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Keywords:

  • allergic rhinitis;
  • anti-H1 compound;
  • bronchial hyperresponsiveness

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

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.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

Patients

Twelve adult patients (10 men, two women, aged 19–36 years) participated in the study. All subjects gave histories (during the last 2 or more years) of rhinitis and asthma symptoms during May and June, with or without mild nasal and/or chest symptoms outside the pollen season. All patients also reported that seasonal exacerbation of rhinitis resulted in worsening of their asthma symptoms. All patients demonstrated an immediate reaction on skin prick testing with mixed grass pollens. Skin test response to grass pollen extracts (Lab. Stallergènes, Paris, France), assessed as the wheal diameter, was equal to or greater than skin test response to histamine (10 mg/ml) (14). None of the patients had clinical symptoms of asthma (dyspnea, chest tightness, or wheezing), and physical examination and spirometry were normal at the time of their visit to the outpatient clinic. Careful examination of sinus radiographs (absence of opacification of both maxillary sinuses, mucosal thickening, or air-fluid level on occipital-mental view) eliminated sinusitis in all of them. All patients were nonsmokers. None were using regular medications or had ever received immunotherapy. Each subject was in a clinical steady state and had not reported upper or lower respiratory tract infection during the previous 2 months or during the study period. The study was performed between November 1994 and February 1995. The investigation was approved by our local ethics committee, and signed informed consent was obtained.

Lung-function tests and methacholine challenge

All tests were performed by a physician who was unaware of whether the patients had received cetirizine or placebo. All measurements were made with the subjects in the sitting position. In each subject, three flow-volume curves were obtained with a Biomedin spirometer (Biomedin, Padova, Italy), and the highest of the three measurements was selected in order to determine FEV1 and FVC.

Bronchial responsiveness (BR) was assessed by methacholine-challenge testing, performed according to the guidelines of the European Society for Clinical Physiology (15) and of the American Thoracic Society (16). Briefly, after establishing the reproducible baseline FEV1 (two efforts within 5% variations), subjects inhaled nebulized solutions of either normal saline or increasing concentrations of methacholine generated by a MEFAR dosimeter. The latter is derived from the Rosenthal-French dosimeter (Johns Hopkins University, Baltimore, MD, USA), in which the opening of a solenoid valve is triggered by the patient's inhaling. The dosimeter makes it possible to preset the delivery time, the pause between deliveries, and the number of breaths. In our laboratory, we selected a delivery time of 1.2 s and a pause between deliveries of 10 s. The mean volume output of the nebulizer is 0.01 ml per breath, the concentration of methacholine being 0.39 mg/ml during the first inhalation (four breaths), 1.56 mg/ml during the second inhalation (three breaths), 6.25 mg/ml during the third inhalation (three breaths), and 12.5 mg/ml during the last step. Patients wore noseclips and inhaled via mouthpieces from functional residual capacity to total lung capacity. Each subject inhaled three inspiratory capacity breaths of normal saline followed by doubling concentrations of methacholine from 0.0156 mg until FEV1 had decreased by 20% or up to a cumulative dose of 4 mg. Each step was separated by a 5-min interval. Measurements of FEV1 and FVC began 2 min after each dose, and forced expiratory maneuvers were performed twice. Dose-response curves were constructed by plotting the percent change in FEV1 against doses of methacholine on a log scale. The PD20 was determined by linear interpolation from the dose-response curve.

Allergen delivery

To ensure that changes in pulmonary function were the result of nasal allergic response, we sought to use a technique of nasal challenge that would not deliver allergen into the lower airways. We used a commercially available, hand-held atomizer designed for topical nasal therapy (Nostrilla nasal spray; Boerhinger-Ingelheim, Ridgefield, CT, USA), which delivers 0.07 ml per activation. Analysis of the aerosol generated by the atomizer was performed with a laser particle analyzer, which demonstrated that the mass-median particle diameter was approximately 30 µm, a size not likely to penetrate the lower airways (17). Since deposition of inhaled aerosol into the lower airways requires airflow toward the lungs, the allergen was delivered at total lung capacity (TLC) during breath holding. Thus, by the use of a larger, less respirable particle size and breath holding, the delivery of allergen to the lower airways was probably avoided. This is supported by a previous study in which spray of a radiolabeled solution was administered by the same atomizer to each nostril of normal volunteers. The solution was administered at end inspiration followed by 10 s of breath holding. In the subjects studied, there was no detectable deposition of the radiolabeled aerosol in the trachea or lungs at either 1 or 6 h after administration (3).

Nasal provocation

Nasal challenges were performed with timothy-grass extract (four 10-fold dilutions ranging in concentration from 10 to 10 000 AU/ml). Delivery of the allergen was accomplished in the same manner as described above. The challenge solution was administered every 10 min until the nasal blocking index (NBI) doubled or the fourth dose solution was administered.

Nasal patency was assessed with a Mini-Wright peak expiratory flow meter (Clement Clarke International, Ltd, London, UK) with an attached face mask. Oral peak flow was first measured, followed by measurement of nasal peak flow. After nasal and oral PEFRs were determined in triplicate, the best values were used to calculate the NBI by the following formula (18):

  • image

Study design

This was a randomized, crossover, double-blind study. At the first visit (V1), the lung-function test (LFT) and measurements of bronchial responsiveness (BR) after methacholine challenge were performed. After a 1-week interval (V2), LFT and NBI were performed, followed by nasal allergen challenge (AC) as described above. LFT, NBI, and bronchial responsiveness to methacholine were performed 1 and 6 h after allergen challenge. Patients were then randomized to receive for 2 weeks placebo or cetirizine (10 mg/day). After 2 weeks (V3), the same allergen challenge as performed at V2 was repeated, followed by the same measurements. The nasal allergen challenge was in all patients and at each time period performed 2 h after administration of the last dose of cetirizine. For each patient, the nasal challenges and the subsequent measurements were performed at the same time of the day. The patients then received another 2 weeks' placebo or cetirizine, depending what they had received during the first 2 weeks of the trial. At the end of this second 2-week period (V4), another allergen challenge followed by the same measurements was performed. A schematic illustration of the study is represented in Fig. 1.

image

Figure 1. Schematic representation of experimental design. For further explanations, see text.

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At each study period, all the measurements as well as the nasal allergen challenge were performed at the same time of the day. The physician who performed the measurements was unaware of which trial period the patient was in.

Statistics

The two groups obtained after randomization of treatment order were compared with regard to patient characteristics at V1 (selection) and at V2 (after washout period) by Fisher's exact test or the Pearson chi-square test for discrete variables and the Mann–Whitney rank test for continuous variables, because, in such a small group, normal distribution of variables cannot be ascertained. The efficacy parameters measured after a treatment period were compared by the nonparametric method for two-period crossover trials (19).

Comparisons of FEV1 and PD20 after cetirizine and placebo periods were performed by the Wilcoxon test as well as comparisons of NBI before and after challenge. Correlations between NBI and PD20 were found with the nonparametric Spearman test.

Statistical analysis was performed with a BMDP statistical software package (Los Angeles, CA, USA). All statistical tests were carried out in two-tailed fashion at the 5% level of significance.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

All 12 patients who entered the study protocol completed the trial.

Pulmonary function

The mean values in pulmonary function data measured at baseline (V2) and 1 and 6 h after nasal allergen challenge after 2 weeks of cetirizine or placebo (V3 and V4) are shown in Table 1. When they entered the study, i.e., at the first baseline measurement, pulmonary function was normal in all the patients. It should be noted that no significant change in any of the measured parameters occurred during the experiment. Indeed, no statistical difference in the measurements performed at the second baseline (V2), as well as at V3 and at V4 (1 and 6 h after allergen challenge), was observed as compared with the first baseline measurement.

Table 1.  Mean lung-function data (median) for 12 patients during baseline early and late response after allergen challenge with cetirizine and placebo
 Baseline V2PlaceboCetirizine
 EARLAREARLAREARLAR
  1. EAR: early allergic response; LAR: late allergic response; C: cetirizine; P: placebo; FVC: forced vital capacity; FEV1: forced expiratory volume.

FVC (l)4.9904.9905.1455.0004.9154.965
FEV1 (l)4.4204.4424.4904.4804.3304.480

Nasal blocking index

The median NBI measured at V2 amounted to 0.682, 0.698, and 0.799, before, and 1 h and 6 h after allergen challenge, respectively. Before nasal allergen challenge at V3 and V4, NBI for the 12 patients was not significantly different during the cetirizine and the placebo periods, the medians amounting to 0.670 and 0.680 (P=0.31), respectively. At 1 and 6 h after nasal allergen challenge at V3 and V4, NBI increased significantly during the cetirizine and the placebo periods (P=0.0005 and P=0.007 at 1 and 6 h, respectively) as compared to the prechallenge values. However, 1 h after nasal challenge, no significant difference was noted between cetirizine and placebo, the median amounting to 0.830 and 0.790 (P=0.57), respectively. By contrast, 6 h after nasal allergen challenge at V3 and V4, a significant difference was observed between the cetirizine and the placebo periods, the medians amounting to 0.700 and 0.790 (P=0.011), respectively (Fig. 2).

image

Figure 2. Individual values and group median values of NBI (nasal blocking index) before (baseline) and 1 and 6 h after nasal challenge (placebo: open symbols; cetirizine: closed symbols).

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Bronchial methacholine challenge

The results of the bronchial methacholine challenges before and after nasal provocation with allergen, at 1 and 6 h after challenge, are illustrated in Fig. 3 for the two study periods (cetirizine and placebo). Airway responsiveness to methacholine increased markedly in all the patients (approximately two doubling dilutions of methacholine) 1 h after nasal challenge. Indeed, median PD20 for the 12 patients amounted to 1.360 mg of methacholine at both baselines (V1 and V2), and to 0.522 and 0.455 mg of methacholine 1 h after nasal challenge for the cetirizine and the placebo periods, respectively. At that time, 1 h after nasal challenge, no statistical difference (P=0.17) was noted between the median PD20 for the 12 patients during the two study periods (cetirizine and placebo). By contrast, 6 h after nasal challenge, a protective effect of cetirizine against airway responsiveness was noted as compared with the placebo period. Indeed, a significant difference in airway responsiveness in terms of PD20 (approximately one doubling dilution) was observed between the cetirizine and the placebo periods, the median PD20 for the 12 patients amounting to 0.918 and 0.483 mg of methacholine (P=0.042) for the cetirizine and the placebo periods, respectively.

image

Figure 3. Individual data group median value of bronchial responsiveness, as assessed by PD20 methacholine, before (baseline) and after nasal challenge, i.e., 1 h after challenge (+1H, left panel) and 6 h after challenge (+6H, right panel), after 1-week treatment by placebo (open circles) or cetirizine (closed circles).

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During the two study periods, cetirizine and placebo, no correlation was noted between the changes in NBI and PD20 1 and 6 h after allergen challenge.

Drug tolerance and side-effects

None of the subjects complained of any untoward effect, such as sedation.

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

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.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References

We thank UCB Pharma for providing cetirizine and placebo.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. References
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