Allergic Rhinitis: Recent Advances

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Pediatric Allergic Disease

Allergic Rhinitis: Recent Advances

F. Estelle R. Simons, MD, FRCP(C)*

Allergic rhinitis is an inflammatory disorder of the nasal mucosa initiated by an IgE-mediated hypersensitivity. It is the most common chronic disease of the respiratory tract, occurring in approximately 10 per cent of children and over 20 per cent of adolescents and young adults. 76 Physicians frequently underestimate the importance of this disorder as a cause of morbidity, lack of productivity at school or work, and social ostracism.

PATHOPHYSIOLOGY

Patients with allergic rhinitis are predisposed to develop a prolonged immunoglobulin E antibody response within the lymphoid tissue of the respiratory tract, following exposure to inhaled allergens. When symptomatic, they have increased numbers of mast cells and basophils in the nasal mucosa and secretions. 48 Immunoglobulin E molecules are fixed to the surface of these cells by their Fc fragments. Within minutes of reexposure to inhaled, airborne allergens such as pollen to which the patient is sensitive, an antigen-IgE antibody reaction occurs, the antigen reacting with the Fab portion of the IgE molecule. The bridging of two or more cell-bound IgE molecules by allergen results in aggregation of IgE receptors on the cell surface, activation of membrane-associated proteolytic enzymes, and triggering of a cascade of enzymatic reactions within the cells. 30 These cells then undergo an energydependent, noncytolytic process in which intracellular granules fuse with the cell membrane, and preformed mediators of inflammation such as histamine, serotonin, eosinophilic and neutrophil chemotactic factors, and mast cell proteases are released into the extracellular environment. Newly formed, membrane-derived lipid mediators such as prostaglandin D2 and other arachidonic acid metabolites, lipoxygenase products such as the *Professor and Head, Section of Allergy and Clinical Immunology, Department of Pediatrics and Child Health, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

Pediatric Clinics of North America-Vol. 35, No.5, October 1988

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leukotrienes, and phospholipid metabolites such as platelet-activating factor are also released. 62 Some mediators lead to chemotaxis of cells, eosinophils, neutrophils, and mononuclear cells. Some of the cells recruited release inhibitors of mediators, or inhibitors of mediator release, thus maintaining homeostasis. Mediators of inflammation cause increased permeability of the nasal mucosa, permitting the entry of allergens, contact of allergens with submucosal mast cells, and amplification of the original allergic reaction. The mediators directly produce vasodilatation, mucosal edema, mucous secretion, stimulation of itch receptors, and reduction in the threshold for sneezing. They also disturb the autonomic balance in nervous control of nasal function leading to cholinergic predominance and associated further vascular dilatation and hypersecretion of mucus. 34 In the laboratory, after intranasal challenge with allergen in patients with allergic rhinitis, the concentration of mediators in nasal secretions increases during the early response to antigen, within an hour of exposure, and correlates with the presence of symptoms. 42,43 In patients who clinically have a late response 3 to 11 hours after challenge, the concentration of mediators increases again spontaneously without additional allergen challenge. In this late response, prostaglandin D2 production does not increase, and as this mediator is not produced by basophils, it has been suggested that they are partly responsible for the late phase response in the nasal mucosa. 43 Perennial allergic rhinitis is provoked by animal danders, house dust, house dust mites, and molds. In temperate climates, seasonal allergic rhinitis is commonly caused by nonflowering, wind-pollinated plants. Tree pollens cause symptoms in the early spring, grass pollens cause symptoms in the late spring and early summer, and ragweed and other weed pollens cause symptoms in the late summer and autumn, until frost. A priming effect on the nasal mucosa occurs after continued daily allergen exposure; that is, later in the season, smaller quantities of specific antigen cause severe nasal symptoms in patients with allergic rhinitis than at the beginning of the season.ll Although food allergens may cause acute rhinitis as part of the anaphylactic response, they infrequently are confirmed as etiologic agents in chronic allergic rhinitis. Even milk, which by history often contributes to excessive mucous production and nasal symptoms, seldom does this on an immunologic basis. Experimentally, physical and chemical factors and immunologic factors other than antigens may provoke rhinitis symptoms 14, 83, 84, 85 and mediator release. 84 The nasal mucosa of patients with rhinitis is hyperreactive to nonspecific agonists, such as histamine and methacholine, as compared to the mucosa of subjects without rhinitis. 14

DIAGNOSTIC TECHNIQUES The diagnosis of allergic rhinitis is based on a sound history and physical examination. 67 The new techniques being developed for investi-

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ALLERGIC RHINITIS: RECENT ADVANCES

MEDIATORS IN NASAL SECRETIONS DURING ANTIGEN CHAlLENGE DECONGESTANT CONTROL RAGWEED

10

Ull l

1_ Nosal • - wash

: DECONGESTANT I RAGWEED

l~llll III II l~

1

wQ

20

~ E

10

~)(

e

(I) -

zE

~~

0.5 0.1

N

E

0-:

300 200

~Q. 100 ~ I

26 48 72!

: MINUTES :

2 4 6

8 10 12 34

HOURS

MINUTES

Figure 1. Mediators in nasal secretions during early, late, and rechallenge responses of an allergic subject to nasal challenge with ragweed extract. (From Naclerio RM et ali N Engl J Med 313:65-70, 1985; with permission.)

gation of patients with allergic rhinitis and its complications are extremely useful for research purposes, but some of them give a rather restricted view of nasal abnormalities, and therefore care must be taken to interpret them in the context of clinical findings. History The symptoms of allergic rhinitis include nasal congestion (stuffy nose), sneezing, itching, and rhinorrhea or nasal discharge. Symptoms may be

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Table 1. The Differential Diagnosis of Chronic Nasal Obstruction Rhinitis 1. Allergic rhinitis 2. Infectious rhinitis, chronic, or acute (frequent recurrences) 3. Foreign body 4. Rhinitis secondary to medications (e.g., topical decongestants [alpha-adrenergic agonists and imidazoline derivatives)) 5. Nonallergic eosinophilic rhinitis 6. Vasomotor (cholinergic) rhinitis 7. Hormonal rhinitis (e.g., associated with pregnancy or hypothyroidism) 8. Atrophic rhinitis Other 1. Sinusitis 2. Anatomical abnormality, acquired (e.g., deviated septum, enlarged adenoids) 3. Nasal polyps 4. Congenital anomalies (e.g., incomplete choanal atresia, encephalocele, meningocele) 5. Tumor (e.g., angiofibroma) 6. Cerebrospinal fluid leakage secondary to perforation of the cribriform plate by fracture or tumor 7. Granulomatous disorders (e.g., Wegener's granulomatosis, sarcoidosis)

provoked by exposure to irritants such as cigarette smoke, strong paint fumes, or odors, as well as by exposure to allergens. They may be intermittent or continuous, seasonal, or year-round. Noisy breathing, oronasal breathing, "nasal voice," and snoring may be reported. Anosmia or hyposmia may occur. Repeated throat clearing and cough, especially at night, may be noted. Itching of the eyes, erythema of the bulbar conjunctivae, and lacrimation may be present in patients who have associated allergic conjunctivitis. Itching of the pharynx and palate, or symptoms such as hearing loss, "popping" of the ears and earache may be reported by some patients. Fever is unusual unless allergic rhinitis is complicated by otitis media or sinusitis. Anorexia, nausea, headaches, fatigue, irritability, loss of appetite, and other general systemic complaints may be mentioned. A family history of allergic disorders often is obtained. By taking a careful history, the physician should be able to distinguish between chronic allergic rhinitis and frequent recurrent episodes of acute rhinitis caused by viral upper respiratory infections. If the pattern of symptoms is unclear at the time of the initial history taking, the child and parents should keep a diary of symptoms. Examination of the Patient Inspection of the nose is an integral part of the physical examination in every infant and child. 67 Inspection and palpation of the external nose may reveal septal deviation, or broadening of the bony dorsum of the nose secondary to persistent nasal obstruction. The allergic salute, a term describing rubbing and dorsal manipulation of the nose, may result in a transverse wrinkle externally. Facial tics and mannerisms may be evident in a child who is attempting to avoid scratching his or her nose. After initial inspection, a topical vasoconstrictor such as oxymetazoline should be used to constrict the nasal mucosa and permit optimal visualization of the nasal cavity. Without vasoconstriction, less than the lower one

ALLERGIC RHINITIS: RECENT ADVANCES

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third of the nasal cavity can be visualized. Usually, an otoscope is used to visualize the nasal cavity, but visualization will be enhanced by use of a nasal speculum and illumination from a headlight or head mirror. The nasal septum should be checked for deviation. The mucosa has a variable color in health and disease. In patients with allergic rhinitis, it is not necessarily pale or violaceous, although it usually appears edematous and congested. Watery, mucoid, or opaque material may be noted in the nasal cavities or the posterior pharyngeal wall. Children with itchy noses often manipulate the nasal cavity and may have evidence of recent epistaxis, particularly in Kisselbach's area. Infraorbital venous congestion secondary to obstruction of venous drainage in the periorbital region may result in the so-called allergic shiners. Children with nasal obstruction who chronically breathe through the mouth may have hypertrophied gingival mucosa and halitosis. In comparison to children who breathe through the nose, they are also more likely to have long, retrognathic facies, with high narrow palates, and orthodontic anomalies such as posterior dental crossbite. 7 Pharyngeal lymphoid tissue, adenoids, tonsils, or the lymphoid tissue of the anterior cervical region may be hypertrophied; if hypertrophy of the adenoids is marked, obstructive sleep apnea, alveolar hypoventilation, and cor pulmonale may be present. On examination of the ears, retracted tympanic membranes, fluid behind the tympanic membranes, or scarring may be found. Approximately 20 per cent of patients with allergic rhinitis have middle ear abnormalities. 4 Allergic rhinitis often is associated with atopic dermatitis or asthma; hence, meticulous examination of the skin and chest is indicated. Subclinical asthma, as evidenced by asymptomatic bronchial hyperresponsiveness, is often found. 20 • 52

TESTS FOR INVESTIGATION OF ALLERGIC RHINITIS Examination of Secretions For ordinary clinical purposes, examination of nasal secretions usually consists of a search for eosinophils. The optimal method of collection of mucus is to have the child blow into a piece of nonporous paper. In infants, wiping the nose with such paper will produce a satisfactory specimen. Secretions are transferred to a glass slide and air dried before application of an eosin/methylene blue stain. In patients who have allergic rhinitis, the percentage of eosinophils in specimens prepared in this manner will be at least 10 per cent and may be 100 per cent. If polymorphonuclear leukocytes predominate in nasal secretions, and if there is evidence of degeneration of epithelial cells and destruction of cilia, infectious rhinitis should be suspected. Superficial biopsy of the nasal mucosa, using a disposable plastic curette such as a Rhinoprobe, is performed by some allergists. Metachromatic cells and basophils in the nasal secretions and in the mucosa, and mast cells in the lamina propria may be identified by this technique. Rarely, a full-thickness biopsy of the mucosa is necessary, following which specimens are submitted for electron microscopy and study of ciliary morphology.

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Fiberoptic Rhinoscopy Fiberoptic rhinoscopy examination is unnecessary for optimal diagnosis and management in most patients with allergic rhinitis. Specific indications for this type of examination are nasal obstruction unresponsive to pharmacologic treatment; unilateral nasal obstruction; serous sanguineous nasal discharge; refractory sinusitis or refractory eustachian tube obstruction; persistent hoarseness or stridor; and sleep apnea. Fiberoptic rhinoscopy is helpful in diagnosing polyps, foreign bodies, malformations, and malignancies. In children, the procedure may be technically more difficult than in adults and should be performed with the patient under local anesthesia. 60 Research Techniques Intranasal challenge tests using pharmacologic probes such as histamine, 14,84,85 methacholine,14 ammonium, sulfur dioxide; physical challenges such as cold dry air; or immunologic challenges with antigen particles or extracts have contributed greatly to our understanding of the pathophysiology of rhinitis.42, 43 Frequency of sneezes, and weight or volume of fluid secreted can be used as markers of the nasal mucosal response. Extensive investigation of nasal washings is now possible, and not only the volume of aspirated secretions, but also their content of mediators, antibodies, cells, and mucus can be measured. The rate of particle clearance can be studied. Nasal mucosa blood flow can be evaluated using 133Xe injections into the mucosa, followed by measurement of the rate of washout of radioactivity, indicating local perfusion3 or by laser-Doppler velocimetry, in which a beam of light is directed on the mucosa using a fiberoptic probe, and a shift in frequency of the beam, caused by blood cells moving in the superficial vessels is measured. 16 Other research techniques for measurement of nasal blood flow include direct measurement of mucosal temperature using thermocouples, or measurement of radiant heat flux by thermography. Nasal air flow is altered by intranasal disease, by medications, and by nonspecific factors such as inhalation of cold air or irritants, position of the patient, and physical activity. Despite these variables, measurement of resistance to air flow using synchronous recordings of flow and pressure drop through the nose by anterior or posterior rhinometry, measurement of nasal airways resistance by body plethysmography, or quantitation of the work of breathing over time have all become valuable research tools. Anterior rhinometry, the simplest and most rapid of these procedures, is a valid technique for quantifying the symptoms and signs of allergic rhinitis in children. 89 Tests for Complications of Allergic Rhinitis Children with allergic rhinitis have an increased frequency of eustachian tube obstruction and otitis media with effusion. 4 Tympanometry permits early detection and objective recording of middle ear disease, which may not be apparent on physical examination. The nine-step tympanometry test is a useful research tool for investigation of allergic phenomena in the middle ear. Intranasal challenge with antigen or histamine results in transient eustachian tube obstruction in allergic patients. 73, 74, 88

ALLERGIC RHINITIS: RECENT ADVANCES

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For investigation of sinus disease, radiographic examination using a Water's view is the most cost-effective procedure. A-mode ultrasound has been evaluated in some centers. This technique has limitations as far as diagnosis of mucosal thickening is concerned and cannot be used for diagnosis of ethmoid or sphenoid disease because these areas are not anatomically accessible to ultrasound evaluation. 54 Magnetic resonance imaging of paranasal sinuses also has been evaluated, 12 but abnormal images identified by this technique do not correlate well with clinical factors. Blood Tests Eosinophils are elevated in peripheral blood in some patients with allergic rhinitis, but a normal absolute eosinophil count does not rule out the presence of allergic disease. Similarly, total serum IgE levels may be elevated in some patients with allergic rhinitis but also may be normal, especially in patients without associated asthma or atopic dermatitis. Tests for Sensitization to Specific Allergens: Skin Tests and RAST The time-honored, well-validated method of assessing whether sensitization to allergen has occurred is to perform epicutaneous (prick) tests. Patients require such testing if they have severe allergic rhinitis symptoms, if they are not responding well to pharmacologic management of rhinitis, or if they are curious about the etiology of their symptoms and are prepared to modifY their home environment if found to be sensitized to some allergen in it. Children who have mild or infrequent symptoms of allergic rhinitis, or who respond well to simple pharmacologic management, may have skin testing deferred. Skin tests should always be performed using positive and negative control substances, for example, histamine and diluent, as well as antigens. Measurement of allergen-specific IgE in the patient's serum by the radioallergosorbent test (RAST) or enzyme allergosorbent test is preferable to skin testing in some patients with allergic rhinitis, for example, those who also suffer from severe, widespread atopic dermatitis, or those who cannot tolerate withdrawal of HI-receptor antagonists for days or weeks before skin testing. The disadvantages of the RAST include its relative lack of sensitivity compared with epicutaneous tests, interference in the RAST by high levels of IgE or by IgG blocking antibody, lack of standardization and lack of quality control of the RAST as performed in some commercial laboratories and in some physicians' offices, and the expense of the RAST.18 Titers of serum allergen-specific IgE do not necessarily correlate with symptoms of allergic rhinitis in untreated patients. 44 Both RASTs and skin tests are used to confirm the clinical history of allergic rhinitis. They should not be used in place of the history to "screen" for allergic disease. The correlation among skin testing, RAST, and nasal challenge testing is excellent for the best allergens such as pollens, although not quite as good for some other allergens such as house dust. 50 DIFFERENTIAL DIAGNOSIS OF ALLERGIC RHINITIS Patients with eosinophilic nonallergic rhinitis, like those with allergic rhinitis, may manifest profuse watery or mucoid rhinorrhea, marked nasal

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congestion, paroxysmal sneezing, and itching of the nasal mucosa, palate, and eyes, and may have perennial but intermittent symptoms after exposure to cigarette smoke or other irritants or pungent odors, and after weather changes. 57 Eosinophils are prevalent in secretions during symptomatic periods. However, evidence of specific sensitization to allergens cannot be found using skin tests or serum RASTs in these patients, and they do not have asthma or positive methacholine challenge tests. Adults with this condition may have coexisting nasal polyps. Although no long-term followup studies of patients with eosinophilic nonallergic rhinitis have been published, this condition may represent an early stage of allergic rhinitis, as some patients have positive RAST in nasal secretions, but no evidence of sensitization in the skin and the serum, to the same antigens. 40, 75 Vasorrwtor rhinitis is a nonallergic, noninfectious rhinitis characterized by increased parasympathetic activity and pathologic hyperreactivity of the nasal mucosa. 32 This disorder is uncommon in childhood. Symptoms are intermittent and perennial. They often are provoked by changes in environmental temperature or posture and by exposure to irritants. The chief symptoms are watery, profuse rhinorrhea and nasal congestion. On examination, the nasal mucosa may be edematous and pink. In vasomotor rhinitis, there are no eosinophils in the nasal secretions. Eosinophils are not present in excessive numbers in the patient's blood, and total serum immunoglobulin E is normal. No evidence of sensitization to specific antigens can be found using skin tests, RASTs, or nasal challenge tests. Rhinitis secondary to a foreign body should be suspected when unilateral, foul smelling, or bloody discharge occurs in a young child, or if nasal discharge has been unresponsive to pharmacologic treatment. Chronic infectious rhinitis is manifest by mucopurulent rhinorrhea, often associated with low-grade fever, cough, sore throat, and malaise. Sinusitis and recurrent purulent otitis media are often present. The nasal secretions contain polymorphonuclear leukocytes. Many patients with chronic infectious rhinitis have a serious underlying disorder, for example, a structural abnormality such as cleft palate or an immune deficiency disease such as hypogammaglobulinemia. Chronic rhinitis and sinusitis occur in ciliary dysfunction syndromes, associated with chronic secretory otitis media, bronchiectasis, and in some cases, situs inversus. In these disorders, cilia have ultrastructural abnormalities such as lack of dynein arms, and have an abnormal motility pattern resulting in absent or reduced mucociliary transport. 56 Rhinitis medicamentosa results from prolonged overuse of drugs that have a pronounced vasoconstrictive effect on the nasal mucosa, such as the topical imidazoline derivatives naphazoline, oxymetazoline, or xylometazoline, or the phenylamines, phenylephrine or ephedrine, or cocaine. 1 In this disorder, the nasal mucosa often appears bright red and friable. Evidence of bleeding may be present. Rhinorrhea is scanty initially but may be profuse in the later stages of the disease. 82 Rhinitis secondary to oral medications in ordinary therapeutic doses is uncommon in young patients but may be caused by drugs such as oral contraceptive steroids, antihypertensives such as reserpine, hydralazine, guanethidine, methyldopa, prazosin, beta blockers such as propranolol and timolol,31 and antidepressants such as thioridazine and perphenazine.

ALLERGIC RHINITIS: RECENT ADVANCES

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Rhinitis often occurs during pregnancy. 39 Primary atrophic rhinitis, with autosomal-dominant inheritance, rarely occurs in young patients and has its onset around puberty.2 In older patients, atrophic rhinitis usually is secondary to specific infection, granuloma, trauma, or surgery. In atrophic rhinitis, columnar epithelial cells undergo metaplastic changes to squamous cells. A high proportion of nasal epithelial cells are unciliated, and the remaining cilia are dwarfed. The mucous blanket is absent. Wide patency of the nasal cavity, yet paradoxic complaints of nasal obstruction, crusting, odiferous discharge, and anosmia are characteristic. Some patients complain of intermittent nasal obstruction but never have objective signs of chronic rhinitis. These patients may be misinterpreting normal physiologic changes in the nose (the "nasal cycle") as pathologic symptoms. Conversely, objective signs of rhinitis may be found in asymptomatic patients, for example, in a patient with a wide nose and straight septum, whereas the same degree of rhinitis in a patient with a narrow nose or a deviated septum may cause perceptible nasal obstruction. Nasal polyps are pale, mucoid, glistening, gelatinous structures that may occur as complications of rhinitis or as separate entities. The inferior turbinates, which are very easy to visualize in young patients, can occasionally be mistaken for polyps. In children and adolescents, true polyps are uncommon, and, when they are seen, the diagnosis of cystic fibrosis should be strongly suspected. Polyps are present in about one quarter of children with cystic fibrosis and may be the initial symptom ofthe disease. These patients tend to have intermittent, neutrophil-loaded purulent nasal secretions and poor response to topical corticosteroids. Allergic disease is uncommon in young patients with polyps, although the triad of asthma, nasal polyps, and acetylsalicylic acid intolerance may begin with perennial rhinitis in the second decade of life. Aspirin does not act as an allergen in this condition but rather as an inhibitor of prostaglandin synthesis. 63 Chronic sinusitis also may cause a sensation of nasal obstruction and may coexist in children with allergic rhinitis. MANAGEMENT The treatment of allergic rhinitis consists of avoidance of known provoking factors, pharmacologic management, and in selected cases, immunotherapy (allergy shots). AVOIDANCE OF PROVOKING FACTORS Patients with allergic rhinitis should try to avoid all environmental factors that are known to provoke sneezing, rhinorrhea, nasal itching, and congestion. If children are allergic to house dust, house dust mite, molds, animal danders or pollens, as far as possible, they should live in an environment free from these environmental substances. If unavoidably exposed to an allergen to which they are sensitive, they should wash their

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hands and faces, rinse the inferior nasal cavity with isotonic saline solution, and change their clothing. Well-maintained air-conditioning units have been shown to reduce indoor pollen and mold counts and associated symptoms in patients allergic to pollens and molds. 77 Similar, although unproven, beneficial effects are claimed for certain air purifying units. Nonspecific irritants such as tobacco smoke, paint fumes, chalk dust, road dust, and heavily polluted air may contribute to symptoms in patients with allergic rhinitis. Animal models suggest that some of these irritant factors, for example, diesel exhaust fumes, may have an adjuvant effect on IgE production in response to allergens. 4I , 80 Patients who sleep with the head elevated may prevent recumbencyinduced nasal obstruction. Regular vigorous exercise causes temporary vasoconstriction and relief of symptoms of nasal congestion in many patients with allergic rhinitis. Avoidance of sudden air temperature changes and avoidance of ingestion of very hot or very spicy foods may give an additional measure of symptom relief in patients who have troublesome rhinorrhea. PHARMACOLOGIC TREATMENT

Major advances in the pharmacologic treatment of allergic rhinitis have occurred in the past decade. Treatment should be highly individualized. A patient's medication requirements may be quite variable from season to season or from year to year and may range from sporadic use of a single medication for a few days or weeks, to use of several medications yearround. Four main classes of drugs are used: HI-receptor antagonists (antihistamines); adrenergic and anticholinergic drugs; disodium cromoglycate; and topical corticosteroids. HI-Receptor Antagonists Recently, there has been renewed interest in this class of drugs, with considerable reinvestigation of the first-generation Hcreceptor antagonists and the appearance of new nonsedating HI-receptor antagonists. 68, 69 All H Ireceptor antagonists are pharmacologic antagonists for histamine and exert maximal benefit if taken before an anticipated immediate hypersensitivity reaction, so that the antagonists occupy the HI receptors before the agonist (histamine) is released from adjacent mast cells or basophils. Many of the newer HI-receptor antagonists such as terfenadine, astemizole, loratadine, and cetirizine are lipophobic, do not cross the blood-brain barrier readily, and are therefore associated with a lower incidence of sedation than the first-generation drugs. Many of the newer drugs also lack anticholinergic, alpha-adrenergic blocking, local anesthetic, and antiserotonin effects. 8, 53, 78 Pharmacokinetics and pharmacodynamics (the physiologic effects over time in relation to serum concentration) are now well described for most HI-receptor antagonists. Children have shorter elimination half-life values for these drugs than adults do, but nevertheless dosing with most of the drugs, including many of the "classic" ones, dosing once or twice daily, is possible. The peak action of HI-receptor antagonists occurs hours after the mean peak serum concentrations have been attained, and a clinically and

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Table 2. Formulations and Dosage of Some Drugs Commonly Used for Rhinitis GENERIC

HI receptor antagonists Alkylamines Chlorpheniramine maleate

Brompheniramine maleate Other Astemizole

PROPRIETARY'

FORMULATION

RECOMMENDED DOSE

Chlortrimeton

Tablets 4 mg Time-release 8, 12 mg Elixir 2.5 mg/5 ml Parenteral solution 10 mg/ml Tablets 4 mg Time-release 8, 12 mg Elixir 2 mg/5 ml

Pediatric:t 0.35 mg/kg/24 hr Adult: 8-12 mg b.i.d.

Dimetane

Hismanal

Suspension 2 mg/ml Tablet 10 mg

Azatadine maleate

Optimine

Tablet 1 mg

Terfenadine

Seldane

Suspension 6 mg/ml Tablet 60 mg

Oxymetazoline hydrochloride

Nafrine

Xylometazoline hydrochloride

Otrivin

2-3 sprays or drops in 0.05% aqueous each nostril odsolution t.i.d. 0.025% pediatric solution 0.1 % aqueous solution 1-2 sprays q 8-12 hr or 2-3 drops spray or drops q 8-12 hr 0.05% pediatric solution or drops

I midazolines (topical)

i"

il

I I.

I~

Phenylamines (oral) Pseudoephedrine hydrochloride

Sudafed

Syrup 30 mg/5 ml Tablets 60 mg

Pediatric: 15 or 30 mg t.i. d. Adult: 60 mg t.i.d.

Disodium cromoglycate 2 per cent nasal solution

Rynacrom

0.8 mg/0.04 ml spray

1 spray in each nostril 6 X daily

Beconase aqueous solution Beconase Vancenase Nasolide Rhinalar

50 /Jog/spray

2 sprays each nostril b.i.d.

I:

I i"

1; I'

Pediatric: 0.35 mg/kg/24 hr Adult: 8-12 mg b. i. d. Pediatric: age 6--12 yr: 5 mg od age < 6 yr: 2 mg/10 kg od Adult: 10 mg od Pediatric: 0.5-1 mg b.i.d. Adult: 1 mg b. i. d. Pediatric: age 6--12 yr: 30 mg b.i.d. age 3--6 yr: 15 mg b.i.d. Adult: 60 mg b.i.d.

Corticosteroids (topical) Beclomethasone

i"

Flunisolide

50 /Jog/freon-propelled puff 25 /Jog/spray Mechanical pump

*One example given for each generic compound. tFor patients less than 40 kg.

Pediatric: 1 spray each nostril t.i. d. Adult: 2 sprays each nostril b. i. d. or t.i. d. initially then 1 or 2 sprays in each nostril b. i. d.

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RESPONSE TO INTRADERMAL INJECTION OF HISTAMINE 0.1 mg/ml DURING CHRONIC TERFENADINE TREATMENT

*

o

Flare (Mean S.E.M.) lSI Wheal (Mean S.E.M.) ,~ p<0.05 n=8

......... E

o ......,

14

21

28

35

42

49

56

Day Figure 2. Subsensitivity to the Hcreceptor antagonist terfenadine does not occur over 56 days of treatment; the wheal and flare responses to intradermal histamine remain significantly suppressed. (From Simons FE et al: J Allergy Clin Immunol [in press].)

statistically suppressive effect on the wheal and flare, and presumably on signs and symptoms of allergic rhinitis, is still demonstrable when serum concentrations have fallen to low levels. 70 Many of the drugs have active metabolites. One new drug, cetirizine, is the carboxylic acid metabolite of hydroxyzine and, unlike most other HI-receptor antagonists, is not metabolized in the liver but is excreted largely unchanged in the urine. At present, there are very few published double-blind trials of the new HI-receptor antagonists in children with allergic rhinitis.24 In studies in adults, in which the chief criterion for determining efficacy is patientrecorded symptom scores kept over a few weeks during the ragweed or grass pollen seasons, the newer Hcreceptor antagonists have usually but not always been found to be more effective than placebo in controlling and preventing the symptoms of rhinorrhea, nasal itching, and sneezing. Terfenadine, loratadine, and cetirizine have potency comparable to that of chlorpheniramine, as far as can be ascertained from these early studies. Astemizole is more potent that pheniramine or terfenadine,19. 28 and is as potent as hydroxyzine, the most potent first-generation Hcreceptor antagonist. 19 Astemizole is not suitable for sporadic use, as the maximal suppressive effect in the wheal and flare does not occur until several half-life values

ALLERGIC RHINITIS: RECENT ADVANCES

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have elapsed, weeks after treatment has begun. If a loading dose is given, maximal efficacy can be achieved much sooner. 19 Hcreceptor antagonists generally do not give satisfactory relief of nasal congestion. Some of the new drugs have a smaller anticholinergic effect than the first-generation drugs and may be even less effective in relieving nasal congestion than the older drugs are. Therefore, both first-generation and new Hcreceptor antagonists are marketed in fixed-dose combination with alpha-adrenergic agonists such as pseudoephedrine for enhanced decongestant effect. Synergism of Hcreceptor antagonists with H 2-receptor antagonists such as cimetidine or ranitidine mayor may not occur. 9, 61 The additional benefit is not worth the expense, inconvenience, or potential adverse effects from long-term administration of an H 2-receptor antagonist in children. HI-receptor antagonists by mouth prevent and control allergic conjunctivitis symptoms such as itching, tearing, and erythema. 5, 90. 91 Hcreceptor antagonists may be used safely in patients with allergic rhinitis who also have asthma. Most Hcreceptor antagonists result in modest, dose-related bronchodilation in patients with chronic asthma, and inhibit histamine-, antigen-, and exercise-induced asthma in the laboratory.66 Chronic administration of the first-generation Hcreceptor antagonists was formerly thought to be associated with diminished efficacy over time. 38 Recent evidence suggests that this phenomenon may be due partly to lack of compliance with drugs that are sedating when given three or four times daily, as the phenomenon does not seem to occur as readily with the new drugs. 72 Furthermore, subsensitivity was for decades attributed to autoinduction of clearance rates and shortening of half-life values for the He receptor antagonist being administered, but recent evidence suggests that autoinduction does not occur either in the animal modeFI or in humans. 72 Adrenergic Drugs Topically applied imidazoline derivatives such as xylometazoline and oxymetazoline cause vasoconstriction, blanching, and decreased edema of the nasal mucosa. These drugs are useful in patients with severe nasal blockage. They facilitate examination of the nasal mucosa and they increase nasal patency. This is especially useful before instillation of intranasal topical corticosteroids, for decreasing blockage of the eustachian tube orifices during air travel, and for decreasing obstruction of the sinus ostia and facilitating mucociliary clearance from the sinuses in patients whose allergic rhinitis is complicated by sinusitis. 69 Xylometazoline and oxymetazoline may cause rebound congestion. With prolonged use, they may cause chronic rhinitis, secondary hyperemia, tachyphylaxis, and nasal irritability. If these symptoms are then further treated with alpha-adrenergic agonist nose drops or sprays, the drugs can be very difficult to withdraw. Irreversible nasal changes secondary to the use of imidazoline derivatives have not been documented, but relief of rhinitis medicamentosa can be obtained only by withdrawal of the offending drug and treatment with inhaled corticosteroids. In infants and ymmg children, absorption of topically applied imidazoline derivatives may cause

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central nervous system depression, coma, and reduction in body temperature. The use of alpha-adrenergic agonists by mouth does not cause secondary hyperemia or development of rhinitis medicamentosa. Phenylpropanolamine is an effective nasal decongestant and also benefits eustachian tube function. 79 In some patients, it may cause hypertension and other serious side effects. 27. 29 Ephedrine, 10 or 20 mg by mouth is an effective decongestant but may also cause troublesome adverse systemic effects such as palpitations, tremor, and insomnia. Cardiomyopathy has been reported after abuse of ephedrine-containing decongestants. The efficacy of pseudoephedrine in relieving nasal congestion is well documented and the rationale for including this alpha-adrenergic agonist in fixed-dose combination with old and new HI-receptor antagonists is defended on this basis. Pseudoephedrine occasionally may cause visual hallucinations, insomnia, and agitation. 58 Short-term use of any of these sympathomimetic drugs for 5 days or less is preferable to long~term use. Anticholinergic Drugs Postsynaptic blockade of the cholinergic muscarinic receptors on the nasal mucosa, using specific acetylcholine antagonists such as ipratropium bromide, is a safe and effective alternative form of treatment for patients with rhinitis whose predominant symptom is rhinorrhea. 17. 33 Ipratropium bromide does not relieve symptoms such as itching and sneezing, which occur reflexly when sensory nerves in the nasal mucosa are stimulated, or nasal blockage, which is due to engorgement of mucosal capacitance vessels that have predominantly sympathetic innervation. However, it significantly reduces nasal discharge in patients challenged intranasally with methacholine, also in those with "hot soup" or cold air47 or irritant-induced rhinorrhea. There are no pediatric studies of ipratropium bromide in nasal disease. Although ipratropium bromide is a derivative of atropine, it is topically active, has low lipid solubility, and does not pass the blood-brain barrier. It is poorly absorbed by the oral and nasal mucosa. It does not produce adverse central nervous system or ocular effects nor does it result in cardiovascular effects. It does not inhibit salivation or affect sputum volume or movement. 65 After intranasal inhalation of high doses of ipratropium bromide, burning, irritation, or drying of the nasal mucosa has been reported. 33 Disodium Cromoglycate (Cromolyn) Cromolyn suppresses antigen-induced mediator release and nonimmunologic mediator release by chemicals, drugs, and physical stimuli. The "membrane-stabilizing action" attributed to cromolyn still is not fully understood, but it is possible that it blocks calcium channels in the plasma membrane directly and prevents calcium transport across the cell membrane. Its actions are species and tissue specific; for example, it inhibits mediator release from human mast cells, but not from human basophils. It does not inhibit the binding of immunoglobulin E to mast cells or basophils,

1067

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TOTAL NASAL SYMPTOMS ------ cromolyn - - budesonide

6

3

O+--~---~--~~--~

o

7

14

21

28

DAYS Figure 3. In a 28-day double-blind clinical comparison, budesonide resulted in lower mean daily scores for nasal symptoms than cromolyn did. (From Bjerrum P, IlIum P: Allergy 40:65-69, 1985; with permission from Munksgaard International Publishers.)

or the interaction between cell-bound immunoglobulin E and specific antigen. It does not antagonize any chemical mediator. Cromolyn is absorbed poorly after oral administration and must be inhaled or sprayed directly into the nasal cavity. In nasal challenge studies, cromolyn is remarkably effective in preventing both the early and the late responses to antigen. In clinical practice, cromolyn must be used prophylactically on a regular basis, 3 to 6 times daily. A solution of 2 or 4 per cent cromolyn preserved with 0.01 per cent benzalkonium chloride prevents sneezing, rhinorrhea, and nasal itching in patients with seasonal and perennial allergic rhinitis; it is not as effective in prevention of nasal congestion. The degree of improvement in nasal symptoms produced by cromolyn as reported in several double-blind, placebo-controlled studies of 4 to 12 weeks' duration is modest, as evidenced by patient-recorded symptom scores. 59 Nedocromil sodium, a new cromolyn-like drug, shows some promise. 13 Intranasal cromolyn does not have any significant benefit in nonallergic eosinophilic rhinitis. Nasal polyps are not reduced in size by intranasal cromolyn. When instilled in the conjunctival sac, however, cromolyn benefits patients with allergic conjunctivitis or keratoconjunctivitis.

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The chief advantage of cromolyn is its lack of toxicity. The only adverse effects that occur when it is inhaled intranasally relate to occasional irritant effects of the solution. Other adverse effects including symptoms of hypersensitivity such as laryngeal edema, angioedema, urticaria, and anaphylaxis have occurred extremely rarely following intrapulmonary inhalation of cromolyn but have not been reported after intranasal inhalation of the drug. Glucocorticosteroids The topically active synthetic glucocorticosteroids beclomethasone,46, 87 flunisolide,35 fluocortin butyl,25 and budesonide lO, 36, 87 are highly efficacious in the treatment of both seasonal and perennial allergic rhinitis, These drugs have multifactorial effects,49 including relief of inflammation, decreased capillary permeability, and decreased edema of the mucosa (vasoconstrictor effect), decreased mucous production, and decreased IgE in human nasal secretions. They decrease the number of basophils and mast cells, and of eosinophils and neutrophils in the nasal mucosa and in nasal secretions, They decrease hyperreactivity of the nasal mucosa. Topical glucocorticosteroids reduce the intranasal concentrations of mediators of inflammation not only in the late response to inhaled antigen, but also in the early response and in the rechallenge response. In contrast, pretreatment with systemic corticosteroids inhibits the late response, but not the early response to antigen, 51 Glucocorticosteroids are effective when given intranasally in very small doses,87 whether they are administered by freon-propelled metered-dose inhalers or in aqueous solution,46 They are rapidly degraded enzymatically in the nasal mucosa to less active metabolites, and any unchanged drug that is absorbed is metabolized in the first pass through the liver. The risk of suppression of the hypothalamic-pituitary-adrenal axis is small when these newer drugs are given intranasally.21 Still, there is justifiable concern about possible hypothalamic pituitary-adrenal suppression after their longterm use in patients with perennial rhinitis who require treatment for many years, in those who use excessive doses, or in those whose total glucocorticosteroid dose from all sources (nose, lung, and skin) may be high. Atrophy of the nasal mucosa has not been reported after long-term beclomethasone use, although edema and cellular infiltrates are greatly reduced. Positive culture results for Candida albicans and pathogenic bacteria are rare, Local adverse effects such as sneezing and epistaxis may occur but also are reported in patients receiving the placebo vehicle. Flunisolide is reported to cause stinging of the nasal mucosa, nausea, and the sensation of a bad taste in some patients. Inhaled intranasal glucocorticosteroids are the most potent drugs available for relief of seasonal and perennial allergic rhinitis symptoms, also for relief of nonallergic eosinophilic rhinitis. From 80 to 90 per cent of patients with seasonal symptoms will have excellent improvement, along with reduction or elimination of need for concomitant medications such as antihistamines and decongestants. For best results, patients with seasonal rhinitis should begin the medication about 1 week before pollination begins. Children must be taught how to inhale these drugs and require regular monitoring of their technique of inhalation. They should be warned that

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the therapeutic effects do not begin immediately and may not be maximal until 5 to 7 days after beginning treatment. To permit the aerosol to reach the site of action on the nasal mucosa, patients with severe nasal blockage may require a brief intensive course of treatment with antihistamines and decongestants before topical corticosteroid treatment is instituted. The response of patients with allergic rhinitis to topical glucocorticosteroids is generally so favorable that if dramatic relief does not occur after a few weeks of "proper" inhalation of the drugs, another diagnosis should be suspected. Comparative Studies of Pharmacologic Agents for Allergic Rhinitis Inhaled corticosteroids have been found to be superior to cromolyn6 ,26 and to antihistamines for relief of nasal symptoms. 5 Antihistamines relieve ocular symptoms best, however. 5. 91 The combination of inhaled beclomethasone dipropionate and ingested astemizole has been shown to be particularly potent in patients who require long-term symptom prophylaxis. 90 Nonspecific Pharmacologic Treatment Inhalation of isotonic saline or an isotonic solution of propylene glycol is soothing and helps to liquefy tenacious mucus. Antibiotics Antibiotics are not required in the treatment of rhinitis unless it is purulent; associated with structural abnormality of the upper respiratory tract, immune deficiency disease, or ciliary dysfunction; or complicated by sinusitis or otitis media. IMMUNOTHERAPY Immunotherapy is a time-consuming, inconvenient, and expensive form of treatment for patients with allergic rhinitis. Clinical benefit is measured in terms of reduction in symptoms and reduction in medication requirements, not in terms of total eradication of symptoms, or cure. Criteria for selecting patients with allergic rhinitis for immunotherapy have become more strict in recent years; this treatment now is generally reserved for patients whose symptoms are poorly controlled by optimal modification of the environment and by optimal pharmacologic management, including topical glucocorticosteroid treatment. In the past, immunotherapy has been advocated for patients with allergic rhinitis whose symptoms were controlled by medication but who had intolerable side effects, such as sedation from medications. This indication for immunotherapy now has almost disappeared because of recent advances in pharmacologic treatment. Immunotherapy consists of a series of injections of increasing doses of specific antigens identified on the basis of the patient's history, as well as on the basis of positive skin test results or RASTs performed and interpreted according to acceptable techniques. Placebo-controlled, double-blind studies of patients with ragweed pollen- , birch pollen- , or grass pollen-induced

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allergic rhinitis have shown that many patients have significant diminution of nasal symptoms and are able to reduce medication requirements after 1 or more years of antigen injection. The response to immunotherapy is clearly antigen specific and dose related, and administration of high doses of antigen are required in order to achieve significant clinical and immunologic improvement. 46 Immunotherapy has multiple immunologic effects. 15, 45, 55 Antigenspecific IgG blocking antibodies increase gradually. Although specific IgE levels may increase during the first few months of immunotherapy, as treatment proceeds, the postseasonal rise of IgE levels decreases, and after years of treatment, IgE levels eventually decline. Basophils from treated patients become less sensitive to antigen in vitro, as measured by their ability to release histamine. There is decreased lymphocyte proliferation and decreased lymphokine production in response to antigen. Antigenspecific suppressor T cells for IgE increase in numbers81 and antigenspecific T-helper cells diminish in numbers. Correlation of these immunologic findings with clinical improvement, as measured by patients' symptom scores, does not always occur. The duration of treatment required is not perfectly defined, but most allergists advocate at least a 1- to 2-year trial of therapy. If treatment is effective, it should be continued for 3 to 5 years, and then reevaluated and possibly discontinued. Old-fashioned immunotherapy for allergic rhinitis, in which multiple antigens are administered in low doses for decades, is fortunately declining in usage. Adverse effects from immunotherapy are uncommon but include large local reactions at the injection site and, rarely, generalized systemic reactions, including anaphylaxis 37 or serum sickness. 86 Promising new forms of immunotherapy are being investigated. Some modified allergens, such as those polymerized with glutaraldehyde, are safer, yet as immunogenic and effective as conventional allergens. 22 In a recent double-blind, placebo-controlled trial of polymerized whole-grass antigen administered to patients with grass pollen-induced allergic rhinitis, an accelerated dosage schedule requiring only nine weekly injections did not produce any systemic allergic reactions or very large local reactions. Patients developed elevated IgG-blocking antibody titers to grass pollens and during the grass pollen season, their symptom and medication scores were significantly lower than those of the placebo-treated patients. 22 In patients with multiple sensitivities to inhalant allergens, who received injections of individually polymerized grass, tree, and ragweed allergens, equally good results were reported. 23 Other potential advances in immunotherapy that are being explored include administration of intranasal or oral immunotherapy; injection of allergoid (formalin-treated antigen); injection of purified antigens such as ragweed antigen E; injection of allergen linked to polyethylene glycol, isologous gammaglobulin, or nonmetabolized D-amino acid copolymers; and injection of anti-idiotype antibodies. SUMMARY Our understanding of the pathophysiology of allergic rhinitis is increasing as a result of the development of new research tools for investigation

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of patients with this disorder. The pharmacologic treatment of allergic rhinitis has been greatly improved by introduction of relatively nonsedating HI-receptor antagonists and potent, topically active, glucocorticosteroids. Immunotherapy for allergic rhinitis is also changing with the times. Patient selection criteria are becoming more strict, and the introduction of safer, modified allergens with decreased allergenicity and retained immunogenicity will be a major advance.

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22. Grammer LC, Shaughnessy MA, Finkle SM et al: A double-blind, placebo-controlled trial of polymerized whole grass administered in an accelerated dosage schedule for immunotherapy of grass pollinosis. J Allergy Clin Immunol 78:1180-1184, 1986 23. Grammer LC, Shaughnessy MA, Finkle SM et al: Safety and immunogenicity of immunotherapy with polymerized tree, grass, and ragweed in patients with multiple inhalant sensitivities. J Allergy Clin Immunol 77:53-58, 1986 24. Guill MF, Buckley RH, Rocha W et al: Multicenter, double-blind, placebo-controlled trial of terfenadine suspension in the treatment of fall-allergiC rhinitis in children. J Allergy Clin Immunol 78:4-9, 1986 25. Hartley TF, Lieberman PL, Meltzer EO et al: Efficacy and tolerance of fluocortin butyl administered twice daily in adult patients with perennial rhinitis. J Allergy Clin Immunol 75:501-507, 1985 26. Hillas J, Booth RJ, Somerfield S et al: A comparative trial of intranasal beclomethasone dipropionate and sodium cromoglycate in patients with chronic perennial rhinitis. Clin Allergy 10:253-258, 1980 27. Horowitz JD, Howes LG, Christophidis N et al: Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lancet 1:60--61, 1980 28. Howarth PH, Holgate ST: Comparative trial of two nonsedative H, antihistamines, terfenadine and astemizole, for hay fever. Thorax 39:668-672, 1984 29. Howrie DL, Wolfson JH: Phenylpropanolamine-induced hypertensive seizures. J Pediatr 102:143-145, 1983 30. Ishizaka T: Analysis of triggering events in mast cells for immunoglobulin E-mediated histamine release. J Allergy Clin Immunol 67:90-96, 1981 31. Kaufman HS: Timolol-induced vasomotor rhinitis: A new iatrogenic syndrome. Arch Ophthalmol 104:967 and 970, 1986 32. Kimmelman CP, Ali GHA: Vasomotor rhinitis. Otolaryngol Clin North Am 19:65-71, 1986 33. Kirkegaard J, Mygind N, Molgaard F et al: Ordinary and high-dose ipratropium in perennial non-allergic rhinitis. J Allergy Clin Immunol 79:585-590, 1987 34. Konno A, Terada N, Okamoto Y et al: The role of chemical mediators and mucosal hyperreactivity in nasal hypersecretion in nasal allergy. J Allergy Clin Immunol 79:620626, 1987 35. Kwaselow A, McLean J, Busse W et al: A comparison of intranasal and oral flunisolide in the therapy of allergic rhinitis. Allergy 40:363-367, 1985 36. Lindqvist N, Balle VH, Karma P et al: Long-term safety and efficacy ofbudesonide nasal aerosol in perennial rhinitis. Allergy 41: 179-186, 1986 37. Lockey RF, Benedict LM, Turkeltaub PC et al: Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 79:660-677, 1987 38. Long WF, Taylor RJ, Wagner CJ et al: Skin test suppression by antihistamines and the development of subsensitivity. J Allergy Clin Immunol 76:113-117, 1985 39. Mabry RL: Rhinitis of pregnancy. South Med J 79:965-971, 1986 40. Miadonna A, Leggieri E, Tedeschi A et al: Clinical significance of specific IgE determination on nasal secretion. Clin Allergy 13:155-164, 1983 41. Muranaka M, Suzuki S, Koizumi K et al: Adjuvant activity of diesel-exhaust particulates for the production of IgE antibody in mice. J Allergy Clin Immunol 77:61~23, 1986 42. Naclerio RM, Proud D, Peters SP et al: Inflammatory mediators in nasal secretions during induced rhinitis. Clin Allergy 16:101-110, 1986 43. Naclerio RM, Proud D, Togias AG et al: Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 313:65-70, 1985 44. Nickelsen JA, Georgitis JW, Reisman RE: Lack of correlation between titers of serum allergen-specific IgE and symptoms in untreated patients with seasonal allergic rhinitis. J Allergy Clin Immunol 77:43-48, 1986 45. Norman PS: Immunotherapy. Prog Allergy 32:318-346, 1982 46. Orgel HA, Meltzer EO, Kemp JP et al: Clinical, rhinomanometric, and cytologic evaluation of seasonal allergic rhinitis treated with beclomethasone dipropionate as aqueous nasal spray or pressurized aerosol. J Allergy Clin Immunol 77:858-864, 1986 47. Ostberg B, Winther B, Mygind N: Cold air-induced rhinorrhea and high-dose ipratropium. Arch Otolaryngol Head Neck Surg 113:160-162, 1987 48. Otsuka H, Denburg J, Dolovich J et al: Heterogeneity of metachromatic cells in human nose: Significance of mucosal mast cells. J Allergy Clin Immunol 76:695-702, 1985

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49. Pauwels R: Mode of action of corticosteroids in asthma and rhinitis. Clin Allergy 16:281288, 1986 50. Peters son G, Dreborg S, Ingestad R: Clinical history, skin prick test and RAST in the diagnosis of birch and timothy pollinosis. Allergy 41:398-407, 1986 51. Pipkorn U, Proud D, Lichtenstein LM et al: Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids. N Engl J Med 316:15061510, 1987 52. Ramsdale EH, Morris MM, Roberts RS et al: Asymptomatic bronchial hyperresponsiveness in rhinitis. J Allergy Clin Immunol 75:573--577, 1985 53. Richards DM, Brogden RN, Heel RC et al: Astemizole: A review of its pharmacodynamic properties and therapeutic efficacy. Drugs 28:38-61, 1984 54. Rohr AS, Spector SL, Siegel SC et al: Correlation between A-mode ultrasound and radiography in the diagnosis of maxillary sinusitis. J Allergy Clin Immunol 78:58-61, 1986 55. Rocklin RE: Clinical and immunologic aspects of allergen-specific immunotherapy in patients with seasonal allergic rhinitis and/or allergic asthma. J Allergy Clin Immunol 72:323--334, 1983 56. Rossman CM, Lee RM, Forrest JB et al: Nasal ciliary ultrastructure and function in patients with primary ciliary dyskinesia compared with that in normal subjects and in subjects with various respiratory diseases. Am Rev Respir Dis 129:161-167, 1984 57. Rupp GH, Friedman RA: Eosinophilic non-allergic rhinitis in children. Pediatrics 70:437439, 1982 58. Sankey RJ, Nunn AJ, Sills JA: Visual hallucinations in children receiving decongestants. Br Med J 288:1369, 1984 59. Schwartz HJ: The effect of cromolyn on nasal disease. Ear Nose Throat J 65:15-26, 1986 60. Schumacher MJ: Fiberoptic nasopharyngolaryngoscopy: A procedure for allergists? J Allergy Clin Immunol 81:960-962, 1988 61. Secher C, Kirkegaard J, Borum P et al: Significance of HI and H2 receptors in the human nose: Rationale for topical use of combined antihistamine preparations. J Allergy Clin ImmunoI70:211-218, 1982 62. Serafin WE, Austen KF: Mediators of immediate hypersensitivity reactions. N Engl J Med 317:30-34, 1987 63. Settipane GA: Nasal polyps. In Settipane GA (ed): Rhinitis. Providence, Rhode Island, New England and Regional Allergy Proceedings, 1984, pp 133--140 64. Shapiro GG, Furakawa CT, Pearson WE et al: Blinded comparison of maxillary sinus radiography and ultrasound for diagnosis of sinusitis. J Allergy Clin Immunol 77:59-64, 1985 65. Simons FER: Anticholinergic drugs and the airways: "Time future contained in time past." J Allergy Clin Immunol 80:239--242, 1987 66. Simons FER: Antihistamines (Hcreceptor antagonists) in asthma. In Simons FE (ed): The Child with Asthma. Report of the Sixth Canadian Ross Conference in Pediatrics. Montreal, Ross Laboratories, 1986, pp 140-145 67. Simons FER: Chronic rhinitis. Pediatr Clin North Am 31:801-819, 1984 68. Simons FER, Simons KJ: HI-receptor ~ntagonists: Clinical pharmacology and use in allergic disease. Pediatr Clin North Am 30:899-914, 1983 69. Simons FER, Simons KJ: Pharmacologic treatment of rhinitis. Clin Rev Allergy 2:237253, 1984 70. Simons FER, Watson WTA, Simons KJ: The pharmacokinetics and pharmacodynamics of terfenadine in children. J Allergy Clin Immunol (in press) 71. Simons KJ, Simons FER: The effect of chronic administration of hydroxyzine on hydroxyzine pharmacokinetics in dogs. J Allergy Clin Immunol 79:928-932, 1987 72. Simons FER, Watson WTA, Simons KJ: Lack of subsensitivity to terfenadine during chronic terfenadine treatment. J Allergy Clin Immunol (in press) 73. Skoner DP, Doyle WJ, Fireman P: Eustachian tube obstruction (ETO) after histamine nasal provocation-a double-blind dose-response study. J Allergy Clin Immunol 79:2731, 1987 74. Skoner DP, Doyle WJ, Chamovitz AH et al: Eustachian tube obstruction after intranasal challenge with house dust mite. Arch Otolaryngol 112:840-842, 1986 75. Small P, Barrett D, Frenkiel S et al: Measurement of antigen-specific IgE in nasal secretions of patients with perennial rhinitis. Ann Allergy 55:68-71, 1985

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76. Smith JM: The epidemiology of allergic rhinitis. In Settipane GA (ed): Rhinitis. Providence, Rhode Island, New England and Regional Allergy Proceedings, 1984, pp 86-91 77. Solomon WR, Burge HA, Boise JR: Exclusion of particulate allergens by window air conditioners. J Allergy Clin Immunol 65:305-308, 1980 78. Sorkin EM, Heel RC: Terfenadine: A review of its pharmacodynamic properties and therapeutic efficacy. Drugs 29:34-56, 1985 79. Stillwagon PK, Doyle WJ, Fireman P: Effect of an antihistamine/decongestant on nasal and eustachian tube function following intranasal pollen challenge. Ann Allergy 58:442446, 1987 80. Takafuji S, Suzuki S, Koizumi K et al: Diesel-exhaust particulates inoculated by the intranasal route have an adjuvant activity for IgE production in mice. J Allergy Clin Immunol 79:639-645, 1987 81. Tamir R, Castracane JM, Rocklin RE: Generation of suppressor cells in atopic patients during immunotherapy that modulate IgE synthesis. J Allergy Clin Immunol 79:591598, 1987 82. Toohill RJ, Lehman RH, Grossman TW et al: Rhinitis medicamentosa. Laryngoscope 91:1614-1621, 1981 83. Togias AG, Naclerio RM, Peters SP et al: Local generation of sulfidopeptide leukotrienes upon nasal provocation with cold, dry air. Am Rev Respir Dis 133:1133-1137, 1986 84. Togias A, Proud D, Kagey-Sobotka A et al: The effect of a topical tricyclic antihistamine on the response of the nasal mucosa to challenge with cold, dry air and histamine. J Allergy Clin Immunol 79:599-604, 1987 85. Tonnesen P, Mygind N: Nasal challenge with serotonin and histamine in normal persons. Allergy 40:350-353, 1985 86. Umetsu DT, Hahn JS, Perez-Atayde AR et al: Serum sickness triggered by anaphylaxis: A complication of immunotherapy. J Allergy Clin Immunol 76:713-718, 1985 87. Vanzieleghem MA, Juniper EF: A comparison of budesonide and beclomethasone dipropionate nasal aerosols in ragweed-induced rhinitis. J Allergy Clin Immunol 79:887-892, 1987 88. Walker SB, Shapiro GG, Bierman CW et al: Induction of eustachian tube dysfunction with histamine nasal provocation. J Allergy Clin Immunol 76:158-162, 1985 89. Welch MJ, Meltzer EO, Orgel HA et al: Assessment of the correlation of rhinometry with the symptoms and signs of allergic rhinitis in children. Ann Allergy 55:577-579, 1985 90. Wihl J-A, Petersen BN, Petersen LN et al: Effect of the non-sedative H,-receptor antagonist astemizole in perennial allergic and non-allergic rhinitis. J Allergy Clin Immunol 75:720-727, 1985 91. Wood SF: Oral antihistamine or nasal steroid in hay fever: A double-blind double-dummy comparative study of once daily oral astemizole vs twice daily nasal beclomethasone dipropionate. Clin Allergy 16:195-201, 1986 Room AEI0l Children's Hospital of Winnipeg 840 Sherbrook Street Winnipeg, Manitoba, Canada R3A lSI