulties limit its usefulness as a routine clinical procedure. There has been no standardization of challenge doses, and the assessment of response varies according to the parameter under study. Techniques developed in one laboratory have generally not been verified in multiple laboratories to ensure comparability. 39 Tests of Mucociliary Clearance
Clearance of upper respiratory secretions by the cilia is critical for preserving the health of the respiratory tract. Impaired ciliary activity is difficult to measure. The best clinical test available is the saccharin transit time. 40 Some saccharin powder on a toothpick is placed on the anterior tip of the inferior turbinate. The time needed by the patient to taste the saccharin is recorded.
ALLERGIC RHINITIS
793
Values greater than 20 minutes are generally abnormal. This test is not precise, but other measurements made by biopsy and specialized microscopic techniques, such as electron or phase-contrast microscopy, are not widely available. Imaging Techniques It is often difficult to distinguish symptoms arIsmg from the paranasal sinuses from primary nasal pathology. Prolonged rhinitis, postnasal discharge, or cough may be the only presenting symptom of chronic sinusitis. Plain films of the sinuses provide useful images of the maxillary sinuses but are a poor test for visualizing the ethmoid sinuses and detecting obstruction in the area of ostiomeatal complex. For this purpose, the coronal eT scan with bone window settings is the preferred test. Other techniques, including A-mode ultrasonography, MRI, and sinus endoscopy, have limited but specialized applications. 9 Radiologic evaluation of the nasopharynx for adenoid size, shape, and position may be indicated to evaluate severe nasal obstruction, snoring, chronic otitis media, and sleep apnea. MAJOR RHINITIS SYNDROMES Seasonal Allergic Rhinitis
Seasonal allergic rhinitis includes nasal and ocular symptoms occurring during well-defined seasons (Table 2). It is caused by an IgE-mediated reaction to inhalant pollen allergens leading to mediator release, which causes mucosal edema and direct and reflex vasodilatation. The mediator release produces sneezing, itching, and rhinorrhea. Seasonal allergic rhinitis affects approximately 10% to 15% of the population. The disease is equally common in both sexes. The incidence is highest between the ages of 15 and 25 years and decreases in middle age, although the symptoms of allergic rhinitis can begin at any age. It occurs rarely in the first year of life. As observed in studies of immigrants to the United States, on average, 2 years of allergen exposure are needed for pollen-induced allergic rhinitis to develop.28 Seasonal allergic rhinitis is most frequently caused by pollens, pollen fragments, and mold spores. The pollens, molds, and their large fragments (2 to 60 f,Lm) are deposited on the nasal mucosa. The airborne allergen has to come in contact with respiratory mucosa to cause rhinitis symptoms. The amount of allergen in the air correlates well with rhinitis symptoms. Ragweed Table 2. MAJOR SYMPTOMS OF SEASONAL ALLERGIC RHINITIS Eye
Nose
Head/Neck
Systemic
Itching Lacrimation Mild soreness Puffiness Chemosis Hyperemia of conjunctiva
Watery rhinorrhea Nasal congestion Itching Allergic salute Sneezing paroxysms Postnasal drip
Sinus headache Earache Less taste/smell Mild sore throat Itching of palate and throat Throat clearing
Malaise Fatigue Poor quality sleep
794
BADHW AR & DRUCE
is the most troublesome cause of seasonal allergic rhinitis in North America. Pollination occurs predominantly between sunrise and 9 AM during the late summer and fall (August through October). The pollen concentration on any day during the season is determined mainly by the weather. In general, rain reduces the pollen amount, and high wind speeds lead to low pollen concentrations. Mold spores are released into the air when lawns are disturbed by the mowing of grass and by the raking of leaves. Damp conditions inside the home encourage the growth of molds, particularly of the genus Cladosporium and Penicillium. Aspergillus fumigatus colonizes decaying vegetation and moldy hay. The pollination seasons for the Midwestern and Eastern seaboard United States are shown in Table 3. More detailed information for selected regions is readily available in reference books and in pollen travel calendars that can be given to patients. 19 When a patient is exposed continuously to pollen, hypersensitivity of the nasal mucosa to histamine and nonspecific irritants develops. This is accompanied by a pronounced hyperreactivity of the nasal glands to parasympathetic stimulation. This nasal priming effect, described by Connell in 1969/ results in the exacerbation of rhinitis symptoms, which may then continue for some time after the peak of pollen season has passed. The priming effect has recently been shown to be due to the accumulation of neutrophils at the site of nasal challenge:s
Perennial Allergic Rhinitis
Chronic nasal symptoms are due to an IgE-mediated reaction to perennial allergens, such as house dust mite, mold, cockroach, animal saliva, urine, and dander. The signs and symptoms resemble those of seasonal allergic rhinitis, but the duration may be year round. The symptoms are present on most days, but episodic exacerbations can occur. For example, if the patient is allergic to mold, the symptoms may get worse when the patient is exposed to a contaminated air-conditioning system or damp basement or when he or she vacations near a lake or stays in a musty cabin. House dust mite-induced perennial allergic rhinitis is worse in a closed house in the winter months. The nasal symptoms are worse when the patient wakes up in the morning. In patients with animal protein-induced allergic rhinitis, symptoms can occur in an explosive manner when the patient encounters the animal sporadically. When the patient has the offending pet in the home, low-grade constant nasal congestion unrelated to handling the pet directly may occur. If the pet is removed from the home and the home is cleaned, the animal protein remains in the house dust for several months:" The persistence of symptoms may cause the patient to question the causal link. If a patient is allergic to many seasonal allergens, it may also mask a history of any seasonality. Table 3. MAJOR POLLINATION SEASONS (FOR MIDWEST AND EASTERN UNITED STATES)
Trees: end of March/April/May Grass: May/June/early July Weeds: August/September Molds: intense from July through November; absent when snow cover is present
ALLERGIC RHINITIS
795
Food-Associated Allergic Rhinitis
In adults, food allergy is a rare cause of rhinitis. In well-documented cases of IgE-mediated reactions to foods, rhinitis may occur, but other symptoms, such as swelling of the lips, urticaria, or wheezing, are often present. Rhinitis occurring after food ingestion may have another etiology, such as the vagal reflex mediating the rhinorrhea produced by ingestion of hot, spicy foods (gustatory rhinitis). Typical allergic nasal symptoms are seen in infants allergic to cow's milk. These symptoms usually start within a few days to weeks after the introduction of cow's milk feedings. The nasal symptoms are associated with nasal eosinophilia and a positive skin test to milk and can be confirmed by a double-blinded food challenge. 4 Milk is a rare cause of chronic rhinitis in patients more than 4 years of age. A negative skin test to milk is predictive of a negative food challenge. The existence of food-induced allergic rhinitis has been confirmed by double-blinded placebo-controlled food challenges to egg, milk, crustacea, peanut, wheat, and carrot in 28 of 106 (24%) subjects aged 8 months to 51 years. 3 Occupational Allergic Rhinitis
Some patients have characteristic allergic nasal symptoms provoked by exposure to allergens during work, with relief when they are away from the workplace. Occupational allergic rhinitis is probably more common than occupational asthma. 26 Okuda et aJ26 documented the existence of occupational allergic rhinitis in factory workers with characteristic work-induced nasal symptoms, pale nasal mucosa with watery rhinorrhoea, nasal eosinophilia (90%), positive immediate skin tests (96%), and nasal provocation to wood dust, red cedar, pyrethrum, cotton, silk, kallikrein, tea, and hog waste. Occupational allergic rhinitis has been seen in workers performing experimental and drug research who may be exposed regularly to rats, mice, guinea pigs, and rabbits. 13 DIFFERENTIAL DIAGNOSIS Perennial Nonallergic Rhinitis
The syndrome of perennial nonallergic rhinitis has also been called vasomotor rhinitis. The patient has persistent nasal symptoms, mainly nasal congestion and rhinorrhea, without correlation with specific allergen exposure. 24 There is no universally accepted definition of perennial nonallergic rhinitis. It may be defined as a syndrome that persists for more than 9 months each year and produces two or more of the following symptoms: serous or seromucous hypersecretion, nasal blockage, and sneezing or postnasal drainage. The onset is usually in adult life. Nasal and ocular itching are usually absent, and anosmia is common. The nasal symptoms are intensified by changes in temperature or relative humidity, alcohol ingestion, odor (perfumes, paints, tobacco, or smoke), bright lights, and hot spicy foods. The nasal congestion shifts from one nostril to the other and is relieved by exercise. Skin tests are usually negative. Episodic rhinitis induced by hot, spicy foods is caused by a vagally mediated reflex and has been called "gustatory rhinitis."3u
796
BADHW AR & DRUCE
Nonallergic Rhinitis with Eosinophilia
In 1981 Jacobs and colleagues!5 described a series of 52 patients with perennial rhinitis and nasal eosinophilia. These patients lacked evidence of allergic disease as determined by skin testing or by IgE levels. This syndrome has been associated with aspirin sensitivity, non-IgE mediated asthma, and Churg-Strauss syndrome.'"
Atrophic Rhinitis
Primary atrophic rhinitis occurs in elderly patients who report nasal congestion and a constant bad smell (ozena) in the nose!9 This condition is characterized by progressive atrophy of the nasal mucosa and underlying bone of the nose. The turbinates are small, and nasal cavities are enlarged. The etiology has not been established. Secondary atrophic rhinitis may result from Wegener's granulomatosis, chronic sinusitis, radical nasal surgery, trauma, and irradiation.
Rhinitis Medicamentosa
Rhinitis medicamentosa is defined as chronic nasal obstruction and inflammatory hypertrophy of nasal mucosa secondary to medication. It is usually caused by the repetitive use of topical alpha-adrenergic nasal decongestant sprays or other intense vasoconstrictors such as cocaine. Tachyphylaxis to nasal decongestant sprays, clinical tolerance, or rebound nasal congestion upon withdrawal may develop. The patient uses the medication more frequently to provide adequate decongestion. The nasal mucosa is very hyperemic and may show areas of punctate bleeding. Some antihypertensive agents (e.g., reserpine, phentolamine, or guanethidine) or, rarely, sympathomimetics (pseudoephedrine, phenylephrine, phenylpropanolamine) may also cause rhinitis medicamentosa.
Rhinitis Induced by Hormones
Rhinitis may be seen in hypothyroidism, pregnancy, menopause, dysautonomia, and in patients taking oral contraceptives. 48
Nasal Mastocytosis
In nasal mastocytosis, patients have symptoms of rhinorrhea and nasal congestion without pruritus. The nasal mucosa is pale and contains increased numbers of mast cells and few eosinophils. Skin tests are negative. The few studies reported suggest that these patients are usually resistant to treatment. The normal mast cell content of the nose is approximately 200 to 400 cells/mm3 of mucosa. 24 Some patients with nasal mastocytosis have more than 2000 cells/ mm3 of mucosa.
ALLERGIC RHINITIS
797
Nasal Neoplasms
Although comparatively rare, both benign and malignant tumors may cause rhinitis symptoms. The patient may present with nasal obstruction, epistaxis, pain, and otalgia. 18 TREATMENT
Treatment can be divided into four parts: (1) pharmacotherapy-symptomatic and prophylactic, (2) nonpharmacologic therapy, including environmental control, (3) immunotherapy, and (4) surgical therapy. Pharmacologic Therapy
H, Antihistamines
Antihistamines are generally used as first-line treatment for allergic rhinitis. Antihistamines are primarily helpful in controlling sneezing, itching, and rhinorrhea but are ineffective in relieving nasal blockage. 38 They are also effective in reducing associated ocular symptoms. Antihistamines are well absorbed after oral administration. The symptomatic relief of allergic symptoms may last up to 12 hours or longer with the newer agents. The antihistamines compete with histamine for binding to H, receptors. They may also inhibit mediator release (azatadine, terfenadine, ketotifen),4' inhibit tissue eosinophil influx (cetirizine)/' and act as a mild bronchodilator (terfenadine, astemizole, cetirizine).l1 Contrary to previous belief, pharmacologic tolerance to antihistamines does not occur, and poor compliance is considered to be a major factor in treatment failures. 17 Thus, there is no rationale for the practice of rotating patients through the various pharmacologic classes of antihistamines. The most common side effects of classical antihistamines are sedation, dryness of mouth, and impaired performance. The sedation can be reduced by combining an antihistamine with a decongestant, starting at a low dose and increasing the dose gradually over several days, using a long-acting classical agent at night only, or by using a new nonsedating second-generation H, antagonist. Second-generation H, Receptor Antagonists
The first-generation H, receptor antagonists produce sedation or other central nervous system symptoms in approximately 20% of patients.'3 The incidence of sedation in patients using a second-generation antihistamine is comparable to that in patients receiving placebo. The efficacy of these drugs is comparable to that of first-generation antihistamines in the treatment of patients with seasonal and perennial allergic rhinitis. They may also cause a decrease in the release of mediators, such as histamine and prostaglandin D,.47 Topical Antihistamines
Intranasally administered azelastine and levocabastine have been shown to be useful for the treatment of allergic rhinitis in preliminary studies. Currently, these agents are investigational.
798
BADHW AR & DRUCE
H2 Antihistamines Some evidence suggests that a combination of H! and H2 receptor antagonists is more effective in reducing histamine-induced nasal congestion than either an H! or H2 antagonist alone. 35 More evidence is required to recommend this combination in clinical practice. Mast Cell Stabilizing Agents
Cromolyn Sodium. Cromolyn sodium inhibits allergen-induced degranulation and mediator release from sensitized mast cells. It prevents the immediate and late onset of allergic reactions following nasal allergen challengeY Cromolyn is more effective in controlling sneezing, rhinorrhea, and nasal itching than nasal congestion. In the United States, it is available as a 4% solution delivered via a metered dose device. For effective topical nasal use, the medication must be used at least four times daily. In a few patients, cromolyn may cause sneezing or nasal stinging. Nedocromil Sodium. Nedocromil sodium is a drug that has significantly greater effects than cromolyn in inhibiting IgE-mediated histamine release from mast cells when studied in vitro. Nedocromil has been shown to be effective in improving not only sneezing and rhinorrhea but also nasal obstruction. 33 This drug has not yet received Food and Drug Administration approval for use in the United States. Decongestants
Oral decongestants are alpha-adrenergic agonists. Preparations available include pseudoephedrine, phenylpropanolamine, and phenylephrine. Their effectiveness has been proved in several controlled clinical studies. 2 The lowest dose needed to induce symptomatic relief of congestion should be used. The principal side effects of decongestants are nervousness, insomnia, irritability, headache, palpitations, and tachycardia. They may interfere with urinary flow in males and are contraindicated in glaucoma and during monoamine oxidase inhibitor therapy. Their effects on blood pressure are still in dispute. Pseudoephedrine appears to be less likely than phenylpropanolamine to elevate blood pressure, but even pseudoephedrine should be used with caution in patients with hypertension.!2 Nasal decongestant sprays and drops, such as phenylephrine, oxymetazoline, xylometazoline, and naphazoline, are also alpha-adrenergic agonists. They are potent vasoconstrictors. When used frequently, tachyphylaxis may develop. When used for more than 5 to 7 consecutive days, patients may show rebound congestion upon withdrawal of the drug. Prolonged regular use may lead to rhinitis medicamentosa. Their use should be reserved for relief in acute conditions, such as upper respiratory tract infections or acute sinusitis. Combination Preparations
The combination of an antihistamine and a decongestant in a single formulation represents a convenient way of counteracting all of the symptoms of allergic rhinitis on a short-term basis but has no effect on the underlying pathophysiology. A wide variety of proprietary combinations exist. The combination drugs have been shown to be superior to either component alone in the management of allergic rhinitis. Until recently, all of the products available in the United States contained a classical antihistamine. The first combination
ALLERGIC RHIr-..;ms
799
of a nonsedating antihistamine and a decongestant has recently been released. This product combines terfenadine with pseudoephedrine. Corticosteroids
Corticosteroids are the most effective medications available for the treatment of allergic rhinitis. They are frequently used intranasally, but, occasionally, systemic steroids are needed to control severe symptoms. Intranasal Corticosteroids. Intranasal steroids inhibit mediator release from mast cells and basophils. They reduce edema of the nasal mucosa. They are topically effective and lack systemic side effects. Nasal steroids also reduce inflammation, suppress neutrophil chemotaxis, and decrease late responses to nasal allergen challenge. 29 The nasal steroids are relatively long acting and can be used once or twice daily. Their regular use results in few symptoms and better quality of life than when the spray is taken only as required. The use of intranasal turbinate injections is not recommended in view of the reported risk of visual loss and suppressed cortisollevels. 20 Some patients may complain of nasal irritation, nasal burning, drying, and epistaxis with use of nasal sprays. Nasal steroids may occasionally cause septal perforation. 32 The epistaxis is usually due to excessive dryness of the nasal mucosa and the action of the applicator. If the patient reports epistaxis, the intranasal steroids should be stopped for a few days. A careful examination of nasal mucosa should be performed on a regular basis, at least every 6 months, in patients receiving long-term nasal steroids. Studies have shown no evidence of mucosal atrophy after several years of continuous use. l4 The therapeutic effect may take several days to develop. Maximal effect is usually seen within 2 to 6 weeks. In patients with severe nasal obstruction, a limited course of topical sympathomimetic nasal sprays, not to exceed 3 to 5 days, should be added to obtain better application and clinical effect. Systemic Steroids. In therapeutic doses, oral steroids usually abolish all nasal symptoms, but with an unacceptable risk of side effects. Systemic steroids are used occasionally in controlling severe seasonal symptoms of short duration or to gain control before using topical treatment. Depot injections of microcrystalline ester methylprednisolone acetate are effective in controlling nasal symptoms but may cause suppression of adrenal function for up to 3 weeks. Anticholinergic Preparations
Atropine is effective in reducing rhinorrhea produced by both allergic and nonallergic causes. Its use is limited by systemic side effects. Ipratropium bromide, a quaternary congener of atropine, is poorly absorbed from mucous membranes. It has been found to reduce rhinorrhea when used intranasally.44 It does not help in relieving sneezing or nasal blockage. It has not yet been approved for nasal administration in the United States. Nonpharmacologic Therapy
Nasal Saline
The application of saline to nasal mucosa acts as a mild decongestant, soothes irritated mucosa, liquefies mucus, and prevents crusting. Saline is usually administered as a nasal spray from two to four times daily in each nostril. Some patients find steam inhalations of symptomatic benefit.
800
BADHWAR & DRUCE
Table 4. ENVIRONMENTAL CONTROL General Measures 1. Keep relative humidity at 50% or less by using air conditioning and dehumidifier. 2. Eliminate irritants. especially cigarette smoke, from home. Specific Measures Pollens: use air conditioner and keep the windows of the house and car closed. Avoid outside activities during the peak of the pollen season. Molds: outdoor molds can be excluded by keeping the windows closed. Use exhaust fan in bathroom and kitchen to keep humidity less than 50%. Dust mite: cover mattresses, box spring, and pillows with an impermeable encasing. All bedding should be washed in hot water (greater than 130°F) once a week. Use synthetic pillows. Remove carpet if possible. Keep the humidity less than 50%. Pets: remove the pet from the home. If the patient does not agree to remove the pet, the pet should not be permitted in the bedroom.
Environmental Control
The patient should minimize exposure to antigens known to exacerbate symptoms as detailed in Table 4. Immunotherapy
Immunotherapy is the subcutaneous administration of increasing doses of the allergens to which the patient is sensitive. Immunotherapy should be considered in patients who cannot control symptoms with environmental control and pharmacotherapy. The patient's clinical symptoms should correlate with skin or in vitro tests. 8 Appropriate immunotherapy increases patient tolerance to natural exposure to a specific aeroallergen. It decreases the severity of symptoms and medication requirements. 25 Immunotherapy produces increases in specific IgG-blocking antibody to allergen, reduces specific IgE antibody levels, blunts the usual seasonal increase in IgE levels, reduces mast cell and basophil degranulation in response to allergen challenge, and stimulates T-Iymphocyte suppression of IgE productionY The immunotherapy is usually discontinued after 4 to 5 years of good compliance with a steady regimen. Approximately 60% of patients maintain clinical improvement after the immunotherapy is discontinued. The patient should be re-evaluated after 1 year for modification or discontinuation of immunotherapy if there is no significant improvement in clinical symptoms. Immunotherapy is not a cure for allergic rhinitis. Approximately 80% to 85% of patients have significant symptomatic relief during immunotherapy. Surgical Therapy
Various surgical procedures can be employed in rhinitis (Table 5). When nasal obstruction is totally resistant to medical therapy, it is occasionally Table 5. SURGICAL PROCEDURES IN RHINITIS
1. Septoplasty 2. Submucous resection of nasal septum 3. Procedures to reduce turbinate bulk
4. Vidian nerve section 5. Rhinoplasty 6. Polypectomy
ALLERGIC RHINITIS
801
Table 6. NOVEL THERAPEUTIC STRATEGIES IN ALLERGIC RHINITIS
Antihistamines with expanded pharmacologic spectrum Combination H, and H2 antihistamines Drugs active against specific chemical mediators Leukotrienes Platelet-activating factor Mast cell stabilizing agents Immunologic manipulation Production of IgG-blocking antibodies Modulation of T-Iymphocyte control of IgE synthesis Inhibition of IgE binding to mast cells and basophils IgE-toxin combinations Synthetic IgE fragments
necessary to perform reduction of hypertrophied turbinates or to correct a deviated nasal septum. The procedure of vidian nerve section for severe rhinorrhea has fallen out of favor, because symptoms tend to recur with nerve regrowth. INITIAL TREATMENT STRATEGY
For symptoms of sneezing, itching, and rhinorrhea, an antihistamine is usually prescribed as first-line therapy. If nasal obstruction is also present, an oral decongestant may be added either separately or in a combined preparation. When symptoms are not adequately controlled, a search should be made for anti genic triggers. If these are detected, appropriate environmental control is indicated. For chronic or severe symptoms, either cromolyn sodium or a topical nasal steroid should be prescribed. Ideally, this should be started 2 weeks before the known seasonal initiation of symptoms and should be continued until the end of the season. Anticholinergic agents can be added in intractable rhinorrhea. In patients who have failed adequate therapy as just detailed or who cannot tolerate these medications, immunotherapy may be considered. Future Directions
Various novel pharmacologic agents are under development that may reverse the pathophysiology of allergic rhinitis. The types of drugs under study are detailed in Table 6. Increased knowledge of the mechanisms involved in allergic rhinitis together with new strategies for intervention make the future bright for those individuals sustaining allergic rhinitis. ACKNOWLEDGMENT The authors thank Maria J. Weingartner for her excellent secretarial support.
References 1. Adkinson NF Jr: Measurement of total serum immunoglobulin E and allergen-specific immunoglobulin E antibody. In Rose NR, Friedman H, Fahey JL (eds): Manual of
802
2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
21. 22. 23. 24. 25.
BADHWAR & DRUCE
Clinical Laboratory Immunology, ed 3. Washington, DC, American Society for Microbiology, 1986, pp 664-674 Anggard A, Maim L: Orally administered decongestant drugs in disorders of the upper respiratory passages. Clin Otolaryngol 9:43, 1984 Atkins FM, Steinberg SS, Metcalfe D: Evaluation of immediate adverse reactions to foods in adult patients: A detailed analysis of reactions during oral food challenge. J Allergy Clin Immunol 75:356, 1985 Bock SA, Lee WY, Remigio LK, et al: Studies of hypersensitivity reactions to food in infants and children. J Allergy Clin Immunol 62:327, 1978 Bousquet J: In vivo methods of study of allergy: Skin and mucosal tests, techniques and interpretation. In Middleton E Jr, Reed CE, Ellis EF, et al (eds): Allergy: Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, pp 419-436 Connell J: Nasal hypersensitivity. In Gupta S, Good RA (eds): Comprehensive Immunology: Cellular, Molecular and Clinical Aspects of Allergic Disorders. New York, Plenum Publishing, 1979, p 397 Connell JT: Quantitative intranasal pollen challenges. Ill. The priming effect in allergic rhinitis. J Allergy 43:33, 1969 Connell JT, Sherman WB: Hay fever symptoms related to immunological findings. Ann Allergy 25:239, 1967 Druce HM: Emerging techniques in the diagnosis of sinusitis. Ann Allergy 66:132, 1991 Garibaldi E, Slavin RG: Positive multi-test'" reactions do not cause false positive reactions at adjacent sites. Ann Allergy 65:481, 1990 Gong H Jr, Tashkin DP, Dauphinee B, et al: Effects of oral cetirizine, a selective HI antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol 85:632, 1990 Greening GK: The effect of an antihistamine-pseudoephedrine drug on the blood pressure of moderate hypertensives. Curr Ther Res 11:252, 1969 Gross NJ: Allergy to laboratory animals: Epidemiologic, clinical and physiologic aspects and a trial of cromolyn in its management. J Allergy Clin Immunol 66:158, 1980 Holopainen E, Malmberg H, Binder E: Long-term follow-up of intra-nasal beclomethasone treatment: A clinical and histologic study. Acta Otolaryngol Suppl 386:270, 1982 Jacobs RL, Freedman PM, Boswell RN: Non-allergic rhinitis with eosinophilia (NARES syndrome): Clinical and immunological presentation. J Allergy Clin Immunol 67:253, 1981 Jalowayski AA, Zeiger RS: Examination of nasal and conjunctival epithelial specimens. In Lawlor G}, Fischer GJ (eds): Manual of Allergy and Immunology, Diagnosis and Therapy, ed 2. Boston, Little Brown, 1986, pp 431-434 Kemp JP: Does tolerance develop with prolonged use of antihistamines? J Resp Dis 11:527, 1990 Komisar A: Nasal obstruction due to benign and malignant neoplasms. Otolaryngol Clin North America 22:351, 1989 Lewis WH, Vinay P, Senger VE: Airborne and Allergenic Pollen of North America. Baltimore, Johns Hopkins University Press, 1983 Mabry RL: Practical applications of intranasal corticosteroid injections. Ear Nose Throat J 60:23, 1981 Marks MB: Significance of discoloration in the lower orbitopalpebral grooves in allergic children (allergic shiners). Ann Allergy 21:26, 1963 Massey WA, Lichtenstein LM: The effects of antihistamines beyond HI antagonism in allergic inflammation. J Allergy Clin Immunol 86:1019, 1990 Meltzer EO: Performance effect of antihistamines. J Allergy Clin Immunol 86:613, 1990 Meltzer EO, Schatz M, Zeiger RS: Allergic and nonallergic rhinitis. In Middleton E Jr, Reed CE, Adkinson NF Jr, et al (eds): Allergy, Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, pp 1253-1290 Norman PS, Lichtenstein LM: The clinical and immunologic specificity of immunotherapy. J Allergy Clin Immunol 61:370, 1978
ALLERGIC RHINITIS
803
26. Okuda M, Ohtsuka H, Sakaguchi T, et al: Diagnostic standards for occupational nasal allergy. Rhinology 20:13, 1982 27. Pelikan Z, Pelikan-Filipek M: The effect of disodium cromoglycate and beclomethasone diproprionate on the immediate response of the nasal mucosa to allergen challenge. Ann Allergy 49:283, 1982 28. PhilIips EW: Time required for production of hay fever by a newly encountered pollen. J Allergy 11:28, 1939 29. Pipkorn U, Proud 0, Lichtenstein LM, et al: Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med 316:1506, 1987 30. Raphael GO, Hauptschein-Raphael M, Kaliner M: Gustatory rhinitis: A syndrome of food-induced rhinorrhea. J Allergy CIin Immunol 83:110, 1989 31. Rohr A, Hassner A, Saxon A: Rhinolaryngoscopy for the evaluation of allergicimmunologic disorders. Ann Allergy 50:380, 1983 32. Schoelzel EP, Menzel ML: Nasal sprays and perforation of the nasal septum. JAMA 253:2046, 1985 33. Schuller DE, SeIcow JE, Joos TH, et al: A muIticenter trial of nedocromil sodium, 1% nasal solution, compared with cromolyn sodium and placebo in ragweed seasonal allergic rhinitis. J Allergy Clin Immunol 86:554, 1990 34. Schumacher MJ: Advances in tests for the evaluation of rhinitis. Immunol Allergy Clin North Am 7:15, 1987 35. Secher e, Kirkegaard J, Borum P, et aI: Significance of H J and H2 receptors in the human nose: Rationale for topical use of combined antihistamine preparations. J Allergy Clin Immunol 70:211, 1982 36. Selner Je, Koepke JW: Rhinolaryngoscopy in the allergy office. Ann Allergy 54:479, 1985 37. Settipane GA, Klein DE: Nonallergic rhinitis: Demography of eosinophils, nasal smear, blood total eosinophil counts, and IgE levels. Allergy Proc 6:363, 1985 38. Simons FER, Simons KJ: Second-generation Hcreceptor antagonists. Ann Allergy 66:5, 1991 39. Solomon WR, McLean JA: Nasal provocative testing. In Spector SL (ed): Provocative Challenge Procedures-Background and Methodology. Mt. Kisco, NY, 1989, pp 569626 40. Stanley P, MacWilIiam L, Greenstone M, et al: Efficacy of a saccharin test for screening to detect abnormal mucociliary clearance. Br J Dis Chest 78:62, 1984 41. Togias AG, Naclerio RM, Warner J, et al: Demonstration of inhibition of mediator release from human mast cells by azatadine base. JAMA 255:225, 1986 42. Van Arsdel PP Jr, Motulsky AG: Frequency and hereditability of asthma and allergic rhinitis in college students. Acta Genet 9:101, 1959 43. Van Metre TE, Adkinson NF Jr: Immunotherapy for aeroallergen disease. In Middleton E Jr, Reed CE, Adkinson NF Jr, et al (eds): Allergy, Principles and Practice, ed 3. St. Louis, Mosby Year Book, 1988, p 1327 44. Von Haacke NP, Moore-GilIon V, Capel LH: Double-blind crossover trial of ipratropiu m and placebo in chronic rhinorrhea. Br Med J 287:1258, 1983 45. Wachs M, Proud 0, Lichtenstein LM, et al: Observations on the pathogenesis of nasal priming. J Allergy CIin Immunol 84:492, 1989 46. Wood RA, Chapman MD, Adkinson NE Jr, et al: The effect of cat removal on allergen content in household dust samples. J Allergy CIin Immunol 83:730, 1989 47. Woodward JK: Pharmacology of antihistamines. J Allergy CIin Immunol 86:606, 1990 48. Zeiger RS: Allergic and nonallergic rhinitis: Classification and pathogenesis. Am J Rhinol 3:20, 1989 49. Zohar Y, Talmi YP, Strauss M, et al: Ozaena revisited. J Otolaryngol 19:345, 1990
Address reprint requests to Howard M. Druce, MD, FACP Division of Allergy and Immunology Department of Internal Medicine St. Louis University School of Medicine 1402 S. Grand Boulevard-R209 St. Louis, MO 63104-1028