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- Material and methods
Although H1 antihistamine compounds (H1) are highly effective in the treatment of allergic rhinitis (AR), their role in the treatment of asthma is still controversial. Because a strong association between AR and bronchial hyperresponsiveness (BHR) has been reported, this study was designed to assess the effect of a new H1 anti histamine, cetirizine (C), on nonspecific BHR in patients with AR. Twelve patients were included in a double-blind, crossover, placebo-controlled trial. All patients had positive skin tests for common allergens and showed BHR to inhaled methacholine after specific nasal allergenic challenge. After a washout period of 1 week to ensure the stability of the BHR, the patients received, by crossover randomization, C 10 mg daily or placebo (P) for 2 weeks. After each treatment period, BHR and nasal blocking index (NBI) were measured 1 and 6 h after nasal challenge. Bronchial responsiveness was expressed as methacholine PD20, the provocation dose of methacholine causing a 20% decrease in FEV1. Measurements were then performed after 2 weeks of C and after 2 weeks of P. Baseline values of PD20 (median) measured before challenge showed no difference after cetirizine or after placebo (1.36 mg). Results 1 h after allergen did not show significant differences between C (methacholine PD20=0.522 mg) and placebo (methacholine PD20=0.455 mg). By contrast, 6 h after challenge, methacholine PD20 was 0.918 mg for C and 0.483 mg for P (P=0.042). Similarly, NBI showed no change between C and P 1 h after challenge, whereas the difference was significant 6 h after challenge (P=0.011). These data demonstrate a protective nasal effect of C against BHR measured 6 h after nasal allergen challenge in patients with AR. They suggest that C may be useful in patients with asthma associated with AR.
Many patients with allergic rhinitis, but no history of asthma, show abnormal pulmonary function, occurring either spontaneously or after bronchoprovocation with methacholine, histamine, or cold air (1, 2). A recent investigation has also demonstrated that in patients with allergic rhinitis, induction of a nasal allergic reaction resulted in both immediate and late increases in bron-chial responsiveness (3). Furthermore, in some patients with allergic rhinitis and no evidence of asthma, inhal-ation of pollen causes bronchoconstriction, just as it does in asthmatic patients (4), and seasonal variation of airway responsiveness has been demonstrated in these patients (5, 6). These asymptomatic patients with dem-onstrable changes in lung function may be at risk of development of asthma (7).
Various mechanisms have been proposed to explain the link between upper and lower airway disease. These include
elicitation of a nasal-bronchial reflex
increased oral inhalation of cold, dry air or air-borne allergen caused by nasal blockage
absorption of mediators or chemotactic factors
postnasal drainage of inflammatory material into the lower airways (8).
Although several of these mechanisms may be involved in the changes in bronchial reactivity observed in patients with allergic rhinitis, postnasal drip of inflam-matory material into the lower airways has been pro-posed to explain, at least in part, the link between upper and lower airway disease. This mechanism is supported by several studies showing that in patients with allergic rhinitis, nasal corticosteroids decrease bronchial hyperreactivity (9, 11).
Among the mediators implicated in the genesis of allergic rhinitis and asthma, histamine plays an import-ant role. It causes smooth-muscle contraction, increased secretion of mucus, increased vascular permeability leading to mucosal edema, and parasympathetic nerve stimulation (12). Although it has been clearly shown that antihistaminic compounds are highly effective in allergic rhinitis (13), their role in the treatment of asthma is still controversial. However, because of the links between upper airway disease and asthma, antihistaminic compounds may be more effective on the lower airways of patients in whom both diseases are associated than in asthmatics without allergic rhinitis. The aim of this study was therefore to determine the effect of cetiri-zine, a potent H1 antagonist, on nonspecific bronchial hyperresponsiveness (BHR) in patients with allergic rhinitis.
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- Material and methods
This study demonstrates that orally administered cetirizine (10 mg daily for 2 weeks) confers a significant protective effect against BHR to methacholine induced by nasal allergen challenge. This effect was observed on the late-phase response (6 h), but not on the early one (1 h) after nasal allergen challenge.
We chose to use allergen as the provocative agent to examine changes in airway responsiveness associated with nasal challenge. Unlike agonists, such as histamine or methacholine, allergen causes the release of a spect-rum of mediators that might be of potential importance in altering airway caliber or responsiveness (20). We did not observe any change in pulmonary function after nasal allergen challenge either at 1 or 6 h after allergen exposure, indicating that no change in airway caliber occurred. This is in agreement with previous studies (21, 22) that were also unable to document changes in pul-monary function after inducing a significant nasal- allergic response in subjects with seasonal or perennial allergic rhinitis.
However, the protective effect of cetirizine against airway responsiveness observed 6 h after nasal challenge could be attributed to changes in airway caliber induced by the drug. In our study, pulmonary function measured at baseline and after administration of cetirizine and placebo was normal and was not significantly different throughout all the trial periods (Table 1). Thus, we can rule out a bronchodilator effect of cetirizine in our patients, an effect which could by itself have accounted for the protective effect against airway responsiveness observed 6 h after nasal allergen challenge during the cetirizine period. It is also possible that cetirizine may have modified the methacholine response by mechanisms unrelated to nasal allergen challenge. We cannot totally rule out such an hypothesis since we did not study the effect of cetirizine on methacholine challenge alone. However, such a phenomenon is unlikely because no effect of cetirizine was observed on the methacholine response 1 h after nasal challenge, a significant effect being observed only during the late-phase response (6 h). Furthermore, in a study performed in asthmatic patients who did not have any associated upper airway disease, no effect of 2-week therapy with oral cetirizine (10 mg twice a day) was noted against bronchial reactivity to methacholine (23).
Methacholine challenges were repeated on the same day within a 5-h interval. It has been shown that methacholine tachyphylaxis occurs in normal subjects when the inhalation tests are performed 3 h apart, tolerance to methacholine lasting for more than 6 h (24). Hence, the changes in PD20 that we observed at 6 h may have been underestimated as compared to the PD20 measurements performed 1 h after the nasal challenge. Although such a phenemenon cannot be totally ruled out in our patients, it seems very unlikely. Indeed, meth-acholine tachyphylaxis has been essentially described in normal subjects rather than in mild asthmatics (24). In the latter study, mean methacholine PD20 amounted to 47.3 mg/ml in normal subjects and to 1.6 mg/ml in mild asthmatics. This suggests that the development of methacholine tachyphylaxis may depend on the concentrations of methacholine inhaled during the initial challenge. Indeed, a correlation has been found between the initial concentration of inhaled methacholine and the magnitude of subsequent tachylaxis (24). In the pres-ent study, median methacholine PD20 in our patients amounted to 1.36 mg, which is close to what was report-ed by Stevens et al. (24). In this connection, Cheung et al. (25) have shown that methacholine tachyphylaxis may develop only in asthmatics with a methacholine PD20 during the first challenge higher than 256 mg/ml, a much higher PD20 value than that observed in our patients. Furthermore, during the placebo period, no evidence of methacholine tolerance was noted since all the patients exhibited at 6 h marked BHR.
Our patients with seasonal allergic rhinitis were pros-pectively selected on the basis of positive nasal and bronchial responses to allergen challenge. All of them developed not only an immediate but also a late-phase response to allergen challenge. Allergen delivery to both nostrils was performed with an atomizer that distributed allergen to a larger surface area of nasal tissue, as might be expected with natural pollen exposure. With this technique, it has been previously shown that allergens do not reach the lower airways (3). Therefore, we can be sure that the changes in bronchial responsiveness that we observed after nasal allergen challenge originated from a process confined to the nose.
The mechanisms proposed to explain the link between upper and lower airway disease include elicitation of a nasal-bronchial reflex, postnasal drainage of inflammatory material into the lower airways, and dry air caused by nasal blockage (8).
Although neural mechanisms have been a basis for connecting nasal and bronchial disease, nasal anesthesia has obviously failed as a treatment in both rhinitis and asthma (26). Furthermore, it has been shown that topical lignocaine has no effect on allergen-induced nasal symptoms (27). Thus, increased airway responsiveness after nasal challenge secondary to activation of a nasal bronchial reflex appears unlikely.
Previous work has shown that nasal breathing can reduce exercise-induced asthma (28), probably because of the warming and humidification of inspired air before it reaches the lower airways (29). The improvement in NBI that we observed 6 h after nasal challenge during the cetirizine period, as compared with the placebo period, may be important in this regard to explain the decrease in bronchial responsiveness noted in our patients. However, we did not find any correlation between the changes in NBI and PD20 to methacholine after nasal allergen challenge during either the cetirizine or the placebo period.
Postnasal drip of allergen-induced inflammatory products may play an important role in increasing bronchial responsiveness. In an animal model of rhinosinusitis, induction of nasal inflammation resulted in increased bronchial responsiveness without causing airflow limitation (30). This increase in lower airway reactivity was prevented by strategies that blocked drainage of nasal secretions into the lower airways.
Nasal inflammation has been well demonstrated in allergic rhinitis (31), many different stimuli being capa-ble of producing inflammation of the nasal mucosa. Indeed, local accumulation of CD4+ T-helper cells, IL-2-bearing cells, presumed T cells, eosinophils, and neutrophils has been found in the nasal submucosa 24 h after local allergen provocation (32). Furthermore, it has also been demonstrated in the nasal mucosa of patients with perennial rhinitis that mast cells are an important source of preformed cytokines, such as IL-4, IL-5, and IL-6, which may contribute to the chronicity of the mucosal inflammation that characterizes allergic rhinitis (33). Several preformed and/or newly generated inflammatory mediators may be released from resident cells in the nasal mucosa (mast cells, eosinophils, lymphocytes, etc.) (34). These mediators, such as histamine, leukotrienes, prostaglandins, and platelet-activating factor, increase vascular permeability with local tissue edema, secretion of mucus, and glandular proteins (rhin-orrhea) (31). These nasal secretions may be aspirated into the lower airways and increase bronchial responsiveness. H1 antagonists such as cetirizine prevent and relieve nasal rhinorrhea of the early allergic response to antigen (35), an effect which may contribute to a reduct-ion of the postnasal drip of inflammatory products and thus to a decrease in bronchial responsiveness, as observed in our patients 6 h after allergen challenge.
Moreover, besides its potent and specific H1-receptor-blocking activity, cetirizine has several other important effects on eosinophils, which have been shown to play an important role in the genesis of BHR, the main feature of asthma. Cetirizine inhibits eosinophil chemotaxis in vitro (36); in vivo it inhibits eosinophil, basophil, and neutrophil migration into the skin chamber after antigen-induced allergic reactions (37, 38); and it inhibits eosinophil accumulation in the skin whether the challenge is anti-IgE antibodies, platelet-activating factor, or delayed-pressure urticaria (39, 40). In this connection, it has been shown that in moderately asthmatic patients with reproducible late allergic reactions after the bronchial provocation test with allergen, cetirizine produced a significant protective effect against the allergen-induced late-phase response (41). In the same type of patients, Redier et al. have also demonstrated that cetirizine inhibited the recruitment of inflammatory cells (mainly eosinophils) in the bronchoalveolar lavage induced by bronchial allergen inhalation challenge (42). All the above described effects, however, were observed for higher doses of cetirizine (20 or 30 mg daily) than that generally recommended (10 mg daily) for the treatment of allergic rhinitis. However, in a recent study in patients with seasonal rhinitis and concomitant asthma, Grant et al. (43) showed that cetirizine 10 mg daily to be effective in relieving both upper and lower respiratory tract symptoms. These results are in line with our study, which clearly demonstrated a significant effect of 10 mg of cetirizine on bronchial hyperreactivity to methacholine 6 h after nasal allergen challenge. Thus, although cetirizine at high doses may have some effects in asthmatic patients, these effects appear to be greater in patients with asthma associated with allergic rhinitis. In this connection, it is possible that the bronchial protective effect of cetirizine that we observed in our patients 6 h after nasal challenge would have been even greater if we had used a higher dose of cetirizine.
In conclusion, this study confirms the links between allergic rhinitis and BHR and emphasizes the importance of detecting and treating upper airway diseases in patients with asthma, in whom both affections are often associated. Cetirizine, which is a safe and effective anti-H1-receptor treatment for seasonal allergic rhinitis because of its anti-inflammatory effects particularly on eosinophils, may be considered an additional agent for treating patients with asthma associated with allergic rhinitis. Further studies are needed to evaluate the effects of cetirizine in these patients and to determine its optimal dosage, as well as its possible sparing effects, in patients who need high doses of inhaled corticosteroids to control their asthma.