Ragweed counts and the number of subjects enrolled from August 15 through September 20, 2000 (each dot represents the number of patients enrolled in 1 study day).
Mean ± SEM values for the individual domains of the Rhinoconjunctivitis Quality of Life Questionnaire.3 The asterisk indicates P = .04 for the difference in the nasal symptom domain between the 2 groups at visit 2.
Median total symptom scores during the study. There were no significant differences between the groups.
Median total number of eosinophils found in nasal lavage fluids during the study. The asterisk indicates P = .05 for the decrease from visit 1 in the number of eosinophils in the fluticasone propionate group.
Median levels of eosinophil cationic protein (ECP) found in nasal lavage fluids during the study. The asterisk indicates P = .02 for the difference between the fluticasone propionate group and the loratadine + montelukast sodium group on visit 1; the dagger indicates P = .009 for the difference from visit 1 to visit 2 in the fluticasone group.
Saengpanich S, deTineo M, Naclerio RM, Baroody FM. Fluticasone Nasal Spray and the Combination of Loratadine and Montelukast in Seasonal Allergic Rhinitis. Arch Otolaryngol Head Neck Surg. 2003;129(5):557-562. doi:10.1001/archotol.129.5.557
Copyright 2003 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2003
To compare the effectiveness of an intranasal steroid treatment with that of the combination of a histamine1 receptor antagonist and a leukotriene D receptor antagonist in the treatment of seasonal allergic rhinitis.
A 2-week, parallel, randomized, double-blind, double-dummy study with rolling enrollment.
Tertiary care medical center.
A total of 63 adults with a 2-year history of ragweed sensitivity in the Chicago, Ill, area and a positive skin-prick reaction to ragweed pollen.
Subjects were randomized to receive either 100 µg of fluticasone propionate aqueous nasal spray in each nostril or 10 mg of loratadine and 10 mg of montelukast sodium by mouth once daily in the evening for 2 weeks. At visits 1 and 2, subjects completed a quality-of-life questionnaire and underwent nasal lavage to determine total eosinophil count and eosinophil cationic protein (ECP) measurements. Daily symptom diaries were kept for 2 weeks.
Main Outcome Measures
Questionnaire answers, daily nasal symptom scores, eosinophil counts, and ECP levels.
Median total nasal symptom scores were lower in the fluticasone group (4.5 vs 6), but the difference was not statistically significant. The questionnaire answers showed dramatic improvement in overall and individual domains for both groups (P<.01 vs visit 1) with significantly greater reduction in nasal symptoms in the fluticasone group (P<.05). Eosinophil counts and ECP levels were significantly reduced in the fluticasone group.
Both treatments provided clinically meaningful responses, but the overall results favored fluticasone propionate.
ALLERGIC RHINITIS is a major cause of human morbidity. Although there are efficacious treatments, potential new strategies continue to emerge. A recent strategy for treating allergic rhinitis is the combination of a histamine1 receptor antagonist and a leukotriene D receptor antagonist.
The rationale for this combination is that the H1 receptor antagonist blocks the effects of histamine to reduce sneezing and rhinorrhea, and the leukotriene D receptor antagonist blocks nasal congestion, although leukotrienes and histamine have been shown to have other effects during the allergic reaction. Meltzer and colleagues1 showed that the combination of loratadine and montelukast was superior to either treatment alone or placebo in the management of seasonal allergic rhinitis. A subsequent study by Lis and colleagues2 with a larger number of subjects and a similar design showed that treatment with loratadine alone, montelukast alone, and the combination were numerically and statistically superior to placebo in controlling daytime nasal symptoms in patients with seasonal allergic rhinitis. Although the combination treatment showed numerical superiority over each active treatment administered alone, these differences did not reach statistical significance.
For the present study, we compared the efficacy of loratadine (Claritin; Schering-Plough HealthCare Products Inc, Kenilworth, NJ) and montelukast sodium (Singulair; Merck & Co Inc, Whitehouse Station, NJ) with an intranasal steroid, fluticasone propionate (Flonase; GlaxoSmithKline, Research Triangle Park, NC). We chose these medications because studies support their efficacy, and they are dosed once daily.
We performed a 2-week, parallel, randomized, double-blind, double-dummy study with rolling enrollment in subjects with seasonal ragweed pollen allergic rhinitis during the 2000 fall allergy season in Chicago, Ill. Outcome measures were responses to the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ),3 daily nasal symptom scores, and the number of eosinophils and levels of eosinophil cationic protein (ECP) found in nasal lavage fluids. During the first visit, subjects completed the RQLQ and underwent nose lavage with 10 mL of lactated Ringer solution (5.0 mL in each nostril) to obtain a total eosinophil count and to measure the level of ECP. Then subjects were randomized and assigned to either the fluticasone propionate or loratadine plus montelukast sodium group. They were given the medication and instructed in its usage. The only additional medication allowed during the course of this investigation was acetaminophen. No rescue medication was permitted. Subjects kept a daily symptom and medication diary during the season, which they completed twice daily. The subjects returned in 2 weeks for their final visit and underwent nasal lavage and completed another RQLQ. Diaries and medications were collected.
We recruited 63 individuals older than 18 years with histories of sensitivity to ragweed pollen in each of the last 2 years in Chicago and a positive skin-prick sensitivity to ragweed pollen. All subjects were in good health. Patients with nasal polyps, a significantly displaced septum, or perennial rhinitis or asthma were excluded. Those subjects who had been treated with systemic steroids during the previous 30 days or had used topical steroids, antihistamines, decongestants, or cromolyn in the preceding 2 weeks or immunotherapy in the last 2 years were also excluded. Pregnant or lactating women were not permitted to join the study. A urine test for pregnancy was taken by all women at enrollment. Enrollment occurred during the fall pollen season. The institutional review board of the University of Chicago approved the study, and written informed consent was obtained from each subject prior to study entry.
All bottles of study medication were obtained and labeled at the University of Chicago with subject code numbers. The treatment for each subject was assigned by randomized code and blocked in groups of 4. As each subject entered the study, the investigators assigned that subject to the next sequential study code number available. The Grant Hospital Pulmonary Physiology Laboratory recorded ragweed pollen counts for the Chicago area during the study by use of the Rotorod method.
Lavages were performed with 5 mL of 37°C lactated Ringer solution (Baxter Healthcare Corporation, Deerfield, Ill) in each nostril as previously described.4 The total number of cells was counted with a hemocytometer. The lavage solution was then centrifuged at 5000 rpm for 15 minutes at 4°C. The supernatant was discarded and saved for ECP assays, and the cell pellet was resuspended in enough lactated Ringer solution to yield a concentration of 100 000 cells per 200 µL. Two hundred microliters of the suspension was then cytospun onto labeled slides, which were dried, fixed, and stained with a Diff-Quick Stain Set (Dade Behring Inc, Newark, Del). The percentage of eosinophils in 200 cells was counted, and the total number was calculated by multiplication of the percentages by the total cell count. When 200 cells could not be counted, as many cells as possible were examined for differential determination. If the total number of cells available for differential estimation was less than 50, the slide was considered technically inadequate for interpretation, and no value was available for analysis. If the slide had a sufficient number of cells to be examined, but no eosinophils were counted among these cells, then 80 was assigned as the number of eosinophils because this was the lowest number of eosinophils obtained among all the technically adequate specimens.
Eosinophil cationic protein, a marker of eosinophil secretion, was assayed by means of a fluoroenzyme immunoassay technique (Unicap ECP; Pharmacia & Upjohn Diagnostics, Kalamazoo, Mich) sensitive to 2 µg/L. Values lower than the detection limit were assigned a value of 1 µg/L.
Each subject recorded symptom scores in a diary twice a day. The subjects were asked to describe symptoms of the previous 12 hours at each entry. Subjects reported sneezing, rhinorrhea, nasal congestion, and itchy eyes on a scale from 0 to 3 (0, no symptoms; 1, mild symptoms; 2, moderate symptoms; and 3, severe symptoms). A total symptom score was calculated daily for each symptom by adding the 2 daily scores. Symptom scores were evaluated separately for each symptom category, and the total symptom score (the sum of individual symptoms) was also evaluated.
Quality of life was assessed with the self-administered RQLQ, as described and validated by Juniper and Guyatt.3 A change in score of more than 0.5 from baseline was considered a clinically meaningful difference, which has been defined as the smallest amount of change that a person perceives as meaningful.3
The primary variable analyzed was the RQLQ score. We determined the number of subjects for this study based on our previous study comparing as-needed fluticasone to as-needed placebo.5 We chose the overall score for the RQLQ as the primary variable because it had the smallest SD. We selected the fluticasone group data because the same group appeared in this study. Since Juniper and Guyatt3 define a 0.5 shift as clinically significant in the RQLQ, we chose this level of difference. Assuming an α level of .05, a difference of 0.5 in the overall domain of the RQLQ, and a population SD of 0.6, we calculated that having 30 subjects in each group would have 80% power of detecting a difference. The RQLQ data were normally distributed and were analyzed using parametric statistics; data are presented as mean ± SEM.
The secondary variables were the individual and total symptom diary scores, total eosinophil counts, and ECP levels. Because data for the secondary variables were not normally distributed, nonparametric statistics were used for analysis, and the data were graphed as medians. The total diary symptom scores were calculated by addition of the individual symptom scores. We analyzed the score based on the day of enrollment instead of calendar day. This permitted ease of matching, and in a previous study with similar design, this technique showed no difference compared with analysis by calendar day.3
The difference in total symptoms between the 2 treatments was analyzed for each day of the study using a Mann-Whitney U test. The median total symptom score for all 14 days of treatment was also calculated and compared between the active treatments by use of Mann-Whitney U test. Other symptoms were analyzed similarly. Data for levels of ECP and number of eosinophils were analyzed using the Wilcoxon signed rank test to compare visit 1 with visit 2 within each treatment group. Differences between treatments were analyzed at visits 1 and 2 using a Mann Whitney U test, and the change from baseline was compared between treatments using the Mann Whitney U test. Correlations between ECP levels and eosinophil counts were calculated using the Spearman rank correlation. P values lower than .05 were considered significant. All statistics were run using Statview II software (Abacus Concepts Inc, Berkeley, Calif) for the Macintosh computer.
The pollen count during the study period was typical for the Chicago area, and most subjects were enrolled prior to the peak of the season (Figure 1). A total of 63 subjects entered the study. Three subjects from the fluticasone group dropped out of the study: 1 subject did not show up for the second visit, and 2 subjects were noncompliant with taking medications and reporting symptoms. There were no dropouts in the combination group. There were 29 subjects in the fluticasone group and 31 subjects in the loratadine plus montelukast group. The groups were matched for age, sex, race, and skin-prick ragweed pollen sensitivity (Table 1). Minimal adverse effects were reported by some patients: 11 complained of headache (6 in the loratadine-montelukast group and 5 in the fluticasone group).
The overall and individual domains of the RQLQ were similar in the 2 groups at study entry. Both groups had large and significant improvements from the first visit to the second in the sleep, non–nose/eye, practical, nasal, eye, emotional, and activity domains as well as in the overall score (P<.01) (Figure 2). When visit 2 scores were compared between treatments, there were no significant differences except in the nasal symptom domain where subjects taking fluticasone had a lower mean ± SEM score (better quality of life) (1.57 ± 0.22) than those taking loratadine plus montelukast (2.24 ± 0.23) (P = .04). Finally, when the change from baseline in RQLQ scores was compared between treatments, there were no significant differences for any of the domains except for nasal symptoms, where the results were in favor of fluticasone (−0.91 ± 0.29 for loratadine plus montelukast vs –1.72 ± 0.27 for fluticasone; P = .05) (Figure 2).
Total symptoms were similar at entry into the study. Although the median values for the fluticasone group were less than or equal to those of the combination group at every point, there were no significant differences in total or individual symptom scores at any time between the 2 treatment groups (Figure 3 and Table 2).
The number of eosinophils was not significantly different between the groups at either visit 1 or visit 2. The fluticasone-treated subjects had a significant decrease in the number of eosinophils from the first to the second visit (P = .05). The number of total eosinophils did not change significantly between the 2 visits in the loratadine plus montelukast group (Figure 4). When the change from baseline in eosinophil count was compared between the 2 groups, there were no significant differences (median change for the fluticasone group, −975 vs a median change of 0 in the loratadine plus montelukast group; P = .22).
The ECP levels in the fluticasone group were significantly higher than in the loratadine plus montelukast group at entry (P = .02) but not on the second visit (P = .90). In the fluticasone group, the level of ECP significantly decreased from the first to the second visit (P = .009), while there was no significant difference between visits in the loratadine plus montelukast group (Figure 5). When the change from baseline was compared between the 2 groups, there was a significant difference favoring fluticasone (median fluticasone change, −1.1 µg/L vs median loratadine plus montelukast change, 0 µg/L; P = .04). There was a strong positive correlation between the number of eosinophils and the levels of ECP from all visits and all treatments combined (correlation coefficient obtained by Spearman correlation [rs] = 0.7; P<.001).
Nasal challenge with allergens has taught us much about the pathophysiologic characteristics of allergic rhinitis. In patients with allergic rhinitis, histamine causes the acute symptoms of sneezing, itching, rhinorrhea, and, to a lesser extent, congestion experienced during the early-phase response. Although histamine is released from basophils during the late-phase response, its role is not known. Other mediators of inflammation, especially leukotrienes, prostaglandins, and kinins, are thought to also contribute to nasal congestion, which occurs during the early- and late-phase responses.6 Application of leukotriene D4 to the nasal mucosa has been shown to increase nasal airway resistance as measured by active posterior rhinomanometry and also cause subjective nasal congestion but no sneezing or significant rhinorrhea.7 This supports the role of leukotrienes as mediators of nasal congestion. Treating patients involves the reduction of symptoms, which can be accomplished by antagonizing mediators or preventing their production.
H1 receptor antagonists have proven safe and effective in the treatment of seasonal allergic rhinitis.8 Intranasal corticosteroids are also highly effective and safe in the treatment of this disease.8 They reduce the number and activation of inflammatory cells during the late-phase response and have been shown to improve the symptoms and quality of life of patients with allergic rhinitis. Most studies show treatment with intranasal corticosteroids to be more effective than antihistamines, especially for the control of nasal congestion.9- 12
Two leukotriene receptor antagonists (montelukast and zafirlukast) are currently approved for use in the United States for the treatment of asthma, and montelukast has recently been approved for the treatment of allergic rhinitis. Both selectively block the cysteinyl leukotriene receptors and have been shown to effectively reduce airway eosinophilic inflammation, eosinophil chemotaxis, and peripheral blood eosinophil counts.13 Studies of leukotriene receptor antagonists also support a role for these agents in the treatment of allergic rhinitis.14- 16 Donnelly et al17 showed the efficacy of the 20- and 40-mg doses of zafirlukast compared with placebo in a park study. Both doses led to significant reduction of nasal congestion, sneezing, and rhinorrhea in subjects with acute seasonal allergic rhinitis.
However, this efficacy has not been demonstrated in all studies. Pullerits et al18 showed that patients with seasonal allergic rhinitis treated with zafirlukast (20 mg twice a day) had degrees of nasal symptoms similar to those in the placebo group. In this study, treatment with beclomethasone dipropionate nasal spray led to superior control of nasal symptoms compared with placebo and zafirlukast and was the only treatment that reduced the number of eosinophils in the nasal mucosa. In another comparative study, intranasal budesonide and oral montelukast were used in patients with seasonal allergic rhinitis and asthma.19 Both agents showed comparable efficacy on the lower airway and significantly reduced allergic symptoms, but only budesonide had significant efficacy on upper airway inflammatory markers.
Conceptually, the combination of montelukast and loratadine, 2 mediator receptor antagonists, should be more efficacious than either used alone in the treatment of allergic rhinitis. In a 2-week study in patients with mild to severe persistent asthma, the combination of 10 mg/d of montelukast and 20 mg/d of loratadine produced significantly greater improvements in forced expiratory volume in 1 second and symptom scores and more reduction in β-agonist use than montelukast and placebo.20 A similar beneficial effect has been shown in seasonal allergic rhinitis. Meltzer et al1 showed the additive effect of montelukast plus loratadine in relieving symptoms of seasonal allergic rhinitis compared with placebo or each therapy alone. These results were not duplicated by a subsequent similar study by Lis and colleagues.2 Recently, the combination treatment of montelukast and cetirizine was compared with 2 intranasal corticosteroids, mometasone furoate and budesonide, and the efficacy was similar in symptomatic responses and measures of nasal inspiratory flow.21,22
Our present results show similar symptomatic efficacy between the combination of loratadine plus montelukast sodium and fluticasone propionate in total symptom scores and quality of life. When the total symptom scores are examined, the median score of patients in the fluticasone group is numerically lower than that of patients in the loratadine and montelukast group at every measurement time, although the magnitude of the difference did not reach statistical significance. In quality-of-life scores, it is interesting that both treatments demonstrated a similar improvement in the eye domain of the RQLQ, which is consistent with other clinical trials and suggests that antihistamines have no clinical advantage over intranasal steroids in the control of eye symptoms. All the individual and overall domain scores of the RQLQ were reduced by both treatments in a clinically and statistically significant manner. However, fluticasone demonstrated a statistical superiority in the reduction of nasal symptoms. We suspect that we underestimated the effect of the combination in our initial power analysis for this study. A larger number of subjects would probably have added statistical significance to the impression of superiority of fluticasone.
In an asthma study,23 the proportion of eosinophils in induced sputum was significantly lower after 4 weeks of treatment with 10 mg/d of montelukast compared with placebo in adult patients with mild to moderate asthma. In contrast, in a nasal biopsy study of patients with seasonal allergic rhinitis,18 the leukotriene receptor antagonist zafirlukast did not lead to a statistically significant reduction in the number of eosinophils compared with preseason numbers. The combination of loratadine and montelukast did not reduce eosinophil counts or ECP levels in nasal lavages in the present study. Perhaps this is because the treatment was not administered for a long enough period to affect eosinophil influx or because the mechanism of eosinophil chemotaxis is different in asthma than in seasonal allergic rhinitis. However, the major reason behind our observation is related to the lower median eosinophil count at study entry in the loratadine and montelukast group than in the fluticasone group, even though the patients were randomized to the different study treatments. Thus, it is hard to draw any conclusions about reduction of eosinophils by the loratadine and montelukast combination when a very small signal was present at baseline.
In our study design, with rolling enrollment, some subjects were enrolled later in the season than others. One would expect these subjects to have more eosinophils and a higher inflammatory response because they have been primed by prior exposure to the allergen. Thus, one would also expect that the effect of fluticasone (the anti-inflammatory agent) would be more marked in these subjects. Indeed, when the patients were divided into those enrolled in the first half of the season and those enrolled in the second half of the season, and their total symptom scores compared, there was more separation of the symptoms, with lower symptom scores in the fluticasone group than in the combination group in the patients enrolled during the second half of the season. In fact, total symptom scores were statistically different between treatments in favor of the fluticasone group at several points despite the presence of fewer subjects in these subgroups. Perhaps a longer seasonal study or one in perennial allergic rhinitis would show larger differences between the treatment arms.
In summary, our data indicate that the combination treatment of montelukast sodium and loratadine offers no statistical advantage over treatment with the intranasal steroid fluticasone propionate for seasonal allergic rhinitis. In contrast, statistical advantages favored fluticasone in the nasal symptom domain of the RQLQ, and numerical advantages were shown in the control of nasal symptoms. These results suggest that the combination of an antihistamine and a leukotriene receptor antagonist is a viable option for the treatment of seasonal allergic rhinitis in patients who prefer systemic treatment or do not tolerate intranasal steroids. Cost considerations remain important when making these therapeutic choices.
Corresponding author: Fuad M. Baroody, MD, Section of Otolaryngology–Head and Neck Surgery, The University of Chicago, 5841 S Maryland Ave, MC 1035, Chicago, IL 60637 (e-mail: firstname.lastname@example.org).
Accepted for publication August 29, 2002.
Work for this article was supported by a grant from GlaxoSmithKline, and grant AI45583 from the National Institutes of Health, Bethesda, Md.
This article was presented at the 58th Annual Meeting of the American Academy of Allergy, Asthma and Immunology, New York, NY, March 4, 2002.