key: cord-022658-mq91h15t
authors: nan
title: Executive summary
date: 2008-12-30
journal: Allergy
DOI: 10.1111/j.1398-9995.1998.tb04885.x
sha: 
doc_id: 22658
cord_uid: mq91h15t

Allergic rhinitis is now recognized as a major cause of morbidity that significantly impairs function and quality of life. Moreover, it is now widely held that the pathophysiologic mechanisms causing nasal allergy contribute, or predispose many individuals, to the development of other airway diseases, including asthma. Allergic rhinitis may well be a factor in 24% of children with otitis media with effusion (OME), and perhaps 28% of cases of chronic sinusitis. As many as 78% of persons with asthma aged 15 to 30 years have elevated serum IgE antibodies to five common aeroallergens. In many instances, nasal allergy signals the presence of more severe disease. Considerable evidence now suggests that early and appropriate intervention can improve the quality of life and productivity of patients with allergic rhinitis, enhance the academic performance of children, and reduce the prevalence of airway complications. The goal of treatment has shifted from mere symptom alleviation to blocking the pathophysiologic mechanisms that cause chronic allergic inflammation and leave patients vulnerable to airway infections. The earlier in a patient's life that this can be accomplished, the better the anticipated consequences. A panel of experts was convened in Amsterdam, The Netherlands, on 2 September 1996, to explore these issues and their impact on allergy prevention and treatment in primary care. Their undertaking was supported by an unrestricted educational grant from Schering‐Plough Pharmaceuticals.

Allergic inflammation appears to be the first and primary occurrence in the chain of events leading to asthma and other airway disorders. Chemical mediators released during hypersensitivity reactions give rise to the symptoms of allergic rhinitis, and induce the cell infiltration and activation that results in chronic inflammation. A key event in this process is the upregulation of specific intercellular adhesion molecules, including members of the immunoglobulin superfamily intercellular adhesion molecule-1 (ICAM-l), that permits inflammatory cells to migrate into nasal, sinus, and lung tissue. In certain conditions, inflammatory mediators stimulate the expression of ICAM-1, which is also a receptor for the subtype of human rhinoviruses that accounts for 90% of human rhinovirus infections. It is currently under investigation that allergen exposure and viral infection in the first 3 years of life may alter pulmonary and immune function irreversibly in genetically predisposed children. * Moreover, these same mechanisms may contribute to other respiratory problems associated with eosinophilic inflammation, lymphoid hyperplasia, mucosal edema, and viral infection.

Therapies that downregulate ICAM-1 are being investigated as a means of preventing or minimizing allergic inflammation. Treatments presently known to downregulate ICAM-1 include antihistamines (loratadine, terfenadine, cetirizine, and azelastine).

Allergic rhinitis is associated with impairments in how patients function physically, emotionally, socially, and at work or school. Adults may complain of role and activity limitations, frustration, sleep disturbance, irritability, embarrassment over symptoms, cognitive impairment, decreased alertness, and performance deficits. In children, chronic nasal allergies are associated with learning deficits.

Unfortunately, sedating antihistamines can exacerbate these effects by hampering performance and cognition even when subjects have no sense of being impaired. At least one of the newer nonsedating agents, by contrast, can partially reverse allergic rhinitis' effect on cognition and performance.

Nasal allergy may usually be differentiated from other forms of rhinitis by an allergy diagnosis. This includes personal history of symptoms, the timing of their expression, triggers, and physical examination. Skin prick tests and eventually in vitro diagnosis of specific IgE are important. Imaging studies are usually indicated only if the diagnosis is in doubt, if related airway disorders complicate the presentation (e.g., nasal polyps), or when occupational rhinitis is suspected. The

The impact of allergic rhinitis temporal association of nasal or ocular symptoms with the workplace strongly suggests occupational rhinitis.

Treatment of chronic rhinitis and nasal allergies should be individualized, with therapeutic measures aimed at the underlying etiology, likely pathophysiology, and dominant symptoms. Medication is best taken prophylactically for seasonal symptoms before the anticipated onset of symptoms in seasonal rhinitis or for episodic exposures to specific aIlergensand regularly, rather than as needed. Such usage of antihistamines and intranasal steroids has been found to alleviate exacerbations in patients with both nasal allergy and seasonally induced asthma.

Avoidance of inciting factors (e.g., allergens, irritants) can reduce the expression of nasal symptoms and minimize the need for medications. The avoidance measures that are easiest to implement are the ones most likely to be used and therefore to be successful.

Antihistamines. Although traditional agents have some benefits (e.g., low cost), they can no longer be recommended due to their potential for causing CNS impairment. Nonsedating anthstamines are the preferred option. Oral decongestants. Although topical steroids are the first-line treatments for nasal blockage, a-adrenergic agonists such as pseudoephedrine, phenylpropanolamine, or phenylephrine also ameliorate nasal congestion. This symptom is a major factor in perennial rhinitis. Careful dosing of agonists is required to avoid aggravating hypertension. Moreover, these agents generally should be avoided in patients with cardiovascular disease, thyrotoxicosis, glaucoma, or diabetes. Oral corticosteroids. A brief course is indicated only to relieve severe nasal blockage so that topical therapy can proceed. In such cases, patients should be referred to an allergist.

Intranasal corticosteroids are highly effective in reducing inflammation, rhinorrhea, itch, and nasal blockage. They are the first choice for treating nasal blockage and largely reduce, but may not eliminate, the need for other medications to treat ocular symptoms. They may be used safely in children, though youngsters often have difficuIty with sprays. In addition to treating nasal allergies, these medications can be used to treat nonallergic rhinitis with eosinophilia syndrome (NARES) and to shrink small nasal polyps or prevent their recurrence after surgery. The onset of action of topical corticosteroids is slow compared to antihistamines. Topical nasal decongestants may be used to open nasal passages in preparation for the use of other agents, such as intranasal steroids. To prevent rebound congestion, they should be used for 2 to 3 days and no more than 7 to 10 days. Mast-cell stabilizers include intranasal cromolyn and nedocromil sodium. Cromolyn may be used for the prophylaxis of allergic symptoms, and is considered especially safe for elderly patients, children, and pregnant women. The need for frequent administration can raise compliance issues. Nedocromd sodium, unlike cromolyn, can both prevent an allergic reaction and control a reaction in progress. Topical antihistamines allay allergen-induced itching, sneezing, rhinorrhea, and ocular symptoms but are less useful for nasal blockage. Intranasal anticholinergics such as ipratropium bromide are effective in controlling the excessive watery rhinorrhea associated with neurogenic stimuli (e.g., cold air, spicy foods) or the common cold. However, they have no effect on nasal blockage, sneezing or itching, or ocular symptoms.

Patients with rhinitis or asthma caused by allergens for which the clinical efficacy and safety of SIT have been documented by placebo-controlled, doubleblind studies, and those requiring daily pharmacotherapy for longer periods (e.g., preventive treatment during a pollen season or perennially) are candidates for SIT.

SIT is most effective if a single allergen is identified, rather than multiple allergens. Injections should be prescribed by specialists and given by physicians only if a specific allergen has been identified. SIT should never be initiated in pregnant women, though the continuation of maintenance therapy is safe. Considerable care must be taken if allergic rhinitis coexists with moderate or severe asthma. Local immunotherapy offers improved safety and equivalent effectiveness.

When patients respond poorly to standard medical care, clinicians should a) ascertain whether compliance has been poor, b) adjust drug doses, c) consider combination therapy, d) reconsider the diagnosis, e) reassess the patient for a nasal structural defect or a complication of allergic rhinitis, or f) refer the patient to a specialist.

Referral can be helpful under the following circumstances:

in most cases when significant airway comorbidity is present (asthma, chronic sinusitis, nasal polyps, or otitis media with effusion) when the diagnosis is in question or special diagnostic testing is required when occupational rhinitis is suspected, to distinguish between clear-cut allergic reactions and toxic or nonallergic reactions when poor symptom control necessitates a consultation for environmental control measures, pharmacotherapy, or specific immunotherapy when medication side-effects are intolerable when rhinitis is only part of a complex series of mucosal allergies.

Allergic rhinitis is a seasonal or perennial disorder characterized by mild to severe upper respiratory symptoms such as nasal congestion, rhinorrhea, sneezing, and itching. These symptoms arise from an underlying inflammatory process initiated by a reaction between the allergen and immunoglobulin E (IgE), neurogenic stimuli, and other complex cellular processes. A panel of experts was convened in Amsterdam, The Netherlands, on 2 September 1996, to explore these issues and their impact on allergy prevention and treatment in primary care. Their undertaking was supported by an unrestricted educational grant from Schering-Plough Pharmaceuticals. Conclusions and recommendations from that meeting are summarized subsequently and presented in expanded form later in this monograph.

Allergens are primarily responsible for provoking chronic inflammatory processes; viral infections underlie acute exacerbations of asthma, chronic sinusitis, and otitis media with effusion.

There is a growing awareness of how allergic rhinitisand some of the medications used to treat itcan affect patients' quality of life, work or school performance, and emotional well-being. Besides physical symptoms, patients may exhibit fatigue, psychomotor sluggishness, irritability, and mood and cognitive disturbances (1 -5). Learning is impaired in children (6), while some adults may report reduced productivity and concentration (7).

This combination of physical, emotional, and functional problems may diminish quality of life in both adults (7) and adolescents (8). Moderate to severe perennial allergic rhinitis has been found to affect quality of life significantly compared to healthy subjects in eight of the nine dimensions of the Medical Outcomes Study Short-Form Health Survey 36 (SF-36) (9).

The prevalence of allergic respiratory disorders is high and is a burden on the health-care system:

One study of patients in a London general practice found that nearly one in seven adults had allergic rhinitis (10). By the age of 6 years, 42% of 747 children followed from birth in the Tucson Children's Respiratory Study had physician-diagnosed allergic rhinitis (11). Those who developed rhinitis before the age of 1 were more likely to have asthma by age 6 (11). As many as 78% of persons with asthma aged 15 to 30 years have been shown to exhibit high levels of IgE antibodies to five common aeroallergens (12). Of 200 patients with chronic sinusitis, 27.5% also had allergy in one study (13). About 24-50% of children with OME had allergic rhinitis (14) or nasal allergy (15). For comparison, about one-third of the general population has chronic sinusitis or OME. In general, the prognosis for patients with asthma or allergic rhinitis is mixed: Only 10% of patients are cured, about 50% improve, 30% show no change, and 10% deteriorate over time (16).

Medicine has begun to revise its traditional therapeutic approach to allergic rhinitis. It is now acknowledged that impeding the natural course of airway allergies by interfering with the pathophysiologic mechanisms that cause mediator release and chronic inflammation may help prevent related airway disorders. This would reduce overall morbidity and improve patients' quality of life. It also should help make patients less vulnerable to the consequences of viral infection, as well as to environmental factors such as pollution. Recent advances in allergy treatmentsmost notably the introduction of nonsedating selective histamine HIantagonists and intranasal corticosteroid sprayshold the promise of achieving these goals. Of particular interest are the studies showing that tgeatment of allergic rhinitis reduces the incidence and severity of asthma (17) (18) (19) . The purpose of this monograph is to introduce new ways of thinking about and managing allergic rhinitis in the hope that physicians will look for related airway disorders and individualize therapeutic programs, considering tbe special needs of populations such as pregnant women, children, and the elderly.

Persons with allergic rhinitis have IgE antibodies bound to high-affinity receptors on mast cells and basophils, and to low-affinity receptors on other cells, such as eosinophils, monocytes, and platelets. Allergic inflammation is initiated when allergens deposited in the airway bind to IgE molecules, causing cellular degranulation and releasing a number of inflammation mediators (20) . This process entails both an early-and a late-phase rqsponse (Fig. 1) .

The interaction of antigen with specific IgE antibodies leads to the degranulation of mast cells and basophils and the prompt release of preformed and newly generated mediators, such as histamine, neutral proteases, leukotriene C,, prostaglandin D,, cytokines, and kinins (21). The interaction of these chemical messengers with blood vessels, mucous glands, and nerves produces the symptoms of allergic rhinitis, such as sneezing, rhinorrhea, and itching.

Histamine is one of the most important mediators of the early-phase allergic response in the nasal mucosa. Its release stimulates sensory nerves, 

This reaction, manifested by some patients, entails a process of cell infiltration and activation occurring over 4-24 h. Late-phase allergic reactions begin when autocoid mediators and cytokines released from mast cells during the early-phase response upregulate the expression of leukocyte endothelial adhesion molecules in the postcapillary venules of the nose. Especially sensitive to histamine, postcapillary venules are also the site of blood cell extravasation. Once adherent to the endothelium, these cells pass between adjacent cells to the perivascular space. Various chemoattractants, essentially IL-5 and the chemokines, draw primed leukocytes (eosinophils, basophils, neutrophils, and mononuclear cells) into the submucosal tissue. Once there, by interacting with additional stimuli by matrix proteins, they release their own mediators. This perpetuates the inflammatory response and augments aspects of the immediate hypersensitivity reaction, such as mucosal congestion and mucus secretion. Although pruritus The impact af allergic rhinitis and sneezing occur, the major symptoms in latephase reactions are hypersecretion and congestion.

The chronic inflammation caused by repeated allergen exposure lowers the threshold for other provocative stimuli reactions (22) . As a result, allergic individuals react more strongly to a) low levels of the primary allergen, b) other allergens to which they are only mildly sensitive, or c) nonspecific "triggers", such as cold air, cigarette smoke, spicy foods, and strong chemical odors.

A key event in chronic respiratory allergy is the upregulation of specific adhesion molecules that permit inflammatory cells (e.g., eosinophils) to migrate into nasal, sinus, and lung tissue. The first step is the experience of such molecules on endothelial cells and on activated circulating inflammatory cells. The accumulation of eosinophils in these tissues is injurious, and contributes to the pathogenesis of allergic rhinitis, sinusitis, and asthma (23 -26) . In certain conditions, histamine is known to stimulate the expression of adhesion molecules on nasal epithelial cells of normal subjects (27) .

An important adhesion molecule required for effective cell recruitment in allergic disease is intercellular adhesion molecule 1 (ICAM-2) (28) . vascular inflammation induced in a primate madel of allergic sensitization and exposure (29) ; b) on bronchial epithelial and on vascular endothelial cells in symptom-free asthmatics (30) ; c) on epithelial cells of the nose and conjunctiva in patients with perennial and seasonal (31) allergic r~n i t i s (Fig. 2) ; and d) on the nasal and conjunctival epithelium of patients with asymptomatic perennigl rhinitis when exposed to allergen, though not in cohabiting relatives or heqltby volunteers (32) .

Besides its role in allergic inflammation, ICAM-1 serves as a receptor for the major subtype of humqn rhinoviruses; this subtype accounts for 90% of all human rhinoviruses (33, 34) . Rhinoviruses are a major cause of the common cold. Evidence of minimal, persistent inflammation in asymptomatic allergic patients suggests that by inducing ICAM-1, subclinical allergen exposure may incregse the susceptibility of allergic patients to rhinovirus infection, and thereby explain the greater frequency of colds in asthmatic children (30) .

In short, it now appears that both ICAM-1 and viral infection play a role in the patbophysiology of asthma (Fin. 3 ) .

The epidemiologic link between viral respiratpry infection and asthma is. strong. Researchers have shown that such viral infections are associated with:

86% of wheezing episodes that last longer than 48 h in noqhospitalized children (35) 80% to 85% of asthqa exacerbations in 9 to 12-year-old children (36) . Among the viruses associated with childhood asthma exacerbations are rhinoviruses, respiratory syncytial virus (RSV), adenovirus, and coronaviruses (36) . Rhinovirus infection has been implicated in 50% of acute asthmatic episodes in schoolchildren, followed by coronaviruses in 13'%0 of cases (36) . Levels of eosinophil, a major basic protein in children with asthma, have been shown to be higher during exacerbations associated with rhinovirus infection than during asymptomatic periods Adults with allergic rhinitis exhibit bronchial hyperresponsiveness to histamine and antigen following rhinovirus infection. Rhinovirus infection also predisposes the allergic patient to allergenprovoked late asthmatic reactions (38) . In asthmatics, but not in nonasthmatics, eosinophilia in the bronchial mucosa is still evident at 6-10 weeks after rhinovirus infection, probably due to ongoing secretions initiated by the virus in the allergenprimed mucosa (39) . (37) .

Rhinitis can be divided into three categories: allergici.e., acute or chronic conditions characterized by seasonal or perennial symptoms, or both infectiousi.e., nasal disorders caused by viral, bacterial, or fungal agents nonallergichoninfectiousi.e., a heterogeneous group of disorders comprising eosinophilic conditions, such as aspirin idiosyncracy; or noneosinophihc conditions, such as gustatory rhinitis, rhinitis of pregnancy, and vasomotor rhinitis. Table 1 catalogues the characteristic features of the various forms of chronic rhinitis (10, [40] [41] [42] [43] [44] [45] [46] [47] [48] . Despite the considerable overlap, it is usually possible to diagnose the disorder by skin prick test and the patient's symptoms, history (including relevant behavioral practices, such as smoking), and physical examination.

The elements of a diagnosis include elicitation of a detailed patient history and physical examination of the nose, eyes, ears, and lungs. Among the many factors that must be explored are patterns of symptom expression, environmental triggers, medication use, family history, and exposure to workplace allergens or irritants. It is important to determine the severity of symptoms and to uncover possible complications such as asthma, sinusitis, otitis media, or nasal polyps. Questions related to psychosocial or quality-of-life problemssuch as fatigue or cognitive impairmentalso should not be overlooked.

The differential diagnosis of rhinitis primarily depends on use of an allergy skin prick test. Pharmacologic agents that may affect results should be withdrawn for a sufficient time before testing ( Table 2) . Because of its long duration of action (approximately 7-9 days), the antihistamine astemizole can suppress skin test reactivity for 8-12 weeks after its discontinuation (40) . By contrast, this effect lasts only 2-4 days with most other antihistamines.

Most patients who present with rhinitis exhibit clusters of symptoms that define them as either "sneezers and runners" or "blockers". Those with seasonal allergic rhinitis are usually sneezers and runners.

Some patients with rhinitis have only a single symptom or many nonnasal complaints, such as headache, sore throat, postnasal drip, a "full" or a "stuffy" head, recurrent head colds, chronic "sinusitis", chronic cough, plugged ears, hyposmia, loss of the sense of taste, fatigue, or poor concentration. Often, patients use the term "sinuses" or "sinusitis" to describe symptoms caused by nasal pathology.

A thorough patient history yields information needed to classify nasal symptoms, determine their cause, and make appropriate therapeutic decisions.

Family studies indicate that environment generally influences the expression of allergic disease (ll), but genetics determines the severity and specificity of the symptoms (49) . Genetics also is an important component of atopy as a general predisposition, involving multiple as yet unidentified genes. Children not only inherit a tendency to atopy from their parents, but are likely to develop the same allergic disorders (50, 51) . Consequently, the following information should be sought: symptom type, occurrence, and frequency symptom duration and severity aggravating factors current medications illicit drugs. the age at which symptoms began (episodic, seasonal, or perennial) allergen exposure in home or work environment

Although the physical examination of patients with chronic rhinitis centers on the nose, eyes, and throat, clinicians also should evaluate the ears, sinuses, and lungs to identlfy any related airway disorders, which often are present. General signs of an atopic predisposition, such as eczema, also are helpful. 

Imaging studies are usually indicated only in specific circumstancesmost commonly, when the diagnosis is in doubt, when symptoms persis despite appropriate therapy, or when related airway disorders complicate the diagnosis. Persistent symptoms or airway complications may be factors in perennial allergic rhinitis.

plese.g., limiting outdoor activities during the height of the pollen season, shielding young children from passive tobacco smoke and gas heating or wood-burning stoves. They also may entail fairly complex undertakings aimed at specific allergens; e.g., cat dander. As people spend increasing amounts of time indoors, environmental control is focused largely on containing exposure to house dust, animal dander, mold, and cockroaches. As a rule, measures to avoid allergens are effective when they are likely to be usede.g., simple to follow and inexpensive to implement. Patients should be informed that even partial compliance can help control symptoms and lessen the need for medicalion. They should be encouraged to persevere, as it may lake weeks or months of avolddnce before an improvement in sympfoms is noticeable. (See Appendix for a patient information sheet about allergen-control measures.)

The selection of an appropriate and effective medication for the treatment of chronic rhinitis entails consideration of several factors: Although impaired olfaction is frequently overlooked in cases of nasal allergy, it is relatively easy to assess by olfactory threshold tests. Patients who require more sophisticated testingsuch as assessment of mucociliary function or nasal airway patencyshould be referred to a specialist.

Underlying eriology. Especially in patients for whom immunotherapy is being considered, this requires careful diagnosis of the allergen (s), primarily through skin prick testing. a Likely parhophysiology. Symptoms due to inflammatory processes (as in nasal allergy) require differed1 medications than those caused

Treatment options consist of allergen avoidance, pharmacologic therapy, or allergen-specific immunotherapy.

Efforts aimed at environmental control may involve relatively simple activities based on general princi-by-noninflammatory neurogenic mechanisms (as in gustatory, idiopathic, or atrophic rhiniiis). Dominant symptoms. Medications should address the patient's most prominent complaints. Combination therapy may be warranted for patients with a mix of moderately severe lo severe symptoms. Safety. It is important 10 determine whelher medication side-effects may impede a patient's perfarmance at work or scho61, diminish quality of life, or enhance risk of sustairiing personal The impact of allergic rhinitis Table 2 Withdrawal of pharmacologic agents that affect skin test reactions (38) individuals. Regular antihistamine use Over weeks or months has been found to reduce asthma symptoms significantly in allergic rhinitis patients with seasonal and chronic rhinitis (55) (56) (57) . injury or significant morbidity. The potential for drug interactions also must be considered when patients are taking multiple medications. Patient age and other special considerations. The needs of special populationspediatric patients, the elderly, pregnant women, and competitive athletes must be evaluated. Coexistence of related airway disorders. In patients with coexisting airway disease, the treatment of nasal allergy is important to prevent exacerbation of sinusitis or asthma. Patient preferences and compliance historv. In some countries, patients prefer oral medications to sprays (52) . Additionally, individuals differ greatly in their capacity to adhere to therapeutic regimens. Consequently, an attempt should be made to determine each patient's understanding of abd willingness to comply with a specific treatment program. Factors that may adversely affect compliance include poor symptom relief, the nature or severity of the side-effects, and the inconvenience or complexity of the therapeutic rkgimen (53,54).

As a rule, it is best for patients to start therapy before the anticipated onset of symptoms, to suppress those immunologic and mediator mechanisms that cause inflammatory reactions and to minimize the priming effect. Prophylactic therapy is usually possible in seasonal allergic rhinitis, when the onset of symptoms is relatively easy to predict, or for episodic exposures to specific allergens (e.g., before visiting the home of someone with pets). As a rule, patients with seasonal or perennial rhinitis should take their medication regularly, rather thhn as needed, because consistent use best controls mucosal inflammation. In turn, this helps lessen the risk of related airway complications in susceptible

In its 1994 consensus statement, the International Rhinitis Management Working Group advocated a stepwise approach to therapy that took into account specific diagnoses and patient characteristics (40) . This approach is summarized in Table 3 .

Stepwise management certainly represents a reasonable starting point for therapeutic decisions in cases of chronic rhinitis. Nonetheless, the complexity and interrelationship of these disorders suggest that, while taking account of the guidelines, a case-by-case approach provides added value.

What follows is a review of the benefits and limitations of various medications used to treat chronic rhinitis. Among the agents considered are topical and oral antihistamines, topical and oral corticosteroids, topical and oral decongestants, crornolyn sodium, nedocromil, sodium intranasal anticholinergic agents, and saline sprays. The discussion concludes with a review of combination drug therapy and the ihdications for immunotherapy.

There are at least three classes of histamine receptors, designated HI, H,, and H,. Histamine can exert local or widespread effects on smooth muscles and glands. Bronchoconstriction and contrktion of the intestine are mediated by H,-receptors, while gastric secretion results from H,-receptor activation (58) . H,-receptors appear to exist predominantly in the central nervous system (CNS) and at presynaptic nerve endings (58) .

Histamine causes capillary dilation; HI-receptor stimulation leads to a rapid, brief dilator response, while H,-receptors mediate a response that is slowkr to develop and more sustained (58) . It also plays a role in extravascular smooth-muscle contraction and (more rarely) relaxation, with H,receptor activation responsible for contraction and H,-receptor stimulation usually resulting in relaxation (58) .

The class of agents known as HI-receptor antagonists comprises drugs that act rapidly to antagonize the histamine activity of HI-receptors, thereby relieving the maiq symptoms of allergic rhinitis (sneezing, watery rdnorrhea, and itching of the ndSe, eyes, and palate). In addition, some of the hewer agents have been shown to possess antiallergy properties that may contribute to diagnosis and treatment. These properties include the ability to: inhibit histamine release from human basophils block histamine, and partly block prostaglandin D, release, in the nasal secretions of highly allergic subjects (61) directly inhibit eosinophil activation (62, 63) block histamine activation of airway epithelial cells by suppressing the expression of surface markers, such as ICAM-1, and the major histocompatibility complex class I1 antigen HLA-DR, involved in antigen presentation (27) . The ability both to inhibit histamine release and downregulate ICAM-1 makes certain anthistamines (e.g., terfenadine [65, 66] , loratadine [27] , cetirizine [65] , azelastine [65] , oxatomide [65] , and levocabastine [65] particularly suitable for treating allergic inflammation, because ICAM-1 is a marker of allergen-induced inflammation as well as a receptor for human rhinoviruses (33, 65) . (59, 601 reduce vascular permeability (64) Sedating vs nonsedating antihistamines. "Sedating" agents are distinguished from "nonsedating" ones by the higher incidence of drowsiness associated with the former at the doses used to control allergic ,symptoms. In part, this difference is due to the speed with which antihistamines cross the bloodbrain barrieri.e., rapidly in the case of the sedating agents and slowly in the case of the nonsedating agents. The sedative potential of the newer agents is limited further by their specificity for binding to peripheral HI-receptors. Sedating antihistamines, in contrast, affect central HI-receptors and receptors of other types (e.g., muscarinic cholinergic, a-adrenergic, and tryptaminergic) (67) . This may contribute to their sedative and other side-effects (67) . Sedating agents' effect on central HI-receptors may be especially relevant, as hstaminergic transmission originating from the posterior hypothalamus sustains waking arousal (68) . In short, by having a reduced capacity to cross the blood-brain barrier and specifically blocking HIreceptors, the nonsedating agents are less able to cause CNS effects and associated adverse reactions.

(See subsequent discussion of CNS effects.)

Efficacy. Table 4 presents selection criteria for 10 of the antihistamines most commonly used in Europe. Studies have shown that the newer nonsedating antihistamines produce moderate to The impact of allergic rhinitis excellent symptom response in up to 67% of patients with seasonal allergic rhinitis (691, making them as effective as, if not more effective than, the older (i.e., sedating) agents (70, 71) . As a group, the newer agents demonstrate comparable efficacy (72, 73) . A comparison of loratadine and astemizole in patients with seasonal rhinitis found equivalent efficacy in the two (72) . Cetirizine has been shown to lessen nasal blockages (74) .

Although the use of antihistamines in asthma is still controversial, the new nonsedating agents seem to offer some benefit for allergic patients with concomitant asthma. Data indicate that terfenadine (75, 76) and loratadine alone (77) , and combined with pseudoephedrine ( 5 5 ) , astemizole (78), certirizine (79) , and azelastine (80) exhibit modest bronchodilating effects (75), reduce bronchial sensitivity to histamine (55) , and guard against exercise-(78) and antigen-induced bronchospasm. Such effects may require higher than currently recommended doses, however. Loratadine (5.9, cetirizine (56), and terfenadine (57) have been shown to reduce asthma symptoms in rhinitic patients with seasonally induced asthma when taken over weeks or months, though this evidence is disputed. Together, such findings suggest that timely and appropriate use of antiallergy therapy may help prevent lower airway symptoms in susceptible patients if used in an adjunctive manner. Moreover, they dispel the fallacy that antihistamines are contraindicated in asthmatic patients.

CNS effects. Sedating antihistamines can exacerbate the cognitive and functional problems caused by untreated allergic rhinitis (81) . Among their most troubling CNS effects are fatigue, sedation, and performance impairment (81) .

Patient reports of unusual daytime drowsiness have been noted in 25-50% of users of sedating antihistamines (82) -e.g., diphenhydramine, pyrilamine, brompheniramine, chlorpheniramine, triprolidine, hydroxyzine, promethazine, and cyproheptadine. By contrast, when given at the recommended doses, the "nonsedating" antihistaminesastemizole, ebastine, fexofenadine, loratadine, and terfenadinecause no more drowsiness than placebo.

Confusion exists as to the sedating properties of two new agents, acrivastine and cetirizine. Both medications have been associated with significantly more reports of daytime drowsiness than placebo at recommended doses: acrivastine, 8 mg, 11% versus 6% (82); cetirizine, 10 mg, 9% to 25% versus 6% (83) .

Although the lower dose ( 5 mg) of cetirizine is no more sedating than placebo (83) , it has been shown that, if allowed, more than 80% of cetirizine users will titrate the dose upward, to achieve symptom relief (84).

After repeated dosing, some patients may become tolerant of the sedating effects of antihistamines (85) . However, it is unwise to depend upon tolerance to abolish the antihistamine- induced sedation and performance impairment that commonly occurs for at least 1 week after the medication is started (86) . It is generally agreed that tolerance is a highly idiosyncratic phenomenon that is not universal, complete, or predictable. Virtually all antihistamines are equally effective in relieving allergy symptoms (see "Efficacy" section). Consequently, before recommending a particular antihistamine, physicians must weigh the benefits of that agent against its drawbacks. The lower cost of the older "sedating" antihistamines, and their general availability without prescription, may argue in their favor, but their use can no longer be recommended. The nonsedating agents offer the potential long-term benefits of safety and improved performance at work or in school compared to sedating antihistamines, and greater therapeutic compliance owing to their longer half-life and the need for less frequent dosing (81, 82) .

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Consequences of CNS effects. Unfortunately, one's subjective sense of sleepiness or impairment is an unreliable gauge of whether it is safe to operate heavy machinery while taking sedating antihistamines. This is because impairment can occur without the patient's awareness (87, 88) . These factors have important safety implications in areas such as building consltuct ion, manufacturing, pub1 ic transpottation, and automobile driving. Simulated and real-life driving studies verify that these agents Carl impair performance significantly (87, 89, 90) . In one study, lane weaving by drivers given triprolidine 10 mg (emtamed release), was comparable to that ib perS6hS with a blood alcohol level of 0.05%; moreover. at 3-4 h after drug use, the drivers stopped feporting any sense of being impaired (87) (Fig. 4) . Another study found that the effects of a single 10-mg dose of cetirizine resembled those of alcohol (72 g/kg lean body mass), and that the impairment appeared to be greater when alcohol and cetirizine were taken together (91) (Fig. 5) . By contrast, no psychomotor deficits have been observed in drivers given loratadine (87, 91) , or in individuals tested while taking astemizole (92); nor does the use of alcohol with these agents produce an additive effect. Studies have also shown that terfenadine did not impait psychomotor performance or reaction time (65) , and that ebastine at 10, 20, or 30 mg given for 5 days did not impair driving performance compared to triprolidine 10 mg (93).

Besides causing psychomotor problems, sedating antihistamines also adversely affect cognition and functional performance (6, 88, 94, 101), compromising sustained attention and cerebral processing speed in adults (97) and children (95) . The effects of nonsedating agents on somnolence, cognition, and performance, by contrast, are comparable to those of placebo (70, 95, 96, 102) . Specific findings to date include the following: performance on a digit symbol substitution test impaired by diphenhydramine (50 mg t.i.d.), but not by loratadine (10 mg q.d. and 40 mg visuaVmotor coordinationimpaired by promethazine, chlorpheniramine, and clemastine, but not by terfenadine (101,115) clerical skills -8112 skills impaired by diphenhydramine; none by loratadine (96) learning in children with seasonal rhinitisimpaired by diphenhydramine (50 mg) compared to nonallergic, unmedicated children, with the impairment in allergic children offset partly by loratadine (10 mg) (6). Nonallergic, unmedicated children performed significantly better on tests of learning ability than atopic children given placebo, diphenhydramine, or loratadine; performance among atopic children was q.d.) (99)

The impact of allergic rhinitis best among subjects receiving loratadine and worst among those receiving diphenhydramine. This suggests that the learning problems associated with allergy are augmented by sedating antihistamines and offset somewhat by nonsedating agents.

Cardiovascular effects. Two nonsedating agentsterfenadine and astemizolehave been found to cause malignant ventricular arrhythmias, such as torsades de pointes (103, 104), when patient factors or drug interactions result in greatly elevated serum drug levels (105, 106). Although rare, these phenomena can delay cardiac repolarization and prolong the QT interval through blockage of a K rectifier channel, resulting in possible sudden death. At least 11 case reports involving 20 patients have been published in which patients taking astemizole experienced torsades de pointes, QT prolongation, and sometimes other cardiac effects (67) . Eight such reports affecting 22 patients have appeared for terfenadine (67) . Acrivastine, cetirizine, fexofenadine and loratadine appear to be the least likely of the newer antihistamines to be arrhythmogenic (67) . The risk of cardiac arrhythmias can be minimized by reviewing the medical and pharmacologic risk factors for torsades de pointes before prescribing terfenadine or astemizole for any individual. Drug interactions associated with the potential for cardiotoxicity are a major concern of clinicians, as patients frequently fail to report all of the medications they are tdking. Concomitant administration of certain antifungal agents (especially ketoconazole and itraconazole) or macrolide antibiotics (patticularly erythromycin), along with terfenadine or astemizole, inhibit metabolism of these two antihistamines through competition for hepatic P450 enzymes. This results in increased plasma cohcentrations of these antihistamines. Coadministratiori of terfenadine or adtemiztde in users of such medications is thus sttictly contraindicated. Hepatic dysfunction and preexisting cardlovascular disease also ate risk factors for cardiovascblar complication$ with these ztrltihfstamines.

Because the causes of QT Prolongation are additive (106), patients with more risk factors have a potentially greater chance of developing ventricular arrhythmias while taking either terfenadine or astemizole. The use of these drugs at recommended doses without the aforemefitioned concomitant medications by patiedts lacking known rtsk factors carries a low risk of ah adverse catdiac event. Still, such low-risk patients taking terfenadine or &temizble should be warned not to inmease antihistamine doses without 6!dnsulting their physician.

Cytochrome P450 enzymes are responsible for the metabolism of many drugs. All of the currently available nonsedating antihistamines are metabolized by the cytochrome P450 hepatic enzyme system. Cytochrome P450 3A4 is involved in the metabolism of terfenadine, and erthromycin attenuates the metabolic effect of CYP3A4. Loratadine is metabolized primarily by CYP3A4 and secondarily by CYP2D6.

Other considerations. Side-effects involving the digestive tract (e.g., loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea) are among the most common for all antihistamines. Many of the older agents are associated with significant anticholinergic or antimuscarinic sideeffects, such as dryness of the mouth and respiratory passages, urinary retention or frequency, palpitation, blurred vision, hypotension, headache, and tingling or weakness of the hands (58) . Use of astemizole can cause weight gain. In a comparative trial with loratadine, weight gain was significantly greater with astemizole (PcO.012) (72) . This sideeffect may argue against astemizole's use in selected individuals.

Nasal blockage is a major factor in perennial rhinitis, and a possible incitement to related airway disorders such as OME and chrohic sinusitis. Topical steroids are the agents of choice for nasal blockdge (see subsequent section, "Intranasal steroids"); however, leukotriene antagonists or oral decongestants also control this symptom. Examples of the last class of agents include pseudoephedrine, phenylpt-opanolamine, and phenylephrine. These a-adrenergic agonists constrict blood vessels supplying the nasal mucosa, thereby decreasing congestion; they do not control the itchihg, sneezing, or rhinorrhea associated with upper-respiratory allergies. When such syIfiptoni6 coexist with significant blockage, optimal rhariagement requires the use of intranasal steroids. Another option is a combination decongestant/antihistamine medication (see next section).

a-Adrenoreceptor agonists are stimulatory agents that constrict vascular beds throughout the body, not just in the nose. This raises the potential for significant systemic side -effectse.g., hypertensibn, palpitations, tachycardia, and extrasystole, as well as restlessness, insomnia, and headache. As side-effects are dose-related, clirliciahs must choose the ptescribed dosage carefully to prevent aggravating or "unmasking" hypertension. Patiefits shobld The impact of allergic rhinitis be cautioned against increasing dosages on their own. As a rule, oral decongestants should be avoided in patients who have cardiovascular disease, thyrotoxicosis, glaucoma, or diabetes.

Medications that combine an antihistamine with a long-acting oral decongestant offer another option for managing nasal blockage. The value of this practice has been proven in trials using formulations containing pseudoephedrine and either loratadine (107), acrivastine (108), or chlorpheniramine (109) . Such combinations may be especially beneficial for patients at risk of chronic, allergen-induced eustachian tube obstruction, a condition that may favor the development of OME (109) . Combined antihistamine/ decongestants can provide greater overall symptom relief than possible with either agent alone (107, 108), though the tradeoff may be a higher incidence of adverse events (110) . Nevertheless, combination agents decrease the number of drugs patients must take, a fact which may facilitate therapeutic compliance in selected individuals.

Oral corticosteroids and systemic injected depot preparations carry a high risk of systemic sideeffects. Consequently, the only justification for their use in chronic rhinitis is to improve nasal patency in patients with severe or urgent blockage, so that topical therapy can proceed. Even then, systemic steroids should be given only by a specialist, and only to patients who lack contraindications to their use. These agents generally should not be used in children or pregnant women. A course of systemic steroids may be needed to gain control of nasal polyps, after which the patient can be managed with topical steroids (44) . In addition, oral corticosteroids can rapidly relieve anosmia associated with polyps and, by opening the nasal passages, facilitate the access of locally acting nasal corticosteroids.

Alternate-day dosing may improve the riskbenefit ratio of oral corticosteroids, but studies proving this point have yet to be undertaken.

Various topical agents are now available for relieving the symptoms and, in some cases, addressing the underlying pathology, of chronic rhinitis. The benefits, appropriate usage, and drawbacks of specific agents are discussed in this section. General limitations of topical treatments are reviewed in Table 5 . The value of any topical agent in the treatment of allergic or nonallergic rhinitis syndrome may be limited by several factors.

Physical anomalies. Severe septal deviation or enlarged turbinates may impede direct delivery of topical agents to the nasal mucosa.

Poor therapeutic compliance. Compliance studies have shown that patients generally prefer taking pills to using medicinal sprays 150) Slow therapeuric onset. In the case of intranasal steroids and crornolyn sodium. a slower onset of action may leave some patients frustrated and noncompliant. Par!ent handicaps In particular. children and elderly persons may find it difficult to aim sprays or manipulate inhalers.

Intranasal steroids can relieve most of the symptoms of seasonal and perennial allergic rhinitis (112) (113) (114) (115) (116) (117) . They are more effective than cromolyn sodium (17). Intranasal steroids are probably the most effective drug for all symptoms but they are particularly effective on nasal blockage Topical steroids are the agents of choice for relieving nasal blockage. They permit direct delivery to the nasal mucosa, thus minimizing systemic sideeffects. The following specific actions are noteworthy:

inhibition of both the early and late hypersensitivity response to allergens (111) reduction of the number of eosinophils in the nasal mucosa (112, 113) substantial inhibition of the nasal secretory response (1 14) reduction of mast cells and T cells desensitization of nasal irritant receptors (114).

(1 17 -1 19) .

Appropriate use. Intranasal steroids may be used to: relieve seasonal or perennial allergic rhinitis, when the main complaint is moderate to severe nasal blockage treat NARES (only effective therapy at present) shrink small nasal polyps, or manage patients with polyps once control is gained through a course of oral steroids (44) prevent polyp recurrence after surgery reduce the risk of chronic sinusitis, OME, or bronchial asthma in allergic patients with a history of these complications.

Drawbacks. Side-effects of intranasal steroids are generally minor and local, e.g., irritation, burning, and reactive sneezing, which usually disappear after several days; and nasal dryness followed by blood-stained crusts (124). In rare cases, treatment has to be stopped due to epistaxis. A few reports of septal perforation following intranasal steroid use have been published (124,125). Some adverse effects (e.g., mucosal drying) can be avoided by using sprays with an aqueous base. The risk of systemic side-effects is very small, with one published report of a posterior cataract after intranasal steroid use and one report of children's growth being inhibited while taking an adult dose of budesonide (124). It is prudent to use the lowest efficacious dose in children and pregnant women (124).

Once-daily usage probably is sufficient for all glucocorticoids if the nose is patent and dry when the spray is used (124). Some patients or agents may require multiple daily dosing, however, or multiple sprays per nostril.

Patients should be informed that onset of action is delayed compared with that of antihistamines and decongestants, and requires a few days for patients with seasonal allergic rhinitis (124).

Many patients are reluctant to use steroids in any form, and parents may be especially hesitant to sanction their use in children. Individuals should be reassured that intranasal steroids are much safer than oral corticosteroids and that the former should not be equated with the latter.

This anti-inflammatory agent has been proved safe and effective for the treatment of allergic rhinitis (126,127), although in one comparative study (17) it proved less effective than intranasal corticosteroids. Owing to its control of both early-and late-phase hypersensitivity responses, cromolyn can relieve nasal itching, sneezing, hypersecretion, and nasal blockage. Its need for frequent administration (four to six times daily [126], with possible reduction to two to three times daily in periods of low antigen load [127]), may impede therapeutic compliance.

Appropriate use. Cromolyn sodium is best used for the prevention of allergic symptoms. Given its wide safety margin, it often is prescribed for elderly patients, children, and pregnant women with seasonal or perennial allergies. It has virtually no utility in nonallergic rhinitis syndromes. The ocular formulation of cromoglycate is very effective in controlling eye symptoms.

Like cromolyn, nedocromil sodium controls both the early-and late-phase allergic reaction. Unlike cromolyn, nedocromil can both prevent an allergic reaction and control a reaction in progress (126).

Nedocromil has significantly improved symptoms of rhinorrhea, congestion, itching, and sneezing (126). It is about 10 times more potent than cromolyn sodium. Recommended dosing is two to four times daily (126).

Appropriate use. Like cromolyn, nedocromil sodium is very effective at blocking symptoms when used immediately prior to an anticipated allergen exposure (126).

Both nasal challenge studies (128, 129) and those involving seasonal exposures (130) indicate that topical antihistamines can inhibit allergen-induced nasal symptoms, including sneezing and rhinorrhea. Side-effects are locale.g., stinging and itching in the nose and, occasionally, the throatwith the incidence ranging from 7% to 30% of patients (128-131). Azelastine has been shown to lessen nasal blockage, although reported side-effects include burning in the nose and altered taste (132) . The lack of major improvement in nasal blockage (128, 129) in some other studies, however, suggests that congestion entails more than the direct effect of histamine on receptors on the capacitance vessels of the nasal mucosa.

Levocabastine is a potent antihistamine available as nasal spray and eye-drops. Minute amounts applied topically are sufficient to result in an antiallergic effect.

Appropriate use. On the basis of their safety profile, topical antihistamines may be used to relieve ocular or nasal symptoms in patients with mild to moderate seasonal allergies. When patients have severe ocular symptoms, specific topical preparations for ocular application should be used. Azelastine (133) and levocabastine (134, 135) , for example, have been found to be nonsedating.

Topical nasal decongestants constrict the smaller arterioles of the nasal passages, thus reducing blood flow and relieving mucosal edema. These agents can relieve nasal congestion rapidly and effectively, and generally are available without a prescription. This probably explains their popularity among patients with perennial forms of allergic or nonallergic rhinitis. Unfortunately, the overuse of decongestant sprays can cause rebound nasal congestion and rhinitis medicamentosa. Moreover, like oral sympathomimetics, topical sprays are associated with systemic side-effects such as cardiac arrhythmias and exacerbation of hypertension (136) . Thus, The impact of allergic rhinitis patients who overuse decongesting nose-drops should be assessed for hidden allergic nasal disease.

Appropriate use. The primary use for topical decongestants in chronic rhinitis is to open severely blocked nasal passages, so that slower acting drugs (e.g., cromolyn or intranasal steroids) can reach the necessary nasal passages to provide ongoing symptom control. Their potential for causing rebound congestion is such, however, that these agents should never he used for inore than 3 consccurive days.

Ipratropium bromide, an anticholinergic drug, acts on the glandular cholinergic receptors in the nose to control excessive watery rhinorrhea (137) . Rhinorrhea generally improves within 30 min, and remains in check for S-12 h. "here is no improvement, however, in nasal blockage, sneezing, or itching.

Nasal dryness, the main local side-effect of topical anticholinergics, may be alleviated by adjusting the dose. Although rarely required, high doses of these agents may cause systemic side-effects.

Appropriate use. Intranasal anticholinergics may be used to relieve the excessive rhinorrhea associated with allergic or nonallergic rhinitis syndromes e.g., gustatory or idiopathic rhinitis ("skier's nose"). The latter, perennial form of rhinitis entqils little if any nasal blockage, and tends not to respond to other treatments. Intranasal anticholinergics also may help relieve the rhinorrhea associated with common colds (138) .

Various symptoms of perennial rhinitise g , nasal stuffiness, sneezing, rhinorrhea, and nose-blowing may improve with the use of saline or propyleneand-polyethylene glycol sprays. In one trial, patients also showed decreased eosinophil counts with propylene-and-polyethylene glycol spray (139) . Symptom amelioration also may be accompanied by an improvement in nasal airway resistance and nasal biopsy findings (139) . Although wetting agents act slowly, their lack of side-effects makes them attractive therapeutic options for some patients.

Appropriate use. Wetting agents are indicated for the relief of mucosal irritation or dryness, the prevention of mucosal atrophy, and the removal of encrusted or thickened mucus. They also may be used immediately before intranasal steroid dosing, to prevent or mitigate drug-induced local side-effects.

When the use of any of these medications results in poor control of chronic rhinitis, physicians have several options:

Determine whether there has been therapeutic noncompliance. If so, try to ascertain the reason e.g., poor symptom control, inconvenient dosing schedule, high medication cost. Once the cause is known, engage the patient in therapeutic decision-making, as this may enhance treatment satisfaction and compliance. 

Two or more antiallergy medications may be prescribed if a single agent fails to relieve adequately a patient's symptoms. Combination therapy generally is indicated in the following situations.

W h e n syrnptonis are moderately severe, severe, or diverse

Patients with severe nasal symptoms often benefit from taking both an antihistamine/decongestant and a topical nasal steroid. When patients have severe ocular symptoms, specific topical preparations for ocular application should be used. In a study comparing solo and combined drug use in patients with seasonal rhinoconjunctivitis, Juniper et al. found that a ) nasal symptoms responded better to beclomethasone alone than to astemizole monotherapy, b) ocular symptoms were relieved more effectively by asteniiznle alone than by beclomethasone monotherapy, and c) the combination provided the best relief of ocular symptoms (121).

When symptoms are intense or long-lasting Patients who suffer from perennial rhinitis with seasonal exacerbations may benefit from using intranasal steroids on a continual basis and employing "rescue" antihistamines as needed.

Persons with allergic rhinitis and asthma might require a nasal corticosteroid and a bronchodilator to control their upper and lower airway problems.

Reliance on specific immunotherapy (SIT) varies from country to country. Physicians in the south of Europe are more inclined to offer SIT, while a decreasing number of patients receive this therapy in Scandinavia and the UK (141) . Immunotherapy used to be viewed as indicated only for patients responding inadequately to, or developing side-effects from, drug therapy (141) . Current recommendations are to consider SIT for a broader range of patients (see Table 6 ). SIT, unlike pharmacotherapy, modifies the immune system and plays a preventive role in asthma development. It is used in conjunction with drug therapy but should reduce the need for symptomatic pharmacotherapy. The efficacy of SIT for Table 6 Specific immunotherapy for allergic rhinitis 1142) grass pollen, ragweed pollen, and house-dust mites is very well established (141, 142) . Results are best when the patient has a single allergic sensitivity rather than allergies to multiple substances. It must be stressed, however, that SIT should be undertaken only by physicians working in facilities equipped to handle possible adverse reactions (urticaria, laryngeal edema, bronchospasm, and anaphylaxis). Although its safety under these conditions is good, a careful riskhenefit analysis is required for each patient before injections commence. Some experts believe that children may be especially responsive to SIT (142) . Although childhood allergies show a strong tendency toward spontaneous improvement, SIT may hasten this effect in a greater percentage of case% Disagreement exists, however, about the age at which SIT may be started (141, 142) .

Noninjective immunotherapy is another option to consider. Nasal, sublingual, and oral immunotherapy have been demonstrated to be safe and effective (143) . Perhaps the most enmuraging thing about SIT is that it holds out the possibility at present, more than conventional pharmawlogic therapyof "curing" seasonal allergies and even preventing the progression to asthma (141, 142).

Children A variety of genetic and environmental factors favor the development of respiratory allergies in children (Table 7) . Allergy should be considered in the differential diagnosis when children have asthma, IgE levels exceeding 100 IU/ml at age 6, or a maternal history of allergy (11). These were found on logistic regression to be risk factors for development of allergic rhinitis by age 6 in the Tucson Children's Respiratory Study, which followed 747 healthy children from birth to age 6 (11). Presence of dogs as household pets and serum IgE exceeding 100 IU/ml were significant risk factors for development of atopic (vs nonatopic) allergic rhinitis (1 1). Wheezing in infancy usually implies no increased risk of asthma or allergies, but for the minority (14%) of children in whom wheezing persists at age 6, this symptom may signal a predisposition to asthma (144) . A prospective study following 826 children from birth to age 6 years found that risk factors for persistent wheezing were elevated serum IgE at 9 months old and a maternal history of asthma (144) . Preventive therapy may be especially relevant for these children. Special concern is also indicated for those with severe or persistent nasal polyps. Such children should be referred to a specialist, as polyps in the very young may be associated with cystic fibrosis or primary ciliary dyskinesia.

Environmental control assumes particular importance in children with allergic rhinitis, as considerable evidence shows that chronic respiratory symptoms are associated with significant early exposure to allergens (11, 145). The Tucson Children's Respiratory Study of 747 6-year-olds found that 42% had allergic rhinitis, and half of them had been diagnosed with this condition in their first year of life (11). Accordingly, it is important to instruct parents about environmental control measures and the need to.implement them early in the course of their child's disease. Early avoidance not only improves symptoms, but also may affect the natural history of nasal allergy and related disorders such as OME. Moreover, if implemented aggressively at home, it has the added benefit of possibly preventing similar allergies in any siblings that the patient may have.

When drug therapy is needed, a conservative approach to selection is warranted. Nonsedating oral antihistamines are a good choice for children, owing to their lack of CNS side-effects and ease of use. Moreover, once-or twice-daily administration elunnates the need for dosing during school hours. Pediatric formulations of the nonsedating antihistamines generally are available throughout Europe. Cromolyn sodium, nedocromil, or intranasal steroid sprays, although safe and effective, may be difficult for small children to use. This can lead to compliance problems. Moreover, cromolyn must be dosed at least four times a day, whereas nedocromil is used twice a day. Intranasal steroids usually are given at half the adult dose, once daily in the morning. As a rule, systemic steroids and topical vasoconstrictors should be avoided in very young children.

Perennial rhinitis in the elderly is generally idiopathic in nature (42) , with the underlying cause being autonomic imbalance, alteration in muscarinic receptors, or the sequelae of previously treated nasal disorders. Almost invariably, the only symptom of nasal hyperresponsiveness in older persons is profuse rhinorrhea. Treatment with ipratropium bromide, an anticholinergic drug, has been shown to be effective in some cases (146) .

For elderly persons with true allergic rhinitis, treatment plans must take into account age, concomitant illnesses, and the use of other pharmacologic agents. Nonsedating topical or oral antihistamines are a reasonable choice for this population. Older antihistamines are best avoided, not only because of their sedative properties, but also because of the potential for urinary retention, problems with visual accommodation, and CNS impairment. Because of their sympathomimetic effects, oral vasoconstrictors (e.g., phenylephrine, phenylpropanolamine, or pseudoephednne) are generally contraindicated or need to be used with considerable caution in patients with diseases that frequently occur in the elderly such as hypertension,

The impact of allergic rhinitis coronary artery disease, diabetes, glaucoma, or prostate hypertrophy. Finally, elderly patients may require lower doses of certain antihistamines owing to slowed hepatic metabolism. Moreover, because they often take multiple prescription and nonprescription medications, the elderly also run a greater risk of drug interactions than most other patients.

Pregnancy-associated hormones affect the nasal mucosa, and may indirectly affect the nose through increasing circulating blood volume (146) . As a result, some women with allergic rhinitis experience an exacerbation of symptoms, especially congestion, during pregnancy. This phenomenon generally starts toward the end of the first trimester and resolves rapidly after parturition. Other women experience the apparent onset of allergic rhinitis during pregnancy (147) .

Although pharmacologic agents may help control nasal symptoms in pregnant women, chicians should prescribe them cautiously, bearing the following facts in mind:

Despite its probable safety in pregnant women, clinical experience with loratadine is still relatively limited. The safety of diphenhydramine remains uncertain (148) . All oral antihistamines are excreted in breast milk.

In the USA, pseudoephedrine is approved for use in pregnancy at recommended dosages, and is widely prescribed in this population. Owing to their overall safety, saline wetting agents and cromolyn sodium may be used to relieve congestion during pregnancy. In some European countries, topical antihistamines are recommended for the treatment of allergic rhinitis during pregnancy (149) . If cromolyn proves ineffective, intranasal steroids may be tried. Their use at recommended doses has not been associated with teratogenicity or other adverse effects in pregnant women (38) . Unfortunately, nasal congestion in pregnant women is often refractory to medical therapy. In such cases, patients may obtain some relief by using an external nasal dilator and saline douches. Under no circumstances should immunotherapy be started during pregnancy, though continuation of maintenance doses is safe (38) .

Physical exercise causes vasoconstriction that lasts for about 1 h after exertion stops. However, endurance athletes (e.g., long-distance runners or cyclists) may experience long-lasting rebound congestion after a brief period of improved nasal patency. This rebound effect may impair athletic performance.

When managing allergic rhinitis in competitive athletes, physicians must be careful to avoid prescribing medications with doping properties or therapy that may adversely affect performance. Nonsedating antihistamines and topical steroids are generally the best choices for serious athletes. The International Olympic Committee and other international regulatory authorities prohibit sympathomimetic decongestants (e.g., phenylpropanolamine and pseudoephedrine). In large enough quantities, these agents can act as psychostimulants as strong as d-amphetamine. Immunotherapy is recommended for athletes who wish to avoid being dependent on anti-allergy medications, though discomfort at the injection site may impede physical performance for several days at a time.

The successful management of chronic rhinitis depends greatly on how well patients cooperate with the therapeutic program. Educating patients about their disease and its management can promote that cooperation. It has been shown, for example, that allergic symptoms can be well controlled and a reasonable quality of life maintained when patients are given the appropriate medications, education, and written instructions before the pollen season commences (150) .

Specifically, patients benefit from knowing or understanding the following:

H o w and why rhinitis develops. Simple avoidance measures that can minimize exposure to allergens or rhinitis triggers. The

Appendix provides a handout about allergen control measures for patients in primary care.

Complications and related airway diseases that can develop f r o m poor allergy control. Patients who understand the scope of their disease are apt to take it seriously and thus comply better with therapy. This, in turn, may help minimize their risk of developing related airway diseases. How specific medications work, and how to use nasal sprays correctly. Patients must understand that antihistamines and intranasal steroids are most effective when taken on a regular basis and not as needed. For those who require two or more medications, an explanation of how each drug works provides a rationale for their use and may aid compliance.

The necessity for prophylactic medication.

Patients should be informed that early use of medication can prevent the onset of severe symptoms. Individuals with seasonal symptoms should start treatment at the outset of the spring or autumn seasons or in late summer. Those with perennial allergies need to take medication in advance of specific exposuresfor example, before visiting a relative who keeps indoor pets.

The side-effects associated with prescribed medications. Patients should be told about common side-eff ects of particular pharmacologic agents, and what to do in the event of their occurrence.

Possible drug interactions. Patients should understand the importance of informing their physician of all the medications they are taking, both prescription and nonprescription. Because of the risk of torsades de pointes, this is especially vital for users of terfenadine or astemizole. For the same reason, patients taking either of the latter two agents should also be instructed not to increase the dosage without consulting their physician.

The appropriate use of topical decongestants.

The risks and consequences of overuse should be discussed.

Simply written instructions help to reinforce key messages. Still, clinicians should ascertain whether patients truly understand what they have been told. Consider having patients repeat instructions rather than merely asking whether everything is clear. Reviewing key points with patients during subsequent office visits is advisable, especially when therapeutic goals are not being met.

Building a trusting alliance with patients is important in gaining their cooperation with therapy. In part, trust is established by attending to patients' concerns and preferences. Specifically, patients should be asked the following types of questions: How does rhinitis affect you daily? What medications or measures have you tried to reduce your symptoms? What do you expect from anti-allergy therapy? Do you anticipate any problems from treatment? Do you have any preferences in medications? Asking patients about their opinions and experiences in these matters fosters empathy and trust, and so encourages compliance.

Other pathways to improved compliance include the following:

Prescribing drugs with a longer half-life, so that less frequent dosing is possible. Choosing combination agents when more than one medication is needed to control symptoms. Selecting pharmacologic agents with few sideeffects.

Educating patients about their disease and its management (see prior section about patient education). For example, allergic patients who appreciate that poor compliance may increase the risk of asthma may be more motivated to follow pharmacologic and avoidance protocols. Selecting medications that target what the patient considers to be his or her most troubling symptoms. Impressing upon patients that compliance improves disease control and quality of life.

Allergists and immunologists find that compliance can be good, even when patients are not symptomatic, because failure to take medications or practice avoidance guarantees the return of symptoms. In conclusion, iherapeutic intervention in allergic rhinitis aims to relieve symptoms, improve longterm outcome and quality of life, and encourage patient satisfaction with medical management. Patients who are compliant with therapy generally obtain better symptom relief and feel more satisfied with their care.

Allergy and depression: a neurochemical threshold model of the relation between the finesses

Effects of allergy season on mood and cognitive function

Allergic diseases from infancy to adulthood

The allergic irritability syndrome: four case reports and a position statement from the Neuroallergy Committee of the American College of Allergy

Assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials

Assessment of quality of life in patients with perennial allergic rhinitis with the French version of the SF-36 Health Status Questionnaire

Epidemiology of acute asthma: IgE antibodies to common inhalant allergens as a risk factor for emergency room visits

Middle meatus antrostomy: patency rates and risk factors

The role of IgE-mediated hypersensitivity in the development of otitis media with effusion

The role of nasal allergy in otitis media with effusion: a clinical study

Increase in hospital admissions for childhood asthma: trends in referral, severity, and readmissions from 1970 to 1985 in a health region of the United

Nasal beclomethasone prevents the seasonal increase in bronchial responsiveness in patients with allergic rhinitis and asthma

Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness

Once daily intranasal fluticasone propionate (200 mg) reduces nasal symptoms and inflammation but also attenuates the increase in bronchial responsiveness during the pollen season in allergic rhinitis

The role of inflammatory mediators in allergic rhinitis

Quantitative intranasal pollen challenges. 111. The priming effect in allergic rhinitis

Weller PE The immunobiology of eosinophils

The effects of activated eosinophils and neutrophils on guinea pig epithelium in vitro

Eosinophil-and neutrophil-mediated injury of human lung fibroblast cells

Inhibitory activity of loratadine and descarboethoxyloratadine on expression of ICAM-1 and HLA-DR by nasal epithelial cells

The expression of leukocyte-endothelial adhesion cells is increased in perennial allergic rhinitis

Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma

Mucosal inflammation in asthma

Evidence of intercellular adhesion molecule-1 expression on nasal epithelial cells in acute rhinoconjunctivitis caused by pollen exposure

Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy

The major human rhinovirus receptor i s ICAM-1

A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses

A longitudinal study of the role of viral infections in exacerbations of asthma in school children in the community

Community study of role of viral infections in exacerbations of asthma in 9-11 year old children

Increased levels of eosinophil, a major basic protein in nasal secretions in rhinovirus infection

Rhinovirus upper respiratory infection increases airway hyperreactivity and late asthmatic reactions

Lower airways inflammation during rhinovirus colds in normal and in asthmatic subjects

International consensus report on the diagnosis and management of rhinitis

Nonallergic rhinitis with eosinophilia syndrome a precursor of the triad: nasal polyposis, intrinsic asthma, and intolerance to aspirin

The diagnosis and treatment of recurrent and chronic sinusitis in children

Gustatory rhinitis: a syndrome of food-induced rhinorrhea

Nonallergic chronic rhinitis syndromes

Seasonal variation in dust mite and grass-pollen allergens in dust from the houses of patients with asthma

Rhinitis of pregnancy

Intranasal cocaine abuse in an allergist's office

Nasal, pharyngeal, and laryngeal manifestations of hypothyroidism

Allergy in 7000 twin pairs

Parental asthma, parental eczema, and asthma and eczema in early childhood

The familial incidence of allergic disease

Comparison of patients' compliance with prescribed oral and inhaled asthma medications

Determinants of patient compliance with allergen immunotherapy

Is your asthmatic patient really complying?

Treatment of allergic rhinitis with loratadine plus pseudoephedrine in patients with mild asthma: effects on lower airway symptoms and function

Prophylactic treatment of grass pollen-induced asthma with cetirizine

Terfenadine, a potent histamine HI-receptor antagonist in the treatment of grass pollen sensitive asthma

Goodman Gilman's Pharmacological basis of therapeutics

Inhibitory effect of the H, antagonist loratadine on histamine release from human basophils

In vitro inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from human basophils, and of histamine release and intracellular calcium fluxes in rat basophilic leukemia cells (RBL-2H3)

Antiallergic activity of HI-receptor antagonists assessed by nasal challenge

Effect of loratadine on human eosinophil function in vitro

Effect of terfenadine on human eosinophil and neutrophil chemotactic response and generation of superoxide

The effect of antihistamines on the immediate allergic response: a comparative review

Topical azelastine reduces eosinophil activation and intercellular adhesion molecule expression on nasal epithelial cells: an antiallergic activity

Terfenadine exerts antiallergic activity reducing ICAM-1 expression on nasal epithelial cells in patients with pollen allergy

Position paper. The clinical safety of HI-receptor antagonists. An EAACI position paper

Histaminergic transmission in the mammalian brain

A multicentric study of loratadine, terfenadine, and placebo in patients with seasonal allergic rhinitis

Non-sedating antihistamines

A comparison of loratadine, a new nonsedating antihistamine, with clemastine and placebo in patients with fall seasonal allergic rhinitis

Once daily loratadine versus astemizole once daily

The role of antihistamines in the treatment of chronic urticaria

Perennial allergic rhinitis: clinical efficacy of a new antihistamine

Treatment of bronchial asthma with terfenadine: a randomised controlled trial

Effect of terfenadine in asthmatic patients

Effect of a non-sedative antihistamine (loratadine) in moderate asthma: a double-blind controlled clinical crossover trial

The effect of astemizole on exercise-induced asthma

Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-tomoderate asthma

Corticosteroidsparing effect of azelastine in the management of bronchial asthma

Comparative safety of HI-antihstamines

Physicians' desk reference

Double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis

Dose-ranging comparative evaluation of cetirizine in patients with seasonal allergic rhinitis

Sleepiness and performance during three-day administration of cetirizine or diphenhydramine

HI-receptor antagonists. Comparative tolerability and safety

Antihistamines and driving performance: The Netherlands

Cetirizine effects on objective measures of daytime sleepiness and performance

Does cetirizine belong to the new generation of antihistamines? An investigation into its acute and subchronic effects on highway driving, psychometric test performance and daytime sleepiness

Effects of terfenadine on actual driving performance

Hanlon JE Effects of loratadine and cetirizine on actual driving and psychometric test performance, and EEG during driving

Psychomotor effects of astemizole and chlorpheniramine, alone and in combination with alcohol

Acute and subchronic effects of the HI-histamine receptor antagonist ebastine in 10, 20, and 30 mg dose, and triprolidine 10 mg on car driving performance

double-blind, placebo-controlled trial of terfenadine in seasonal allergic rhinitis and conjunctivitis

Benefit/ risk ratio of the antihistamines (H,-receptor antagonists)

The effects of loratadine, diphenhydramine and placebo on worker productivity: results of a double blind trial [Abstract 5601

Differential cognitive effects of terfenadine and chlorpheniramine

Antihistamines, drowsiness, and psychomotor impairment: central nervous system effect of cetirizine

Antihistamines and visual function: studies on dynamic acuity and the pupillary response to light

A double-blind study of the effects of loratadine versus placebo on the performance of pilots

Comparison of the effect of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters

Torsades de pointes associated with drugs and toxins: recognition and management

Loratadine and pseudoephedrine sulfate: a double-bhd, placebo-controlled comparison of a combination tablet (SCH 434) and its individual components in seasonal allergic rhinitis

A cross-over comparison of acrivastine, pseudoephedrine and their combination in seasonal allergic rhinitis

Fireman l? Effect of an antihistamineldecongestant on nasal and eustachian tube function following intranasal pollen challenge

Effects of terfenadine and pseudoephedrine, alone and in combination in a nasal provocation test and in perennial rhinitis

Intranasal allergen challenge during corticosteroid treatment

The impact of allergic rhinitis

Efficacy of oncea-day intranasal administration of triamcinolone aceto

Once daily triamcinolone acetonide nasal spray is effective for the treatment of perennial allergic rhinitis

Topical corticosteroids and nasal reactivity

Fluticasone propionate nasal spray for allergic rhinitis

Intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy

A comparative study of beclomethasone dipropionate aqueous nasal spray with terfenadine tablets in seasonal allergic rhinitis

Pegelow K-0. Efficacy of an oral antihistamine, astemizole, as compared to a nasal steroid spray in hay fever

A comparative study of dexchlorpheniramine maleate sustained release tablets and budesonide nasal spray in seasonal allergic rhinitis

Comparison of beclomethasone dipropionate aqueous nasal spray, astemizole, and the combination in the prophylactic treatment of ragweed pollen-induced rhinoconjunctivitis

Oral antihistamine or nasal steroid in hay fever: a double-blind double-dummy comparative study of once daily astemizole vs twice daily nasal beclomethasone dipropionate

Local effect of intranasal beclomethasone dipropionate aerosol in hay fever

Glucocorticosteroids and rhinitis

Nasal septa1 perforation associated with topical corticosteroid therapy

The effect of cromolyn on nasal disease

Blychert L-0. Effects of topical treatment with H, and H, antagonists on clinical symptoms and nasal vascular reactions in patients with allergic rhinitis

Comparison of levocabastine, a new selective HI-receptor antagonist, and disodium cromoglycate, in a nasal provocation test with allergen

Topical levocabastine, a selective HI-antagonist, in seasonal allergic rhinoconjunctivitis

Azelastin in der allergologischeu praxis

Doubleblind assessment of azelastine in the treatment of perennial allergic rhinitis

A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential

Absence of central effects with levocabastine eye drops

Effects of topical administration of levocabastine on psychomotor and cognitive function

Topical nasal sprays: treatment of allergic rhinitis

Anticholinergic treatment of watery rhinorrhea

The common cold: current therapy and national history

Beneficial effects of propylene and polyethylene glycol and saline in the treatment of perennial rhinitis

A novel therapy concept for the treatment of allergic rhinitis

EAACI Position Papers

Report of BSACI working party

Alternative routes of immunotherapy: a review

Asthma and wheezing in the first six years of life

The effect of genetic and environmental factors on the prevalence of allergic disorders at the age of two years

Ipratropium (Atrovent) in the treatment of vasomotor rhinitis of elderly patients

The course and management of asthma and allergic diseases during pregnancy

Drugs in pregnancy and lactation

Pharmacotherapy of allergic rhinitis

Aqueous beclomethasone dipropionate nasal spray in treatment of seasonal (ragweed) rhinitis


