Antihistamines and decongestants have been the main therapeutic agents for the treatment of allergic rhinitis for more than 50 years. The safety and efficacy of these drugs in treating allergic disease in children have been well established. Bronchial asthma occurs in a high percentage of children with allergic rhinitis. Although the general clinical impression is that effective treatment of allergic rhinitis greatly assists in the management of bronchial asthma when the two conditions coexist, the value of antihistamine therapy in asthma treatment is not entirely clear and somewhat controversial. The purpose of this article is to examine the mechanisms of action of antihistamine and decongestant medications in nasal allergy and to identify their effects on the lower airway.
Allergic rhinitis usually first occurs in childhood. The prevalence rate is variable in different populations, but approaches 20% in the United States.1 Genetic and environmental factors influence the severity of expression, the time of onset, and the course of the condition. In those children who have bronchial asthma, allergic rhinitis precedes the appearance of lower respiratory illness more often than not. As with asthma, the prevalence of allergy in general, and allergic rhinitis in particular, is increasing.2'3
Allergic rhinitis and asthma share a common immunopathology. In both conditions, airborne allergen must contact the respiratory mucosa. Particles smaller than 5 µp\ can deposit in the lower respiratory tract; larger particles such as pollen (20 to 35 µtt\) usually impact mucosal surfaces in the supraglottic airway. Fragments of larger allergens and water-soluble allergens can also sensitize the lower respiratory tract. Specific IgE antibody is formed, which, in turn, binds to mucosal mast cells and basophils. Re-exposure to allergen leads to degranulation of mast cells and the release of the preformed inflammatory mediator histamine (H1) and the rapid synthesis and release of leukotrienes (LTC4, LTD4, LTE4), prostaglandin D2, kinins, kininogenase, and tosylarginine methyl ester esterase in nasal secretions.4 The net effect of mediator release is increased vascular permeability, tissue edema, and recruitment of inflammatory cells, which further a more sustained inflammatory response.
Within minutes after the exposure of an allergic individual to an antigen, there is the onset of sneezing and increased nasal secretions. After approximately 5 minutes, mucosal swelling develops, leading to reduced nasal airflow.5 A "priming effect" on the bronchial and nasal mucosa occurs with repeated exposure to an allergen during a "season." Lower doses of allergen can initiate mast cell degranulation when there is more frequent exposure to allergen. With repeated or constant allergen exposure (as with a pet or dust mites in the home), the affected tissue may react in a chronic "late phase" with inflammatory cells sustaining inflammation rather than releasing early mediators of inflammation. Hence, persistent symptomatology of asthma or chronic rhinitis may be seen even in the absence of immediate early-phase symptoms on allergen exposure. Cytokines produced by tissue mast cells and macrophages further the inflammatory process by recruiting inflammatory cells such as eosinophils, neutrophils, and basophils to sites of allergic injury where they, in turn, release a wide range of inflammatory mediators.
BRIEF REVIEW OF MECHANISMS
Neural mechanisms mediate, to some degree, upper and lower inflammatory activity. These are reviewed in more detail in the article by Lieberman in this issue. Briefly, sensory nerve stimulation in the nose recruits parasympathetic reflexes that lead to sneezing, vasodilation, and rapid secretion of submucosal gland mucus, and an increase in nasal airflow resistance. Nociceptive sensory nerve stimulation in the tracheobronchial tree may induce bronchospasm, vasodilation, vascular permeability, and glandular secretion. Kaufman and Wright demonstrated that increased airway resistance in the lung produced by irritation of the nasal mucosa by silica particles was prevented by the pretreatment of nasal tissue with atropine.6 The same investigators later found that a prior resection of the trigeminal nerve could prevent this bronchoconstriction. Settipane described a "rhinobronchial reflex" where the afferent arm of the reflex consists of fibers of the trigeminal, glossopharyngeal, and facial nerves and the efferent arm is the vagal nerve7 (Fig. 1). Lung function can be altered by nasal airway obstruction. It has been demonstrated that there is a decrease in forced expiratory volume 1 second (FEV1) when one nostril is blocked.
In addition to neural and immunologic connections between upper and lower airway inflammation, direct effects of nasal dysfunction may influence asthma. It has been postulated that postnasal drip can carry inflammatory mediators to the lower respiratory tract. Mouth breathing may influence asthma under certain circumstances (eg, in exercise-induced asthma).8
In 1984, Rachelefsky et al. described an association of chronic sinus disease with asthma in children.9 Aggressive treatment of the upper airway disease resulted in improvement in asthma in a number of children studied. Linkage of the sinus disease to worsening of asthma was thought to be through direct mechanisms (irritation and inflammation of the lower airway by direct contact with infected upper airway secretions) and by common inflammatory stimuli and neural reflex stimulation.
However, in a study of 13 patients with chronic sinusitis and asthma by Bardin et al., pulmonary aspiration of radionuclide placed in the upper airway was not documented.10 An earlier study by Huxley et al. did demonstrate pharyngeal aspiration in normal adults and patients with depressed consciousness using a radiolabled marker placed in the nose.11 Therefore, the issue of whether nasal and sinus disease exacerbates asthma by direct seeding of the lower respiratory tract with infected or inflammatory secretions is unresolved.
Another linkage of allergic rhinitis to asthma was provided by Corren et al., who performed double-blind, randomized nasal challenges with allergen or placebo in patients who had a prior history of asthma exacerbations after the onset of symptoms of seasonal allergic rhinitis. They then demonstrated a relative increase in bronchial hyperresponsiveness to methacholine after allergen challenge.12 Interestingly, no lower airway obstruction, as measured by FEV1, specific conductance, lung volumes, or serial peak flow rates after antigen challenge, was identified in the 10 patients who completed the study.
Figure 1 . Rhinobronchial reflex. Stimulation of receptors found in the nose, pharyngeal, and sinus areas can produce bronchospasm through neural reflexes. The receptors involved are thè histamine (H1) and irritant receptors that send afferent neural impulses through the trigeminal, facial, and glossopharyngeal nerves to the medulla oblongata, where the vagal nucleus is stimulated. The efferent arm of this reflex is the vagal nerve with its ramifications sending neural impulses to the bronchial tree, causing bronchospasm. (Reprinted with permission from Settipane GA. Rhinitis: introduction. In: Settipane GA, ed. Rhinitis, 1 st ed. Providence, Rl: Oceanside Publications; 1984:6.)
Antihistamines have been the cornerstone of pharmacologic management of allergic rhinitis for half a century. Allergic stimulation of the H1 receptor produces pruritis, pain, initiation of airway defense measures such as sneezing, increased generation of prostaglandin, increased release of inflammatory mediators, and recruitment of inflammatory cells.13 The therapeutic effect of antihistamines is based on blockade of these H1 receptors located on the nasal vasculature and nerve endings.14 Antihistamines have the best effect when employed before allergen exposure. Older antmistamines compete with histamine to bind to receptor sites. Newer "secondgeneration" antiHstamines have more complex receptor interactions and often much longer halflives than do the first-generation agents. The term antihistamine belies the true value of the drug class because these agents are broadly antiinflammatory (to a mild degree). The second-generation agents in particular inhibit release of leukotrienes and other mediators, as well as histamine. Inhibition of mediator release is probably not a function of H1 blockade.
Most of the older, first-generation antihistamines readily penetrate the blood-brain barrier, producing sedation and other undesirable central nervous system effects.15 Cognitive function and reaction times can be impaired in patients taking older antihistamines. Sleep latency, or the time required to fall asleep, is decreased with first-generation, as compared with second-generation, agents. This can lead to levels of drowsiness not appreciated by patients. One study of children with allergic rhinitis demonstrated that learning impairment was exacerbated by older antihistamines.16 Because of their larger molecular size, newer second-generation antihistamines do not generally penetrate the central nervous system and are preferable for allergy therapy in most individuals.
The onset of histamine-antagonist activity is prompt after oral administration, occurring within 1 to 2 hours with most of the older agents and more rapidly with several second-generation antihistamines. Maximum H1 blockade occurs several hours after peak plasma concentrations and persists after plasma levels of the agents decline to undetectable ranges. The pharmacokinetics of first- and second-generation antihistamines are such that both are best used prophylactically - before allergen exposure.
Oral and topical decongestants improve nasal airway patency by reducing blood volume in the paranasal sinuses and nasal mucosa. Decongestants are a-adrenergic agonists binding to aadrenergic receptors on vascular smooth muscle. Receptor activation by a-agonists results in decreased sympathetic output.
When combined with antihistamine in an oral preparation, decongestants give better symptom relief in allergic rhinitis than does antihistamine alone. Nasal airway mechanics are improved in addition to providing relief from sneezing, pruritis, and excessive mucus secretion.
Primary side effects of decongestants such as phenylephrine, pseudoephedrine, and phenylpropanolamine are nervousness, irritability, headache, tachycardia, palpitations, sleep disturbance, and increased blood pressure in individuals prone to hypertension. If used longer than 5 to 7 days, topical decongestants may produce rebound nasal congestion and a condition of intense, chronic inflammatory rhinitis called rhinitis medicamentosa.
Oral decongestant medication is not as effective as topical corticosteroids in relieving nasal mucosal edema and congestion. The therapeutic index of oral a-agonists is low. Oral decongestants are not thought to have bronchodilatory effects.
EFFECTS OF ANTIHISTAMINES ON THE LOWER RESPIRATORY TRACT
Beneficial effects of antihistamines on the lower respiratory tract in patients with allergic rhinitis and concomitant asthma may involve one or more of these four mechanisms:
1. Bronchodilation or reduction of bronchomotor tone through direct action on smooth muscle or influence on airway caliber.
2. Reduction of inflammatory activity in the upper airway, which, by way of neural pathways, promotes lower airway obstruction.
3. Reduction of nasal airway congestion and obstruction, which is related to obstruction of lower airway airflow.
4. Reduction of inflammatory activity in the lower airway by histamine antagonism.
Histamine does contribute to the pathogenesis of asthma symptoms. Therefore, therapy for asthma with antihistamines should theoretically be beneficial.17 First-generation antmistamines were relatively weak in therapeutic asthma effects, and also possessed sedative and anticholinergic effects. Because they can be used at higher doses, second-generation antihistamines produce subjective and minimally objective improvement in asthma in individuals with allergic rhinitis. Rafferty reviewed the effects of terfenadine in patients with mild asthma in a randomized, double-blind, crossover study during the grass pollen season.18 Cough and wheeze were significantly reduced (77% and 47%, respectively), but peak expiratory flow rates (PEFRs) rose only between 5.5% and 6%. In a study by Cieslewicz et al., the second-generation antihistamine loratadine provided no protective action against early asthmatic reactions after single allergen challenge, but effectively blocked late asthmatic reactions as assessed by bronchial responsiveness to histamine challenge.19
In one of the few studies of the effects of antihistamines on pulmonary function in pediatric asthma, Lewiston et al. observed 28 children and 2 adults with bronchial asthma and symptomatic seasonal allergic rhinitis during the height of grass pollen season.20 Patients who were sensitive on skin test to perennial rye grass antigen were paired according to age, height, requirement for maintenance asthma medication, and percentage of predicted baseline pulmonary function tests. One member of each pair was assigned to an experimental group receiving 0.50 mg/kg/d of chlorpheminramine to a maximum of 24 mg/ d. The control group received placebo and the study was double blinded.
Measurements of FEV1, maximal expiratory flow, forced expiratory flow (FEF25-75), and expiratory flow rates at 50% and 25% of vital capacity were made on days 2, 4, 7, 11, and 12. The trends in pulmonary function were plotted as a function of time, and a linear regression of each plot was made. Statistical differences in pulmonary function for the two study groups were achieved only for FEV1, where the slope of the regression line was better for the group receiving chlorpheniramine than for the control group. The group treated with chlorpheniramine also reported fewer symptoms than did the placebo group. The positive effects on pulmonary function were not overly impressive, even when there was substantial relief of nasal symptoms.
Inhibition of histamine-induced bronchospasm has been demonstrated with cetirizine in patients with asthma. For example, Ghosh et al. examined the effect of cetirizine on histamineand LTD4-induced bronchoconstriction in patients with atopic asthma.21 Patients with mild extrinsic asthma who had positive results on skin test to at least three common inhaled allergens were given either 15 mg of cetirizine twice daily or a matched placebo for 7 days, with a washout period of 2 weeks between treatments, in a randomized, double-blind manner. Inhaled ß2-agonists and corticosteroids were continued during the study, but withheld 12 hours before each test. Histamine bronchial provocation challenges were performed before and 2 hours after medication on the first and eighth days of each treatment period. FEV1 was the pulmonary function parameter measured. The procedure for LTD4 was similar. The challenge was performed 1 hour after the second histamine inhalation challenge (3 hours after treatment) and when FEV1 readings had returned to within 5% of posttreatment values.
After a single dose and 7 days of treatment, cetirizine and placebo did not alter the mean baseline FEV1 significantly. However, the mean dose of histamine in the group treated with cetirizine (single dose) required to cause a decrease of 20% from baseline in FEV1 was 74 times that of the group treated with placebo. The provocation challenge (PC20) LTD4 in the group treated with a single dose of cetirizine was minimally, but significantly, greater than that of the group treated with placebo. Inhibition of histamine and LTD4 was considerably less in the 7-day treatment phase for both challenges. Therefore J cetirizine, at doses considerably higher than those currently approved by the Food and Drug Administration, shifted the histamine dose-response curve (PC20) by 74-fold to the right after a single dose and 32fold after 7 days.21
Figure 2. Mean percentage change in forced expiratory volume 1 second (FEV1) adjusted for baseline and placebo effect as a function of time after the administration of 20 (diamonds), 10 (squares), or 5 mg (circles) of oral cetirizine alone, as well as 1 80 µ?, of inhaled albuterol alone (plus symbols) (n = 12). (Reprinted with permission from Spector SL, Nicodemus CF, Corren |, et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. J Allergy Clin Immunol. 1 995;96:1 74-1 81 .)
Figure 3. Mean percentage change in FEF25 _7S adjusted for baseline and placebo effect as a function of time after the administration of 20 (diamonds), 10 (squares), or 5 mg (circles) of oral cetirizine alone, as well as 180 pg of inhaled albuterol alone (plus symbols) (n = 1 2). (Reprinted with permission from Spector SL, Nicodemus CF, Corren J, et al. Comparison of the bronchodilatory effects of cetirizine, albuterol, and both together versus placebo in patients with mild-to-moderate asthma. / Allergy Clin Immunol. 1995;96:174-181.)
BRONCHODILATORY EFFECTS OF ANTIHISTAMINES
Mild bronchodilatory activity has been ascribed to several first-generation antihistamines. Chlorpheniramine was shown to cause a significant increase in FEV1 when given intravenously to patients with asthma and to cause some bronchodilation when given by nebulization.22 Clemastine has also been demonstrated to increase FEV1 and PEFR quantitatively, similar to the effect of albuterol.23 The antihistamine was administered by inhalation and it is certain that similar airway doses of the drug could not be achieved by oral administration of standard doses. Indeed, direct effects of most antihistamines on lung function are achieved in doses that, for reasons of sedation or potential toxicity cannot be delivered systemically.
Spector et al. compared the bronchodilatory effects of the second-generation antihistamine cetirizine to those of albuterol, albuterol plus cetirizine, and placebo in patients with mild to moderate asthma.24 The study, performed on adults, employed doses of 5, 10, and 20 mg of cetirizine and 2 puffs of albuterol from a metered-dose inhaler (90 ^g per puff of active drug). Four measures of pulmonary function were determined at each of eight visits (forced vital capacity, FEV1, PEFR, and FEF2^75). Patients received eight treatments in a random fashion employing combinations of cetirizine at varying doses, placebo antihistamine, active albuterol, and placebo aerosol. Twelve patients completed the study.
The 20-mg dose of cetirizine increased FEV1 significantly more than did placebo at all time points except 30 minutes (P < .02). Treatment with 5 and 10 mg of cetirizine yielded significantly greater percentage increases than did placebo at 150 minutes and at all time points from 4 through 8 hours (P < .02). Albuterol increased FEV1 significantly more than did placebo at all time points from 60 minutes through 4 hours, but not at 5 through 8 hours24 (Fig. 2). The effect of 20 mg of cetirizine was greater on the FEF25 ^ from baseline (mean change in FEF25-75 from baseline) than on the FEV1 (Fig. 3). Twenty milligrams of cetirizine, the dose that produced the greatest change in resting bronchomotor tone in the patients, is twice the standard dosing of the drug for adults and children weighing more than 60 pounds in the United States. Cetirizine, at any of the study doses, neither potentiated nor inhibited the bronchodilatory action of albuterol in these patients.
Another second-generation antiHstamine, terfenadine, diminishes resting bronchial tone in asthmatic airways, but does not alter methacholine-induced bronchospasm.25,26 In a large, . double-blind European study, cetirizine given to individuals with grass pollen-induced asthma led to reductions in wheezing, coughing, and dyspnea. However, there appeared to be no significant effect on the measure of pulmonary function (PEFR) in either of the groups treated with 10 or 15 mg of cetirizine during a grass pollen season (all individuals additionally had grass pollen allergic rhinitis).27
A more recent large, 6-week, multicenter study by Grant et al. examined the effects of cetirizine in adult patients with seasonal rhinitis and concomitant mild asthma.28 They were randomized to treatment with 10 mg of cetirizine or matching placebo once daily in the morning. Study participants were allowed to use 30 mg of pseudoephedrine every 6 hours as rescue medication for nasal congestion, with asthma treated as needed by a metered-dose inhaler with albuterol. Pulmonary function was assessed with daily measurement of PEFR and weekly measurement of FEV1. Improvement in asthma and rhinitis was assessed by patient logs, and symptoms were scored on a 5-point scale. Mean symptom scores and drug usage were determined weekly.
In the treatment group, cetirizine effectively reduced all rhinitis symptoms except for nasal congestion. The patients treated with placebo had significant worsening of total rhinitis symptom scores during the study period (a major pollen season). In the group treated with cetirizine, total asthma symptom scores were significantly lower at weeks 1 to 5 for all periods except week 3 (Fig. 3). There were no significant differences, however, in pulmonary function; neither PEFR nor FEV1 changed with the onset of the pollen season and neither was significantly altered with or without therapy during the study. The number of inhalations of albuterol, used as rescue medication, between the placebo group and the treatment group did not reach statistical significance.28
An intriguing study of the effects of antihistamine on the development of asthma in allergyprone infants and toddlers deserves mention. First results of the European Early Treatment of the Atopic Child study group were reported by Wahn.29 The premise was that infants and toddlers with atopic dermatitis and a family history of atopic disease in a parent or a sibling would be more likely to have asthma, particularly if IgE levels were elevated. Eight hundred seventeen such children from 1 to 2 years old were treated for 18 months with either cetirizine (0.25 mg /kg twice daily) or placebo. The relative risk (RR) for asthma developing was elevated in those with a raised level of total IgE (2* 30 kU/L) or specific IgE (^ 0.35 kUA/L) for grass pollen, house dust mites, or cat dander (RR = 1.4-1.7).
Compared with placebo, cetirizine significantly reduced the incidence of asthma for patients sensitized to grass pollen (RR = 0.5) or to house dust mites (RR = 0.6). The mechanism for this apparently meaningful intervention was postulated to be prevention of eosinophil trafficking in infants genetically prone to allergy and asthma and sensitized to allergens at an early age.29
The first study to evaluate a combination of antihistamine-decongestant medication in the treatment of patients with seasonal allergic rhinitis and concomitant mild asthma was done by Corren et al. They found that treatment with loratadine plus pseudoephedrine improved not only nasal symptoms, but also improved asthma symptoms and pulmonary function.30 Patients 12 to 70 years old were randomized to receive either placebo or 5 mg of loratadine and 120 mg of pseudoephedrine during a 6- week period in the fall. Quality-of-life questionnaires were completed and pulmonary function was assessed with serial measurements of PEFR and FEV1. Patient assessments occurred at clinic visits on weeks 1, 2, 4, and 6 after starting medication; diaries were reviewed, rhinitis and asthma symptom scores were calculated, and pulmonary function was measured. Patients were allowed to use only albuterol by metered-dose inhaler as asthma rescue medication. No additional medication was allowed for rhinitis symptoms.
Total rhinitis symptoms (congestion, sneezing, pruritis, and rhinorrhea) were significantly improved in patients treated with loratadine and pseudoephedrine, compared with those given placebo. Total asthma symptom severity scores measured in the morning were significantly improved (vs placebo) throughout all 6 weeks of the study; evening symptom scores were reduced during weeks 3 through 5. Mean improvements in peak flow rates were twofold to threefold higher in patients receiving loratadine and pseudoephedrine compared with those receiving placebo. FEV1 increased significantly relative to placebo at weeks 1, 2, 4, and 6, with morning PEFR improvement occurring during weeks 2 through 630 (Figs. 4 and 5). A possible mechanism for improvement in asthma symptoms was the blocking effect of antihistamine on the nasal mucosa and the reduction of nasal airway obstruction. The safety of the loratadine and pseudoephedrine regimen was established in the adult population of mis study.
Figure 4. Forced expiratory volume 1 second (FEV1) (mean ± standard error of the mean) measured at clinic visits, expressed as changes from baseline. *P< .05. (Reprinted with permission from Corren J, Harris AC, Aaronson D, et al. Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma. / Allergy CHn Immunol. 1997;1 00:786.)
Figure 5. Peak expiratory flow rates (PEFRs) in the morning (A.M.) and the evening (P.M.), expressed as mean changes from baseline. *P< .05. (Reprinted with permission from Corren J, Harris AG, Aaronson D, et al. Efficacy and safety of loratadine plus pseudoephedrine in patients with seasonal allergic rhinitis and mild asthma. iAllergy Clin Immunol. 199 7; 100:786.)
The effect of aggressive treatment of nasal congestion associated with allergic rhinitis may be greater on lower airway disease in children than in adults. Relative nasal airway resistance is significantly higher in children than in adults because of anatomic considerations. Children are more prone to viral upper respiratory tract infections than adults because of immunologic naivete and frequent exposure in school and day care settings. This may result in a more chronic nasal congestion state during certain times of the year (fall through spring) in children with allergies. Optimal doses of antihistamines and decongestants to provide effects on the lower respiratory tract in children are not known. Few studies on the effects of treatment of rhinitis on childhood asthma are available for review. Indeed, most of the studies that form the basis for therapeutics in allergy have been conducted in adults. Pediatric studies often rely on subjective assessments of improvement such as patient or parental reporting of symptoms. There is a paucity of pulmonary function measurement information to assess the effects of therapy for rhinitis in children.
In the executive summary report of the American Thoracic Society Workshop, current therapies and future prospects for the concomitant treatment of asthma and rhinitis were reviewed.31 The committee felt that there were not enough convincing data to recommend that H1 antagonists be used for the treatment of asthma. Objective measurements of asthma control have "not consistently improved." Antihistamines, according to the committee, should be used as adjunctive therapy for asthma.
The literature does support the thought that antihistamine therapy, antihistamine-decongestant therapy, or both in the treatment of allergic rhinitis is probably beneficial to patients who also have asthma. However, few direct pulmonary effects of the therapy are evident at customary dosing of antihistamines. It may be assumed from adult studies that such therapy would also be beneficial to children with allergic asthma. However, children's upper and lower airways are different from those of adults. The longer duration of asthma may be associated with permanent lower airway asthmatic changes, so the response to antihistamines, antiinflammatory agents, and bronchodilators may be quantitatively different in children as compared with adults.
Antihistamines and decongestants are definitely important in the management of allergic rhinitis, and, at the very least, should not be withheld from children who also have asthma. Physicians treating allergic rhinitis alone or asthma alone should be aware of the immunobiologic interrelationships of the two diseases and should understand the possible benefits of pharmacologic management of allergic rhinitis in patients with asthma. More investigation in this area involving longer-term and longitudinal studies could help elucidate the true value of antihistamines for lower respiratory function in children who have allergic rhinitis and concomitant asthma.
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