THE EFFICACY OF CETIRIZINE IN THE TREATMENT OF ALLERGIC RHINITIS AND ALLERGIC BRONCHIAL ASTHMA

Introduction
Both allergic rhinitis and allergic bronchial asthma are relatively common disorders with rising incidence despite effective treatment and use of known preventive measures (1).  Patients with seasonal or perennial allergic rhinitis and/or allergic bronchial asthma experience an immediate allergic response caused by allergen-specific immunoglobulin E-mediated histamine release (IgE) (2). Traditional antihistamines generally have little effect on airway responses at pharmacological doses, and the use of higher doses is limited by associated side effects (3).  In contrast, second generation antihistamines have a potent, nonsedating, histamine (H1) receptor antagonist with activity in seasonal and perennial allergic rhinitis. They have effective control of allergic rhinitis and asthma symptoms and decrease the total IgE levels (4). The second generation H1 -anthistamines have become widely used in the treatment of urticaria, atopic dermatitis and allergic rhinitis (5).  Their use for treatment in asthma is still limited despite the fact that the same histamine is present in the upper and lower airway and can be released spontaneously. Although very effective in alleviating and preventing symptoms caused by histamine release in allergic rhinitis, antihistamines still have not gained the same popularity  in  the  treatment  of  allergic bronchial asthma (6).  Second generation antihistamines have a potent, nonsedating, histamine (H1) receptor antagonist with activity in seasonal and perennial allergic rhinitis. They have effective control of allergic rhinitis and asthma symptoms and they decreased the total IgE levels. They also decrease the frequency of disease exacerbations, the total amount  bronchodilators and prophylactic cortisone treatment. This study described our experience in the efficacy and safety of cetirizine in the treament of patients with both allergic rhinitis and allergic bronchial asthma.

Methods  
Between February to July 2000, fifty  patients with allergic rhinitis and/or allergic bronchial asthma were referred to the allergy clinic at King Hussein Medical Center (KHMC). Patients enrolled in the study should have had their symtomps for at least two consecutive years, in addition, they should have positive skin prick test (SPT) for at least one allergen, high initial blood level for eosinophils and total serum IgE.  Seven patients were excluded (14%); two with immotile cilia syndrome, three with cystic fibrosis, one with hypogammaglobulinemia, and one with bronchiectasis.  Forty three (86%) were included in the study.  The age ranged between 3-15 years, 30 (69.8%) were males and 13 (30.2%) were females. After detailed history and examination, all patients underwent the epicutaneous skin testing (StallargenesTM ) (Table I). The daily requirement for  selective β2 agonist (Salbutamol 100 microgrmas per puff) and steroid (Beclomethasone 250 micrograms per puff), Metered Dose Inhalers (MDI) and the  numbers  of  asthma  exacerbations  were documented  on  each  follow-up  visit.   To  evaluate  the extent  and  severity  of  the  condition, a locally developed  allergy  scoring  system  (Table II) was applied to these patients on the first visit and on subseqent visits. Patients were seen at 1,-3-6 weeks, 3 - and - 6 months. All patients were started on cetirizine at their initial visit. The dose of cetirizine used was 5mg for children aged two to six years and 10mg for those above 6 years according to the manufacturis recommendations. Blood was  extracted for absolute eosinophil count  and total IgE on the  initial and the six month-visit.  Total  IgE was measured by Enzyme-linked Immunosorbent Assay (ELISA). Electrocardiogram (EKG) and  liver function were  tested before and after the end of treatment.

Table I. Locally developed allergy-scoring system*.

Index
Frequent sneezing	Headache
Nasal itching	Fullness in the ear
Clear rhinorrhea	Hearing loss
Nasal obstruction	Ear pain or discomfort
Symptoms interfere with sleeping	Tinnitus
Eye itching	Vertigo
Throat itching	Cough
Ear itching	Shortness of breath
Allergic salute	Wheeze
Transverse nasal crease	Exercise-induced asthma
Mouth breathing	Decreased air entry
Snoring	Prolonged expiratory phase
Orofacial-dental abnormalities	Skin itch
Red eye	Skin rash
Facial discomfort	Typical atopic dermatits

* Patients were given a score of 1 for each positive item and zero for each negative item

Table II.  Changes of the allergy scores.

Initial presentation	First week	Third week	Sixth week	3 Months	6 Months
27	16	5	4	2	2

Results
The  average  allergic  score  was  27  before  cetirizine  treatment  and  showed  progressive   decrease through  out  the  study   period  to  reach  an  average score  of  2  by  the  end  of 6 months.  The average IgE levels dropped from 900 IU (930 IU ± 146) before adding cetirizine to 150 IU (150 IU ± 12) six months after treatment P  (<0.0001). Also the average eosinophils count dropped from 2000/mm3 (2016. /mm3 ± 125) to 250/mm3 (251/mm3 ± 12) P<0.0001.  Table (III) the requirements for both maintenance and rescue inhalers were significantly decreased by the end of treatment as shown in Table IV. The monthly numbers of asthma exacerbations were 3 in the initial visits while they were one at the end of the study (P<0.0001). The side effects were mostly nonspecific and did not require discontinuing cetirizine (Table V).

Table III. Changes of the total serum IgE, eosinohpils count and asthma severity.

	At initial presentation. (mean±SD)	After six months. (mean±SD)	P. value
Average concentration of serum total IgE.	900 IU (930±146)	150IU (150±12)	<0.0001
Average concentration of Eosinohpils.	2000/mm3 (2016±125)	250/mm3 (251±12)	<0.0001
The average number of Ventolin puffs per day.	5 (5±1)	2 (2.628± 0.952)	<0.0001
The average number of cortisone puffs per day.	4 (3±1.463)	2 (1.9±0.9)	<0.0001
Asthma exacerbations per month.	3 (3.023±1.0165)	1 (1.0372±0.900)	<0.0001

Table IV.  Adverse events of Cetirizine.

Adverse  events	Number of patients experiencing at least one side effect	% of patients with side effects
Abdominal pain	4	9
Agitation	1	2
Allergic reaction	0	0
Anorexia	2	4
Appetite increase	2	4
Palpitations and/or EKG* changes	0	0
Fatigue	1	2
Hyperkinesia	1	2
Insomnia	3	6
Somnolence	5	11
Decreased school performance	0	0

* EKG = electrocardiogram.

Table V.   Adverse effects reported by the study conducted by the manufacturing company.

		Cetirizine
Adverse Experiences	Placebo (N=309)	5 mg (N=161)	10 mg (N=215)
Headache	12.3%	11.0%	14.0%
Pharyngitis	2.9%	6.2%	2.8%
Abdominal Pain	1.9%	4.4%	5.6%
Coughing	3.9%	4.4%	2.8%
Somnolence	1.3%	1.9%	4.2%
Diarrhea	1.3%	3.1%	1.9%
Epistaxis	2.9%	3.7%	1.9%
Bronchospasm	1.9%	3.1%	1.9%
Nausea	1.9%	1.9%	2.8%
Vomiting	1.0%	2.5%	2.3%

Discussion
This study showed that by adding cetirizine to the treatment of patients with allergic rhinitis and/or bronchial asthma, there was improvement in the allergy score system over six months.  Permanent changes like allergic salute, transverse nasal crease and orofacial abnormalities were included in the scoring system to refer to the severity and chronicity of allergic rhinitis.  We do not expect improvement within six months of treatment as the case in the study. The decrease was sustained even after the onset of pollens season. At six month visit, the total IgE and absolute eosinophil counts were 6 and 20 times less than those at the initial visit, respectively.  Also there was a decrease in the requirement for (salbutanol) and steroid inhalers as well as in the number of asthma exacerbations.  The effect and value of non-sedating 2nd generation H1-antihistamines were well documented in the treatment of urticaria, atopic dermatitis and allergic rhinitis (7).  In a double blind study Mansman et al showed that cetirizine was effective in reducing symptoms when compared to placebo (8), particularly in relieving postnasal discharge and sneezing in perennial allergic rhinitis (8). Another double blind study, which looked at 263 patients with seasonal allergic rhinitis, found that both astemizole and cetirizine were well tolerated and equally effective in alleviating symptoms, with the difference that the former did not inhibit skin reactivity to histamine within 3 days of the end of the treatment (9). Until recently, the use of traditional antihistamines for the treatment of patients with allergic bronchial asthma (ABA) achieved mixed results, in part because of the multiple cellular interactions stemming from release of mediators other than histamine from mast cells (10). The traditional first generation H1antihistamines generally have little effect on airway responses at pharmacological doses, and the use of higher doses to obtain beneficial effects are limited by the associated side effects (11). With the recent introduction of a new generation of antihistamines that are pharmacologically different from the earlier H1 antagonists   there has been renewed interest in the role of  these  agents  against  histamine-induced bronchospasm (12,13).  In studies of histamine-induced bronchial hyper responsiveness in asthmatic patients, prophylactic treatment with loratidine 10 mg once daily effectively inhibited histamine induced bronchoconstriction (14,15) Loratidine also appeared to prevent the development of allergic asthma associated with airway infammation from pollen-induced rhino-conjunctivitis (16).  There is also evidence of drug sparing effect when loratidine was administered as adjunctive therapy with established standard antiasthma treatment, including theophylline, sympathomimetics, and inhaled steroids.  Two randomized crossover studies of terfenadine and placebo reported improvement in symptoms and lung function in treated patients with atopic asthma (17).  In these two studies the dose of the terfenadine was high, and as now considered contraindicated because of the risk of cardiac arrhythmias with higher doses. Studies using astemizole showed no changes in symptoms or bronchodilator use in asthmatic patients. Higher doses of the latter might be associated also with cardiac arrhytmias. Cetirizine (Zyrtec) another antihistamine was found to be safe and well  tolerated  and  to  a  comparative  efficacy in asthma (17,18). Cetirizine treatment was associated with improvement in symptoms of both allergic rhinitis and asthma. Compared with placebo, cetirizine in a dose of 10 mg twice daily was associated with significant improvement in symptoms and no significant change in pulmonary functions in pollen asthma: forced expiratory volume in one second or forced vital capacity.  Lower doses of cetirizine have been considered ineffective in the treatment of asthma. Recently, Andrew et al in a double-blind, placebo controlled study involving 93 patients with allergic rhinitis and asthma, found that a lower dose of cetirizine (10mg daily) was safe and effective in relieving both upper and lower respiratory symptoms.   We used the same dose of cetirizine used in Andrew et al study and we have a comparable result regarding allergic score and ventolin usage.  Moreover, we  were  able  to  reduce  the dose  of  steroids  inhaler in  most  of  our  patients  within  two  weeks  of  starting cetirizine.

Our patients showed a significant decrease of eosinphils counts and total IgE at the end of the treatment. We do not have any explanation for this decrease. It is well known that cetirizine inhibits eosinophils accumulation at antigen-challenged skin sites and also in the airways (15)  but no one looked to the effect of cetirizine on the eosinophil counts in the peripheral blood. These phenomena should be further studied. Our study was not a placebo controlled but it was unique in using cetirizine for 6 months, which is the longest duration that has been ever used in the studies. Even with this duration cetirizine proved to be a safe drug with very minimal side effects.  The side effects reported by the company are illustrated in Table V.

Conclusion
The results of this study showed that Cetirizine (5-10 mg/day) according to age, was safe and effective treatment of seasonal and perennial allergic rhinitis. In addition, cetirizine controlled asthma symptoms in patients with allergic rhinitis and mild to moderate asthma, and alleviated symptoms of asthma at the usual dose for treatment of allergic rhinitis. Slightly higher doses are needed in severe asthma. Cetirizine has excellent safety record and may be considered an additional agent for treating patients with asthma.

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