The effect of regular versus on-demand desloratadine treatment in children with allergic rhinitis

Results Though symptoms were lower in the evening than in the morning ( p < 0.001), there was no difference between the two groups. There was no difference between the groups with respect to medication score except that the salbutamol use was lower in the regular treatment group during the fourth week ( p = 0.032) in the pollen season. Nasal flow rate and inflammatory markers failed to show any difference between the groups. A significant reduction in PC20 values (provocative concentration of Mch causing a 20% fall in FEV 1 ) was observed in regular ( p = 0.016) and on-demand ( p = 0.005) treatment groups compared to the pre-season measurements. The number of children with a PC20 below 8 mg/ml increased significantly in the on-demand group. Conclusion Our study demonstrates that on-demand use of desloratadine during the pollen season is clinically as effective as regular treatment. However, regular treatment may provide better control of lower airway symptoms and airway reactivity. Keywords Allergic rhinitis Children Desloratadine On demand 1 Introduction Allergic rhinitis is a global health issue affecting between 10 and 25% of the population [1] . It is a significant cause of morbidity and impairs physical and cognitive functions. It has an impact on quality of life and school performance [2] . It is a highly prevalent condition that adds considerably to the burden of health care costs [3] . Comorbid conditions such as asthma, sinusitis, otitis media and lower respiratory tract infections should also be considered as indirect costs of allergic rhinitis. Oral H 1 antihistamines are recommended as first-line treatment for mild to moderate allergic rhinitis [4] . They have demonstrated efficacy in the relief of the rhinitis symptoms of sneezing, itching, and nasal discharge and ocular symptoms of allergic conjunctivitis. However, they have a lesser effect on nasal congestion [5] . Desloratadine is reported to be a potent, nonsedating antihistamine which is an active metabolite of the H 1 antihistamine loratadine. It has been shown to relieve symptoms of seasonal allergic rhinitis including nasal stuffiness and congestion in a number of studies [5,6] . Many in vitro studies have shown that desloratadine has direct effects on inflammatory mediators in human cells [7,8] . Although H 1 antihistamines have been found to be effective on an as-needed basis, they are offered to be taken as maintenance therapy to achieve optimal therapeutic benefit [4] . In accordance with this data, regular treatment with a topical antihistamine azelastine was found to be more effective than on-demand use as assessed by clinical evaluation and anti-inflammatory action [9] . Many other studies also confirmed the efficacy of a long-term therapeutic strategy in controlling allergic inflammation [10,11] . To our knowledge, clinical and anti-inflammatory effects of regular and on-demand use of desloratadine in children has not been previously compared. Based on the results of the studies and the anti-inflammatory effect of desloratadine, we hypothesized that regular use of desloratadine has an effect on rhinitis symptoms. In this study, we aimed to assess the effects of regular versus on-demand desloratadine treatment on symptom scores, nasal flow, bronchial hyper-responsiveness and bronchial inflammation in children with seasonal allergic rhinitis. 2 Methods 2.1 Patients Thirty seven patients with a minimum of a 2-year history of pollen-induced rhinitis with or without mild asthma were enrolled in the study. Inclusion criteria included age between 12 and 18 years, positive skin prick test (area of the wheal response at least as big as that of the positive control, histamine 10 mg/ml) or specific IgE for grass pollen (>class 2) as titrated with a sandwich immunoassay (Unicap; Pharmacia Diagnostics, Uppsala, Sweden), and positive history of allergic rhinitis during the last pollen season. Patients having signs and symptoms of allergic rhinitis during the entire year, clinically significant upper or lower airway disease within the last 2 weeks, structural nasal abnormalities, history of taking any medication within 1 month before the study that might affect the test parameters (oral or topical antihistamines and nasal, systemic or inhaled steroids) or immunotherapy within the last 5-year period, and any chronic systemic disease were excluded. All study procedures were done in accordance with a protocol approved by the Ethics Committee of Hacettepe University. All subjects provided written informed consent for the study procedures. 2.2 Study design The study was designed as a randomized, open, parallel group study. Thirty-seven patients were enrolled in two parallel groups. The patients in the first group used desloratadine one tablet (5 mg) in the morning regularly for 4 weeks, while the second group used desloratadine on demand once a day. In addition, patients were allowed to take additional rescue medications including oral pseudoephedrine, inhaled salbutamol and lodoxamide eyedrops if needed. They were asked to record the drugs and symptoms. Patients presented for two visits, one at the beginning of the study before pollen season (February 2004) and one at the end of the study after the treatment period during pollen season (May 2004). Nasal symptoms, nasal flow rate by rhinomanometer (Manual Rhinotest 2000, Allergopharma, Germany), inflammatory markers such as peripheral blood eosinophil counts and eosinophil cationic protein (ECP) levels in nasal lavage, and total IgE levels in the serum were evaluated at both visits. The lung function tests and the PC20 values were also determined in all study subjects both before the season and at the completion of the 4-week treatment period in the pollen season. Patients were put on nasal steroids at the end of the study in the follow-up visit if their nasal symptoms persisted while using the study drugs. Data of these patients were also used in the analysis. Patients refrained from taking the study medications for 24 h before clinic visits at the end of the treatment period. 2.3 Pollen counts Pollen counts were obtained using the “Seven Day Volumetric Spore Trap” (Burkard Manufacturing Co., Hertfordshire, England) device during the 2004 season. They were expressed as the total weekly count of grains per cubic meter of air. The pollens counted included lolium, phleum, poaceae, avena, dactylis, and cynadon. 2.4 Rhinomanometry Nasal analyses were performed by active anterior rhinomanometry using a nasal volume flow (cm 3 /s) with a transnasal pressure difference of 150 Pa (Rhinomanometry 2000; Allergopharma Joachim Ganzer KG. Hamburg, Germany). Both nasal flow rates and nasal resistances were calculated. All measurements were made with the patient's mouth closed in the sitting position with a good seal around-built soft face mask. 2.5 Clinical evaluation Subjects were instructed to record their symptoms on diary cards twice daily, upon waking and 12 h later in the evening. Nasal (itching, sneezing, obstruction, rhinorrhea), eye (conjunctival itching, lacrimation, conjunctival hyperemia) and respiratory (cough, dyspnea, wheezing) symptoms were graded on a Likert scale as: 0 = absent, 1 = mild, 2 = moderate, and 3 = severe, as described previously [11] . Any rescue medication taken by the patient was also recorded on the diary card. 2.6 Compliance All patients were reached by telephone twice during the 4-week study period to improve treatment compliance. The numbers of tablets taken and daily card records were also used to estimate compliance. 2.7 Statistical analysis Statistics was performed using Statistical Package for Social Sciences (SPSS) 10.0. Data were presented as mean ± standard error of the mean or as median with interquartile ranges depending on the data distribution. Wilcoxon test was used for intragroup comparisons and Mann Whitney test for intergroup comparisons. McNemar and Fisher's exact test were used for comparison of ratios. Differences were considered significant at two-sided p values ≤0.05. 3 Results 3.1 Patient demographics Nineteen subjects (8 female, 11 male, age 14.3 ± 0.5 years) in the regular treatment group and 18 subjects (11 female, 7 male, age 15.3 ± 0.5 years) in the on-demand treatment group were enrolled in the study. All patients completed the study and no side effects were reported. Baseline characteristics of the groups were similar except for the rate of mild asthmatics ( Table 1 ). 3.2 Study drugs The mean number of desloratadine tablets used in the on-demand treatment group was 2.75 tablets/patient/week, which was significantly lower than in the regular treatment group ( p < 0.001). The mean weekly decongestant tablet and antiallergic eyedrop consumptions were similar in both groups ( Fig. 1 ). However, average use of salbutamol puffs during the fourth week of the study was significantly lower in the regular treatment group than in the on-demand group ( p = 0.032, Fig. 1 ). At the end of the study, the number of patients requiring nasal steroid was similar in both groups. 3.3 Symptom scores The weekly nasal, eye and respiratory symptom score analysis did not reveal a significant difference between the groups ( Fig. 2 ). Respiratory symptom scores were generally low during the study period. Concerning the symptom scores that were recorded twice daily (am/pm), desloratadine provided significant reduction in the total nasal and non-nasal (eye, respiratory) symptom scores. Nasal and non-nasal symptom scores were lower in the evening than in the morning in both groups ( p < 0.001 for both groups, Fig. 3 ). Differences in nasal flow rates and nasal resistances did not reach statistical significance between groups (data not shown). 3.4 Bronchial hyper-responsiveness Pulmonary function tests performed in both groups were normal both before and during the pollen season. Within the pollen season, a significant reduction in PC20 values was observed both in the regular and on-demand treatment groups compared to the pre-season measurements ( p = 0.016 and p = 0.005, respectively). The number of children with PC20 below 8 mg/ml increased significantly in the on-demand group (from 33% pre-season to 72% within the season, p = 0.016) but not in the regular treatment group (from 47% pre-season to 63% within season, p = 0.25) ( Fig. 4 ). 3.5 Inflammatory parameters ECP levels in nasal lavage, peripheral eosinophil counts and serum total IgE levels were similar in the two groups both at baseline and after treatment. Higher ECP levels were detected in the pollen season period compared with pre-season; however, this increase in the pollen season was not significant in either group. There was a significant increase in total IgE levels during the pollen season in the on-demand treatment group ( p = 0.01). 4 Discussion In this study, on-demand use of desloratadine during the pollen season was found to be as effective as regular treatment with respect to symptoms. However, unlike with on-demand treatment, regular treatment provided significant control over bronchial hyper-responsiveness, which is an indirect marker of lower airway inflammation. Oral H 1 antihistamines are recommended as first-line treatment for mild to moderate allergic rhinitis [4] . To our knowledge, there is only one study comparing the therapeutic efficacy of regular and on-demand use of antihistamines. In this study reported by Ciprandi et al. comparing regular versus on-demand cetirizine treatment [10] , 20 pollen-allergic adult patients were enrolled in parallel groups to receive either cetirizine or matching placebo. All patients were allowed to take an additional daily cetirizine tablet if needed. They evaluated nasal symptom scores, additional cetirizine tablets taken and markers of inflammation (neutrophil and eosinophil counts obtained by nasal scrapings). There was a significant reduction in clinical symptom scores in both groups starting the second week; however, regular treatment reduced clinical and inflammatory variables more than symptomatic treatment. The authors concluded that on-demand therapy resulted in acceptable clinical control, but did not reduce allergic inflammation. In this study, regular treatment did not result in better control of symptoms when compared to on-demand treatment. Both on-demand and regular use of desloratadine in our study also appeared to control nasal and non-nasal symptoms similar to Ciprandi's study. Symptoms alone, especially in children, are not always reliable. Since children perceive rhinitis symptoms less than adults, they may not always objectively express their symptoms like adult patients, and this may obscure minor differences between the two types of use in our study. Another point was the great variability in the duration of time children spent outdoors, which is a very important factor affecting the severity of the symptoms during pollen season. Allergic rhinitis is not just an inflammation of the nasal mucosa but is associated with systemic inflammation. The inflammatory reaction in the nares ultimately culminates in bone marrow stimulation, increase in circulating inflammatory cells, and recruitment of these cells into the airway, thereby resulting in bronchial hyper-responsiveness. The increasing recognition of allergic rhinitis as a systemic inflammatory disorder has many implications for its management. Therefore, treatment of allergic rhinitis should be directed not only at relieving nasal symptoms but also at the underlying inflammatory processes [12] . New generation antihistamines have shown inhibitory effects on the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on epithelial cells, on eosinophil activation and chemotaxis, and on inflammatory chemokine and cytokine release. Desloratadine was also demonstrated to inhibit basophil cytokines such as interleukin IL-4 and IL-13 [13] . By inhibiting the generation and release of histamine and other inflammatory mediators, desloratadine results in a positive impact on early phase reaction symptoms and chronic inflammation. On the basis of the ongoing inflammation in allergic rhinitis patients, it seems more logical to use the antihistamines considering their anti-inflammatory effects. A number of studies in the literature demonstrated effective reductions in neutrophil and eosinophil counts in nasal scrapings and lower ICAM-1 expression on epithelial cells with continuous antihistamine treatment [9,11] . In our study, the number of patients with bronchial hyper-responsiveness (assessed with PC20 values) and serum IgE levels in the pollen season significantly increased in patients in the on-demand usage group, but not in those with continuous use of desloratadine. There are strong epidemiologic associations between allergic rhinitis and asthma, and it has been suggested that allergic rhinitis patients with bronchial hyper-responsiveness are more likely to develop asthma [14] . Therefore, this favorable effect on inflammation merits regular use rather than on-demand use when the subsequent results of inflammation are considered. One conflicting finding was the similarity of nasal flow rates in both treatment groups. Measuring the nasal flow rates and resistance by rhinomanometry only once in our study might not be sufficient to demonstrate the differences. Therefore, it would be better to obtain daily nasal flow rate measures. Another point is the objectiveness of rhinomanometry without symptom scores. It is also questionable in evaluating nasal congestion in the pertinent literature [15] . As a result, variability and reliability of rhinomanometry might be another cause of such discordance in results. Our study has a number of limitations. First, as mentioned before, the age group of the patients may play a role and the reliability of the children's scores may be lower than that of adult patients. The small number of participants is another limitation which leads to an increased likelihood of a statistical type 2 error. Because of the well-known benefits of antihistamines on allergic rhinitis symptoms, we did not assign a placebo arm in our study for ethical reasons. Placebo-prescribed children might have increased symptoms and a diminished school performance. Nevertheless, absence of a placebo arm decreases the strength of the study. Finally, the follow-up period after the initiation of the drugs was 1 month in our study. The studies in the literature demonstrating a favorable symptomatic effect of continuous treatment either have a longer follow-up or were conducted in adult patients. Therefore, a longer follow-up could reveal a significant difference in symptomatic relief with continuous treatment. In conclusion, both regular and on-demand use of desloratadine provided similar control of allergic rhinitis. However, regular treatment suppresses inflammatory response more than on-demand use. The clinical implication of this suppression remains to be determined. This is the first study with desloratadine comparing regular versus on-demand use in children with allergic rhinitis. 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