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The efficacy of montelukast in the treatment of cat allergen–induced asthma in children
The efficacy of montelukast in the treatment of cat allergen–induced asthma in children Asthma, rhinitis, other respiratory diseases
Wanda Phipatanakul, MD,a Anna Nowak-Wegrzyn, MD,b Peyton A. Eggleston, MD,c Mark Van Natta, MS,d Jana Kesavan, PhD,e Kenneth Schuberth, MD,c and Robert A. Wood, MDc Boston, Mass, New York, NY, and Baltimore, Md
Background: Montelukast is a leukotriene antagonist approved for the treatment of childhood asthma in children age 2 years and older. There are limited studies on its effects on allergic asthma in children. Objective: We sought to evaluate montelukast’s effects on upper and lower airway responses to intense cat allergen exposure. Methods: In a double-blind, placebo-controlled, cross-over trial 18 subjects aged 6 to 14 years with cat-induced asthma were randomly assigned to receive 1 week each of either montelukast or placebo, followed by a 1-hour cat challenge in an environmental exposure unit. Upper and lower respiratory tract symptoms were rated, and spirometry and acoustic rhinometry were performed. Challenges were stopped early if the subject became too uncomfortable or had a greater than 50% decrease in FEV1. Results: Overall changes in FEV1 were significantly different with montelukast treatment and remained significant after adjusting for allergen level (P = .02; adjusted P = .01). Lower respiratory tract symptom scores were significantly reduced with montelukast versus placebo (P = .007) but lost significance after adjusting for allergen level (P = .16). Challenge length was significantly longer with montelukast versus placebo (P < .001) and remained significant after adjusting for allergen level (P = .019). Montelukast did not significantly affect upper respiratory responses, as measured by means of symptom scores (P = .43) and changes in acoustic rhinometry (P = .078). Conclusions: Montelukast was significantly more effective than placebo in attenuating lower respiratory responses and extending challenge length when cat-sensitive children with mild persistent asthma were exposed to high levels of cat allergen. (J Allergy Clin Immunol 2002;109:794-9.)
From athe Department of Pediatrics, Division of Allergy and Immunology, Children’s Hospital, Harvard Medical School, Boston; bthe Department of Pediatrics, Division of Allergy and Immunology, Mount Sinai School of Medicine, New York; cthe Department of Pediatrics, Division of Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore; dthe Department of Epidemiology, Division of Biostatistics, and ethe Department of Environmental Health Sciences, Division of Environmental Health Engineering, Johns Hopkins University School of Public Health, Baltimore. Supported by National Institutes of Health Institutional Training grant no. AI07007, Merck & Co, and The Eudowood Fund for the Consumptives of Maryland. Received for publication December 5, 2001; revised January 28, 2002; accepted for publication January 30, 2002. Reprint requests: Wanda Phipatanakul, MD, Boston Children’s Hospital, Harvard Medical School, Division of Immunology, Fegan 6, 300 Longwood Ave, Boston, MA 02115. © 2002 Mosby, Inc. All right reserved. 0091-6749/2002 $35.00 + 0 1/81/123530 doi:10.1067/mai.2002.123530
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Key words: Montelukast, acoustic rhinometry, cat challenge, cat allergen, pediatric asthma
Montelukast, a leukotriene receptor antagonist that selectively inhibits the cysteinyl leukotriene receptor and blocks the effects of leukotriene D4, has been shown to improve asthma control in adults1,2 and children.3 Studies have also shown that montelukast attenuates both early and late-phase responses to allergen challenge in adults4 and exercise-induced bronchoconstriction in both adults5 and children.6 Because allergen exposure is an important trigger of acute and chronic asthma symptoms in 80% to 90% of children with asthma,7 control of allergeninduced asthma would be significant for any asthma medication; however, there have been no previous studies evaluating the effects of montelukast on allergen challenge in children. Cat sensitivity has been shown to be present in up to approximately 60% of children with asthma, and cat exposure is extremely common on both a chronic and an intermittent basis.8,9 Furthermore, many children with asthma are unable to endure even brief exposures to cat allergen because of the reactions they experience. In this study we sought to evaluate the effects of montelukast on upper and lower airway responses to cat allergen exposure in children with cat-induced asthma by using our well-characterized cat challenge model.10,11
METHODS Eighteen children aged 6 to 14 years with mild persistent asthma and a history of cat-induced asthma who were otherwise in good health were recruited for the study. All subjects had mild persistent asthma, as determined by their physician and in concordance with National Heart, Lung, and Blood Institute guidelines for classification of asthma severity. All subjects were taking one maintenance anti-inflammatory medication, such as a low-dose inhaled corticosteroid or inhaled cromolyn sodium. Those subjects already taking montelukast were restricted from the study. The study was approved by the Joint Committee for Clinical Investigation of the Johns Hopkins University School of Medicine, and all participants and their parents provided written informed consent. On recruitment, subjects were evaluated by means of a questionnaire regarding medical history and current medication use. Exclusion criteria included cat owners, a history of unstable asthma (defined as a recent hospitalization, recent episodes requiring prednisone, or daily symptoms), chronic illness other than asthma or allergies, an upper respiratory tract infection within 2 weeks of study entry, inability to comply with required medication restrictions before cat challenge, a history of severe reactions (ie, anaphylaxis or
Abbreviations used LRSx: Lower respiratory tract symptoms MCA: Minimum cross-sectional area URSx: Upper respiratory tract symptoms
a severe asthma exacerbation requiring an emergency department visit or hospitalization) after cat exposure, or the use of systemic steroids within 4 weeks of entry. Subjects underwent prick puncture skin tests to cat, dog, dust mite, cockroach, mold (2 mold mixes, including Aspergillus, Penicillium, Mucor, Fusarium, Alternaria, Helminthosporium, Hormodendrum, and Botrytis species), and grass (orchard), tree (oak and maple), and ragweed pollens. A positive skin test response to cat allergen, defined as a wheal greater than one half the diameter of that induced by the histamine control and at least 3 mm larger than the diameter of the wheal induced by the glycerin-saline control, was required for entry into the study. All subjects avoided short-acting antihistamines for 72 hours, long-acting antihistamines for 7 days, and tricyclic antidepressants for 6 weeks before skin testing. After the initial screening, eligible subjects underwent a baseline cat challenge. Before all cat challenges, medications were restricted as follows: antihistamines (short acting, 72 hours; long acting, 7 days), short-acting inhaled β-adrenergic agonists (4 hours), salmeterol (24 hours), oral β-adrenergic agonists (short acting, 6 hours; long acting 24 hours), theophylline (24 hours), nasal or inhaled cromolyn sodium (48 hours), and nasal or inhaled corticosteroids (72 hours). Cat exposure challenges were performed as previously described in a 13.7-m3 room with 2 cats, a bed, and a small carpet.10,11 Before the challenge, the cats were placed in a cage, and bedding was shaken to disturb allergen. In addition, baseline symptom scores, spirometry (spirometry model WinDX Computerized Spirometry; Multi SPIRO, Inc, San Clemente, Calif), and acoustic rhinometry11,12 measurements were obtained. Patients were required to have an FEV1 of greater than 70% of predicted value to undergo a cat challenge. The subjects then entered the cat room for a 1-hour challenge. During the challenge, upper respiratory tract symptoms (URSx; congestion, rhinorrhea, and pruritis) and lower respiratory tract symptoms (LRSx; tightness and wheezing) were scored every 5 minutes by the subject according to an arbitrary scale of 0 to 3, which correlated with a rating of none, mild, moderate, and severe. Repeat acoustic rhinometry and spirometry results were obtained at 15-minute intervals for the 1-hour challenge. At those times, bedding in the cat room was shaken once again to maintain high airborne allergen levels. Challenges were terminated early if the subject became too uncomfortable or had a drop in FEV1 of greater than 50% from the baseline value. Air samples were collected during the challenge with use of a personal airsampling device (Gilian Instruments, Wayne, NJ) to determine the level of allergen exposure, and airborne cat allergen 1 (Fel d 1) was quantified as previously described.10,13 Each subject had to demonstrate a fall in FEV1 of 15% or greater during the screening cat challenge to qualify for the study. Qualified subjects were then randomized to receive 1 week of either montelukast, 5 mg daily, or placebo. The subject, active investigator, and study coordinator were blinded to treatment identity. Subjects were instructed to take the pill at bedtime. The second cat challenge was then performed with the same protocol as the baseline challenge the following day after the 1-week period of montelukast or placebo treatment. Each subject had his or her baseline and subsequent cat challenges during the same time of day. This was followed by a 1-week washout period, after which subjects were treated for another week in a cross-over fashion, followed by
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another cat challenge. The patients continued their other regular maintenance medications during the washout period but not during either treatment period. Adverse events were tabulated and reported for each treatment period. The acoustic rhinometry data from all challenges were collected and analyzed, as previously described.11,12 The minimum crosssectional areas (MCAs) for each side were determined every 15 minutes. The percentage change from baseline was calculated at each time point, and the left and right sides were averaged to determine the mean change in MCA. For symptom scores, each symptom was rated on a scale from 0 to 3, and scores were averaged to provide URSx and LRSx scores at each time point. These scores in turn were averaged to provide mean symptom scores for each 15minute interval and for the entire challenge. Data for subjects who withdrew before a 15-minute time point were included for analysis at the next 15-minute time point. Drug and placebo challenges were compared with regard to URSx scores, LRSx scores, change in FEV1, challenge length, and change in nasal cross-sectional area, as measured by means of acoustic rhinometry. A P value of .05 or less was considered significant. In the unadjusted analyses differences in median challenge outcome measures were tested with the Wilcoxon matched-pairs signed-rank test at each time point. Subjects who prematurely exited the cat room had all missing observations replaced with their last nonmissing values (ie, last value carried forward). All data points for each challenge were compared by using the generalized estimation equation test to compare challenge outcomes over the duration of the entire challenge.14 Because the cat challenge protocol relies on naturally generated cat allergen from live cats, there is unavoidable variability in allergen levels from one challenge to another. Therefore data were also reanalyzed, adjusting for differences in allergen level with the generalized estimation equation model. Because montelukast is a bronchodilator, results were also analyzed after adjusting for baseline FEV1. Finally, results were analyzed by adjusting for treatment to ensure that there was no carryover effect from the prior treatment period.
RESULTS Subjects and baseline challenges Eighteen children were enrolled. Demographic data are shown in Table I. Patient ages ranged from 6 to 14 years (median, 10 years). Twelve of the subjects were boys, and 6 were girls. The net cat skin test wheal size ranged from 5 to 10 mm (median, 7 mm). All of the subjects took daily maintenance medication for their asthma. Seventeen of the 18 children took inhaled corticosteroids, and 1 took cromolyn sodium. All of the subjects had a history of both asthma and allergic rhinitis, and 15 of 18 had additional positive skin test responses. Responses to the baseline challenges are also shown in Table I. Maximum FEV1 changes ranged from 15% to 67% (median, 30.3%). Mean LRSx scores ranged from 0.25 to 2 (median, 0.87), and mean URSx scores ranged from 0 to 2.67 (median, 1.5). Mean maximum changes in MCA ranged from 0% to 61% (median, 20.2%). The number of sneezes ranged from 0 to 32 (median, 4), and the number of coughs ranged from 0 to 112 (median, 14.5). Challenge lengths ranged from 3 to 60 minutes (median, 10 minutes), with 12 subjects lasting less than 15 minutes, 2 subjects lasting 15 minutes, 1 subject lasting between 15 and 30 minutes, 1 subject lasting 45 minutes, and 2 subjects lasting 60 minutes.
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TABLE I. Demographic characteristics and baseline challenges
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Median age, y (range) 10 (6-14) Sex 12 male, 6 female Median cat wheal, mm (range) 7 (5-10) Subjects with other positive skin test results 15/18 Median baseline FEV1 % predicted (range) 87 (74-102) Response to baseline challenges Median challenge length, min (range) 10 (3-60) Median maximum decrease in FEV1, % (range) 30.3 (15-67) Median LRSx score (range) 0.87 (0.25-2) Median URSx (range) 1.5 (0-2.67) Median maximum change in MCA, % (range) 20.2 (0-61) Median no. of sneezes (range) 4 (0-32) Median no. of coughs (range) 14.5 (0-112)
FIG 1. Kaplan-Meier curves comparing challenge lengths for montelukast and placebo challenges.
FIG 2. Median percentage of change from baseline in FEV1 over time. Median percentage changes were 11%, 15%, 15%, and 15% with montelukast and 21%, 21%, 21%, and 21% with placebo. *Statistically significant differences were detected at the 15- and 30-minute time points (P < .05) without adjustment for differences in allergen exposure.
Challenge outcomes after treatment Airborne cat allergen (Fel d 1) levels ranged from 1073 to 16,480 ng/m3 (median, 4487 ng/m3) in the montelukast challenges and from 1463 to 89,537 ng/m3 (median, 7764 ng/m3) in the placebo challenges and were significantly different (P = .04). Outcome measures were adjusted to account for these differences in allergen exposure, and the following results include analyses of both the raw data and the allergen-adjusted data.
Fig 1 is a Kaplan-Meier curve depicting challenge lengths for the montelukast and placebo challenges. Challenge lengths were significantly longer with montelukast (montelukast range, 3-60 minutes; montelukast median, 15 minutes; placebo range, 3-45 minutes; placebo median, 10 minutes; P < .001) and remained significant after adjusting for allergen level (P = .019, Table II). While receiving montelukast, 8 subjects lasted less than 15 minutes, 2 subjects lasted 15 minutes, 1 subject lasted between 15 and 30 minutes, 3 subjects lasted 30 minutes, 2 subjects lasted 45 minutes, and the remaining 2 subjects lasted 45 to 60 minutes. While receiving placebo, 12 subjects lasted less than 15 minutes, 3 subjects lasted 15 minutes, 2 subjects lasted 30 minutes, and 1 subject lasted 45 minutes. Challenge length was longer with montelukast in 13 subjects and with placebo in 4 subjects, with the remaining subject having equal challenge lengths while receiving montelukast and placebo. All challenges that were terminated early were due to either LRSx or a greater than 50% fall in FEV1. Fig 2 represents the median percentage change in FEV1 in the challenges after active and placebo treatment. The overall change in FEV1 was significantly reduced with montelukast (P = .02) and remained significant after adjusting for allergen level (P = .01). The median decreases in FEV1 at 15, 30, 45, and 60 minutes were 11%, 15%, 15%, and 15% with montelukast and 21%, 21%, 21%, and 21% with placebo. At 15 and 30 minutes, there were significant differences in favor of montelukast (P = .005 and .043, respectively), although not at 45 and 60 minutes (P = .08 and .098, respectively). The maximum fall in FEV1 was reduced with montelukast, although these differences were not significant (median, 15% vs 21.2%, P = .065; P = .38 after adjustment for allergen level). FEV1 results were also analyzed with regard to the time it took for subjects reach their maximum fall in FEV1; significant differences were detected in favor of montelukast in the unadjusted analysis (P = .01), although not in the allergenadjusted analysis (P = .08). Median LRSx scores were significantly reduced with montelukast treatment compared with placebo (montelukast range, 0-1.7; montelukast median, 0.5; placebo range, 0-2, placebo median, 1.07; P = .007; Fig 3 and
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FIG 3. Median change in LRSx scores over time. Median scores were 0.4, 0.5, 0.5, and 0.5 with montelukast and 0.87, 1.08, 1.21, and 1.21 with placebo. Statistically significant differences were detected at the 15-, 30-, 45-, and 60-minute time points (P < .05) without adjustment for differences in allergen exposure.
TABLE II. Comparison of challenge outcome measures Montelukast
Challenge length (min) Mean change in FEV1 (%) Maximum change in FEV1 (%) Mean LRSx score Coughs/min Mean URSx score Sneezes/min Maximum change in MCA (%) Fel d 1 (ng/m3)
15 (3-60) 15 (0-51) 15 (0-55) 0.5 (0-1.7) 0.04 (0-0.47) 1.33 (0.33-2.83) 0.13 (0-0.54) 19.7 (0-76) 4487 (1073-16,480)
Placebo
10 (3-45) 21.2 (8-63) 21.2 (5.3-63) 1.07 (0-2) 0.06 (0-1.25) 1.36 (0.67-2.67) 0.33 (0-1.4) 33.2 (0-55) 7764 (1463-89,537)
P value
<.001 .02 .065 .007 .075 .43 .007 .078 .04
Adjusted P value*
.019 .012 .38 .16 .08 .49 .039 .082 NA
Values are given as median (range). NA, Not applicable. *Adjusted for allergen level.
Table II), although this difference was no longer significant after adjusting for allergen levels (P = .16). The median LRSx scores at 15, 30, 45, and 60 minutes were 0.4, 0.5, 0.5, and 0.5 with montelukast and 0.87, 1.08, 1.21, and 1.21 with placebo and were significantly different at all time points (P < .03). The number of coughs per minute ranged from 0 to 0.47 (median, 0.04) with montelukast and from 0 to 1.25 with placebo (median, 0.06), which approached significance (P = .075), with similar differences after adjusting for allergen level (P = .08). Median URSx scores were not significantly different between active and placebo treatment overall (P = .43) or at any specific time point. The median URSx scores at 15, 30, 45, and 60 minutes were 1.25, 1.33, 1.38, and 1.5 with montelukast and 1.33, 1.41, 1.42, and 1.41 with placebo. The number of sneezes per minute ranged from 0 to 0.54 (median, 0.13) with montelukast and from 0 to 1.4 (medi-
an, 0.33) with placebo and were significantly different at 15 minutes (P = .036) and over the whole challenge (P = .007; P = .039 after adjusting for allergen level). The overall change in MCA was reduced with montelukast but did not reach significance (P = .078; adjusted P = .083). At 15, 30, 45, and 60 minutes, changes in MCA were 18.6%, 15.3%, 15.3%, and 11.3% for montelukast and 31.7%, 24.9%, 25.1%, and 25.1% for placebo (P = .058, .21, .20, and .11 at 15, 30, 45, and 60 minutes, respectively). The mean maximum percentage change in MCA ranged from 0% to 76% (median, 17.6%) for those receiving montelukast and from 0% to 55% (median, 33.2%) for those receiving placebo, which was not significantly different (P = .09). Data were also reanalyzed to adjust for baseline FEV1 and for treatment order, which revealed no appreciable differences in the results for any outcome measure.
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Three subjects had mild adverse effects during treatment with montelukast, including dry mouth in one subject, somnolence in another subject, and headache in another subject. Two subjects had mild adverse effects during placebo treatment, with nasal congestion in one subject and nausea for 3 days in another subject. None of these effects caused prolonged harm or discomfort, and all resolved without medical intervention. None of the subjects were withdrawn from the study as a result of adverse events or noncompliance.
DISCUSSION This study, the first to specifically evaluate the efficacy of montelukast on allergic asthma in children, demonstrated that montelukast significantly reduces lower respiratory tract responses to intense cat exposure. Montelukast produced an overall attenuation in FEV1 change, even after adjusting for differences in allergen levels, and allowed these cat-sensitive children to tolerate longer exposures to cat allergen. LRSx scores were significantly different in favor of montelukast, but this effect was no longer evident after adjusting for allergen level. We did not find significant effects on upper respiratory tract responses in terms of symptom scores or changes in nasal anatomy, as measured by means of acoustic rhinometry, aside from a significant difference in the number of sneezes per minute. These findings indicate that montelukast is more helpful for treatment of lower airway responses than upper airway responses after intense allergen exposure. Despite the positive results for lower airway responses, the effects of montelukast might have been underestimated in this study. Allergen levels in the cat room are between 10- and 100-fold higher than those found in typical homes with cats (10-200 ng/m3),15 and it is possible that this intense exposure overwhelmed some of the effects of the drug. Furthermore, many of the subjects were unable to tolerate the challenges for longer than even 15 minutes, and complete data were only available on 3 subjects past 30 minutes. This perhaps explains why we saw a greater effect of montelukast on FEV1 changes during the first half of the challenge. The fact that montelukast showed any significant effect with such intense allergen exposure is encouraging, and it is likely that with lower levels of allergen, the effects would be even more apparent. Further studies at lower antigen levels would therefore be useful. Although there have not been other studies evaluating the effect of montelukast on cat allergen–induced asthma, previous studies have examined the effects of another leukotriene antagonist, zafirlukast, on cat allergen challenge. Findlay et al16 evaluated cat-sensitive adult asthmatic patients and found that zafirlukast was effective in increasing the predicted dose of inhaled cat allergen to induce a 20% decrease in FEV1 by 10-fold. In addition, we have studied adults with cat-induced asthma by using the same cat challenge model with zafirlukast and found significant preservation of pulmonary function and a
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modest benefit in symptom scores.17 Corren et al18 studied 18 adults with cat-induced asthma by using a similar cat challenge model with zafirlukast and found protective effects on LRSx scores and pulmonary function tests but no significant effect on markers of sputum inflammatory cells after sputum induction. With regard to montelukast and allergen-induced asthma, Diamant et al4 evaluated a group of adult dust mite–sensitive asthmatic patients and found that montelukast was effective in attenuating early and late asthmatic responses to inhaled dust mite allergen but did not find a significant difference in allergeninduced changes in sputum eosinophils. Our results for montelukast in children generally agree with the results of these studies and confirm that leukotriene antagonists are effective in attenuating lower airway responses to acute allergen exposure in susceptible subjects. We did not demonstrate any significant benefit with montelukast on upper airway responses. Less is known about the effect of leukotriene antagonists on nasal responses, with previous studies providing somewhat conflicting results. Pullertis et al19 studied 33 grasssensitive adolescents and adults with allergic rhinitis during the grass pollen season and found no significant difference between zafirlukast and placebo in symptoms or numbers of activated eosinophils in nasal tissue. However, Donnelly et al20 did find a significant difference in nasal symptoms among subjects with ragweed-induced rhinitis who received zafirlukast. Our previous study with adults receiving zafirlukast found some reduction in nasal responses, as assessed by acoustic rhinometry, without any effect on symptom scores.17 Similarly, the study by Corren et al18 did not find significant differences in URSx scores but did see some reduction in inflammatory cells in nasal lavage fluid. With regard to montelukast, Meltzer et al21 analyzed a group of adults with tree pollen allergy during the pollen season with montelukast and loratadine and found that monotherapy with either medication did not improve nasal symptom scores over those seen with placebo but that combined therapy did improve symptoms. Because our challenges involved intense allergen exposure and shorter challenges caused by significant lower airway responses, it is not surprising that we did not find a reduction in nasal responses. It is possible that the intense allergen levels overwhelmed the medication’s effect on the nose or that the subject’s acute and often intense lower respiratory tract responses masked the perception of an improvement in URSx scores. The degree of upper respiratory tract obstruction, as measured by means of acoustic rhinometry, did approach significance, and perhaps greater effects on this measure would have been seen with longer challenges. Additional studies with lower allergen levels and subjects with primarily catinduced rhinitis might be useful to better appreciate the effects of montelukast on URSx. In conclusion, the results of this study show that montelukast provides a significant benefit for cat-sensitive children with mild persistent asthma on lower respiratory tract responses after challenges with high levels of cat allergen. It also allowed these children to tolerate the
challenges for longer periods of time. Although the true clinical role of the leukotriene antagonists in allergic asthma is not yet completely clear, this study does provide encouraging information as to their potential benefit. REFERENCES 1. Reiss TF, Chervisnky P, Dockhorn RJ, Shingo S, Seidenberg BC, Edwards TB, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;11:1232-9. 2. Noonan MJ, Chervinsky P, Brandon M, Zhang J, Kundu S, McBurney J, et al. Montelukast, a potent leukotriene receptor antagonist, causes doserelated improvements in chronic asthma. Eur Respir J 1998;11:1232-9. 3. Knorr B, Mtz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, et al. Montelukast for chronic asthma in 6 to 14 year old children: a randomized double-blind trial. JAMA 1998;279:1181-6. 4. Diamant Z, Grootendorst DC, Veselic-Charvat M, Timmers MC, De Smet M, Leff JA, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999;29:42-51. 5. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339:147-52. 6. Kemp JP, Dockborn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6-to 14-year-old children with asthma. J Pediatr 1998;133:424-8. 7. Niemeijer NR, de Monchy JGR. Age-dependency of sensitization to aero-allergens in asthmatics. Allergy 1992;47:431-5. 8. Ingram JM, Sporik R, Rose G, Hosinger R, Chapman MD, Platts-Mills TAE. Quantitative assessment of exposure to dog (Can f 1) and cat (Fel d 1) allergens: relationship to sensitization and asthma among children living in Los Alamos, New Mexico. J Allergy Clin Immunol 1995;96:449-56. 9. Sporik R, Ingram JM, Price W, Sussman JH, Honsinger RW, Platts-Mills TAE. Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon’s breath. Am J Respir Crit Care Med 1995;151:1388-92.
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10. Wood RA, Lheri AN, Eggleston PA. The aerodynamic characteristics of cat allergen. Clin Exp Allergy 1993;23:542-7. 11. Phipatanakul W, Kesavanathan J, Eggleston PA, Johnson EF, Wood RA. The value of acoustic rhinomtery in assessing nasal responses to cat exposure J Allergy Clin Immunol 1998;102:896-901. 12. Hilberg O, Jackson AC, Swift DL, Pederson OF. Acoustic rhinometry: evaluation of the geometry of the nasal cavity by acoustic reflections. J Appl Physiol 1989;66:295-303. 13. Chapman MD, Aalberse RC, Brown MJ, Platts-Mills TAE. Monoclonal antibodies to the major feline allergen Fel d I, II: single step affinity purification of Fel d I, N-terminal sequence analysis, and development of a twosite immunoassay to assess Fel d I exposure. J Immunol 1988;140:812-8. 14. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22. 15. Bollinger MB, Eggleston PA, Johsnson EF, Wood RA. Cat antigen in homes with and without cats may induce allergic symptoms. J Allergy Clin Immunol 1996;97:907-14. 16. Findlay SR, Barden JM, Easley CB, Glass M. Effect of the oral leukotriene receptor antagonist, ICI 204, 219 on antigen induced bronchoconstriction in subjects with asthma. J Allergy Clin Immunol 1992;89:1040-5. 17. Phipatanakul W, Eggleston PA, Conover-Walker MK, Kesavanathan J, Wood RA. A randomized, double-blind placebo controlled trial of the effect of zafirlukast on upper and lower respiratory responses to cat challenge. J Allergy Clin Immunol 2000;105:704-10. 18. Corren J, Spector S, Fuller L, Minkwitz M, Mezzanotte W. Effects of zafirlukast upon clinical, physiologic, and inflammatory responses to natural cat allergen exposure. Ann Allergy Asthma Immunol 2001;87:211-7. 19. Pullertis T, Praks L, Skoogh BE, Ani R, Lotvall J. Randomized placebocontrolled study comparing a leukotriene receptor antagonist and a nasal glucocorticoid in season allergic rhinitis. Am J Respir Crit Care Med 1999;159:1814-8. 20. Donnelly AL, Glass M, Minkwitz MC, Casale TB. The leukotriene D4 receptor antagonist ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Respir Crit Care Med 1995;151:1734-9. 21. Meltzer EO, Malmstrom K, Lu S, Prenner BM, Wei LX, Weinstein SF, et al. Concomitant montelukast and loratadine as treatment for seasonal allergic rhinitis: a randomized placebo-controlled trial. J Allergy Clin Immunol 2000;105:917-22.
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Wanda Phipatanakul, MD,a Anna Nowak-Wegrzyn, MD,b Peyton A. Eggleston, MD,c Mark Van Natta, MS,d Jana Kesavan, PhD,e Kenneth Schuberth, MD,c and Robert A. Wood, MDc Boston, Mass, New York, NY, and Baltimore, Md
Background: Montelukast is a leukotriene antagonist approved for the treatment of childhood asthma in children age 2 years and older. There are limited studies on its effects on allergic asthma in children. Objective: We sought to evaluate montelukast’s effects on upper and lower airway responses to intense cat allergen exposure. Methods: In a double-blind, placebo-controlled, cross-over trial 18 subjects aged 6 to 14 years with cat-induced asthma were randomly assigned to receive 1 week each of either montelukast or placebo, followed by a 1-hour cat challenge in an environmental exposure unit. Upper and lower respiratory tract symptoms were rated, and spirometry and acoustic rhinometry were performed. Challenges were stopped early if the subject became too uncomfortable or had a greater than 50% decrease in FEV1. Results: Overall changes in FEV1 were significantly different with montelukast treatment and remained significant after adjusting for allergen level (P = .02; adjusted P = .01). Lower respiratory tract symptom scores were significantly reduced with montelukast versus placebo (P = .007) but lost significance after adjusting for allergen level (P = .16). Challenge length was significantly longer with montelukast versus placebo (P < .001) and remained significant after adjusting for allergen level (P = .019). Montelukast did not significantly affect upper respiratory responses, as measured by means of symptom scores (P = .43) and changes in acoustic rhinometry (P = .078). Conclusions: Montelukast was significantly more effective than placebo in attenuating lower respiratory responses and extending challenge length when cat-sensitive children with mild persistent asthma were exposed to high levels of cat allergen. (J Allergy Clin Immunol 2002;109:794-9.)
From athe Department of Pediatrics, Division of Allergy and Immunology, Children’s Hospital, Harvard Medical School, Boston; bthe Department of Pediatrics, Division of Allergy and Immunology, Mount Sinai School of Medicine, New York; cthe Department of Pediatrics, Division of Allergy and Immunology, Johns Hopkins University School of Medicine, Baltimore; dthe Department of Epidemiology, Division of Biostatistics, and ethe Department of Environmental Health Sciences, Division of Environmental Health Engineering, Johns Hopkins University School of Public Health, Baltimore. Supported by National Institutes of Health Institutional Training grant no. AI07007, Merck & Co, and The Eudowood Fund for the Consumptives of Maryland. Received for publication December 5, 2001; revised January 28, 2002; accepted for publication January 30, 2002. Reprint requests: Wanda Phipatanakul, MD, Boston Children’s Hospital, Harvard Medical School, Division of Immunology, Fegan 6, 300 Longwood Ave, Boston, MA 02115. © 2002 Mosby, Inc. All right reserved. 0091-6749/2002 $35.00 + 0 1/81/123530 doi:10.1067/mai.2002.123530
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Key words: Montelukast, acoustic rhinometry, cat challenge, cat allergen, pediatric asthma
Montelukast, a leukotriene receptor antagonist that selectively inhibits the cysteinyl leukotriene receptor and blocks the effects of leukotriene D4, has been shown to improve asthma control in adults1,2 and children.3 Studies have also shown that montelukast attenuates both early and late-phase responses to allergen challenge in adults4 and exercise-induced bronchoconstriction in both adults5 and children.6 Because allergen exposure is an important trigger of acute and chronic asthma symptoms in 80% to 90% of children with asthma,7 control of allergeninduced asthma would be significant for any asthma medication; however, there have been no previous studies evaluating the effects of montelukast on allergen challenge in children. Cat sensitivity has been shown to be present in up to approximately 60% of children with asthma, and cat exposure is extremely common on both a chronic and an intermittent basis.8,9 Furthermore, many children with asthma are unable to endure even brief exposures to cat allergen because of the reactions they experience. In this study we sought to evaluate the effects of montelukast on upper and lower airway responses to cat allergen exposure in children with cat-induced asthma by using our well-characterized cat challenge model.10,11
METHODS Eighteen children aged 6 to 14 years with mild persistent asthma and a history of cat-induced asthma who were otherwise in good health were recruited for the study. All subjects had mild persistent asthma, as determined by their physician and in concordance with National Heart, Lung, and Blood Institute guidelines for classification of asthma severity. All subjects were taking one maintenance anti-inflammatory medication, such as a low-dose inhaled corticosteroid or inhaled cromolyn sodium. Those subjects already taking montelukast were restricted from the study. The study was approved by the Joint Committee for Clinical Investigation of the Johns Hopkins University School of Medicine, and all participants and their parents provided written informed consent. On recruitment, subjects were evaluated by means of a questionnaire regarding medical history and current medication use. Exclusion criteria included cat owners, a history of unstable asthma (defined as a recent hospitalization, recent episodes requiring prednisone, or daily symptoms), chronic illness other than asthma or allergies, an upper respiratory tract infection within 2 weeks of study entry, inability to comply with required medication restrictions before cat challenge, a history of severe reactions (ie, anaphylaxis or
Abbreviations used LRSx: Lower respiratory tract symptoms MCA: Minimum cross-sectional area URSx: Upper respiratory tract symptoms
a severe asthma exacerbation requiring an emergency department visit or hospitalization) after cat exposure, or the use of systemic steroids within 4 weeks of entry. Subjects underwent prick puncture skin tests to cat, dog, dust mite, cockroach, mold (2 mold mixes, including Aspergillus, Penicillium, Mucor, Fusarium, Alternaria, Helminthosporium, Hormodendrum, and Botrytis species), and grass (orchard), tree (oak and maple), and ragweed pollens. A positive skin test response to cat allergen, defined as a wheal greater than one half the diameter of that induced by the histamine control and at least 3 mm larger than the diameter of the wheal induced by the glycerin-saline control, was required for entry into the study. All subjects avoided short-acting antihistamines for 72 hours, long-acting antihistamines for 7 days, and tricyclic antidepressants for 6 weeks before skin testing. After the initial screening, eligible subjects underwent a baseline cat challenge. Before all cat challenges, medications were restricted as follows: antihistamines (short acting, 72 hours; long acting, 7 days), short-acting inhaled β-adrenergic agonists (4 hours), salmeterol (24 hours), oral β-adrenergic agonists (short acting, 6 hours; long acting 24 hours), theophylline (24 hours), nasal or inhaled cromolyn sodium (48 hours), and nasal or inhaled corticosteroids (72 hours). Cat exposure challenges were performed as previously described in a 13.7-m3 room with 2 cats, a bed, and a small carpet.10,11 Before the challenge, the cats were placed in a cage, and bedding was shaken to disturb allergen. In addition, baseline symptom scores, spirometry (spirometry model WinDX Computerized Spirometry; Multi SPIRO, Inc, San Clemente, Calif), and acoustic rhinometry11,12 measurements were obtained. Patients were required to have an FEV1 of greater than 70% of predicted value to undergo a cat challenge. The subjects then entered the cat room for a 1-hour challenge. During the challenge, upper respiratory tract symptoms (URSx; congestion, rhinorrhea, and pruritis) and lower respiratory tract symptoms (LRSx; tightness and wheezing) were scored every 5 minutes by the subject according to an arbitrary scale of 0 to 3, which correlated with a rating of none, mild, moderate, and severe. Repeat acoustic rhinometry and spirometry results were obtained at 15-minute intervals for the 1-hour challenge. At those times, bedding in the cat room was shaken once again to maintain high airborne allergen levels. Challenges were terminated early if the subject became too uncomfortable or had a drop in FEV1 of greater than 50% from the baseline value. Air samples were collected during the challenge with use of a personal airsampling device (Gilian Instruments, Wayne, NJ) to determine the level of allergen exposure, and airborne cat allergen 1 (Fel d 1) was quantified as previously described.10,13 Each subject had to demonstrate a fall in FEV1 of 15% or greater during the screening cat challenge to qualify for the study. Qualified subjects were then randomized to receive 1 week of either montelukast, 5 mg daily, or placebo. The subject, active investigator, and study coordinator were blinded to treatment identity. Subjects were instructed to take the pill at bedtime. The second cat challenge was then performed with the same protocol as the baseline challenge the following day after the 1-week period of montelukast or placebo treatment. Each subject had his or her baseline and subsequent cat challenges during the same time of day. This was followed by a 1-week washout period, after which subjects were treated for another week in a cross-over fashion, followed by
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another cat challenge. The patients continued their other regular maintenance medications during the washout period but not during either treatment period. Adverse events were tabulated and reported for each treatment period. The acoustic rhinometry data from all challenges were collected and analyzed, as previously described.11,12 The minimum crosssectional areas (MCAs) for each side were determined every 15 minutes. The percentage change from baseline was calculated at each time point, and the left and right sides were averaged to determine the mean change in MCA. For symptom scores, each symptom was rated on a scale from 0 to 3, and scores were averaged to provide URSx and LRSx scores at each time point. These scores in turn were averaged to provide mean symptom scores for each 15minute interval and for the entire challenge. Data for subjects who withdrew before a 15-minute time point were included for analysis at the next 15-minute time point. Drug and placebo challenges were compared with regard to URSx scores, LRSx scores, change in FEV1, challenge length, and change in nasal cross-sectional area, as measured by means of acoustic rhinometry. A P value of .05 or less was considered significant. In the unadjusted analyses differences in median challenge outcome measures were tested with the Wilcoxon matched-pairs signed-rank test at each time point. Subjects who prematurely exited the cat room had all missing observations replaced with their last nonmissing values (ie, last value carried forward). All data points for each challenge were compared by using the generalized estimation equation test to compare challenge outcomes over the duration of the entire challenge.14 Because the cat challenge protocol relies on naturally generated cat allergen from live cats, there is unavoidable variability in allergen levels from one challenge to another. Therefore data were also reanalyzed, adjusting for differences in allergen level with the generalized estimation equation model. Because montelukast is a bronchodilator, results were also analyzed after adjusting for baseline FEV1. Finally, results were analyzed by adjusting for treatment to ensure that there was no carryover effect from the prior treatment period.
RESULTS Subjects and baseline challenges Eighteen children were enrolled. Demographic data are shown in Table I. Patient ages ranged from 6 to 14 years (median, 10 years). Twelve of the subjects were boys, and 6 were girls. The net cat skin test wheal size ranged from 5 to 10 mm (median, 7 mm). All of the subjects took daily maintenance medication for their asthma. Seventeen of the 18 children took inhaled corticosteroids, and 1 took cromolyn sodium. All of the subjects had a history of both asthma and allergic rhinitis, and 15 of 18 had additional positive skin test responses. Responses to the baseline challenges are also shown in Table I. Maximum FEV1 changes ranged from 15% to 67% (median, 30.3%). Mean LRSx scores ranged from 0.25 to 2 (median, 0.87), and mean URSx scores ranged from 0 to 2.67 (median, 1.5). Mean maximum changes in MCA ranged from 0% to 61% (median, 20.2%). The number of sneezes ranged from 0 to 32 (median, 4), and the number of coughs ranged from 0 to 112 (median, 14.5). Challenge lengths ranged from 3 to 60 minutes (median, 10 minutes), with 12 subjects lasting less than 15 minutes, 2 subjects lasting 15 minutes, 1 subject lasting between 15 and 30 minutes, 1 subject lasting 45 minutes, and 2 subjects lasting 60 minutes.
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TABLE I. Demographic characteristics and baseline challenges
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Median age, y (range) 10 (6-14) Sex 12 male, 6 female Median cat wheal, mm (range) 7 (5-10) Subjects with other positive skin test results 15/18 Median baseline FEV1 % predicted (range) 87 (74-102) Response to baseline challenges Median challenge length, min (range) 10 (3-60) Median maximum decrease in FEV1, % (range) 30.3 (15-67) Median LRSx score (range) 0.87 (0.25-2) Median URSx (range) 1.5 (0-2.67) Median maximum change in MCA, % (range) 20.2 (0-61) Median no. of sneezes (range) 4 (0-32) Median no. of coughs (range) 14.5 (0-112)
FIG 1. Kaplan-Meier curves comparing challenge lengths for montelukast and placebo challenges.
FIG 2. Median percentage of change from baseline in FEV1 over time. Median percentage changes were 11%, 15%, 15%, and 15% with montelukast and 21%, 21%, 21%, and 21% with placebo. *Statistically significant differences were detected at the 15- and 30-minute time points (P < .05) without adjustment for differences in allergen exposure.
Challenge outcomes after treatment Airborne cat allergen (Fel d 1) levels ranged from 1073 to 16,480 ng/m3 (median, 4487 ng/m3) in the montelukast challenges and from 1463 to 89,537 ng/m3 (median, 7764 ng/m3) in the placebo challenges and were significantly different (P = .04). Outcome measures were adjusted to account for these differences in allergen exposure, and the following results include analyses of both the raw data and the allergen-adjusted data.
Fig 1 is a Kaplan-Meier curve depicting challenge lengths for the montelukast and placebo challenges. Challenge lengths were significantly longer with montelukast (montelukast range, 3-60 minutes; montelukast median, 15 minutes; placebo range, 3-45 minutes; placebo median, 10 minutes; P < .001) and remained significant after adjusting for allergen level (P = .019, Table II). While receiving montelukast, 8 subjects lasted less than 15 minutes, 2 subjects lasted 15 minutes, 1 subject lasted between 15 and 30 minutes, 3 subjects lasted 30 minutes, 2 subjects lasted 45 minutes, and the remaining 2 subjects lasted 45 to 60 minutes. While receiving placebo, 12 subjects lasted less than 15 minutes, 3 subjects lasted 15 minutes, 2 subjects lasted 30 minutes, and 1 subject lasted 45 minutes. Challenge length was longer with montelukast in 13 subjects and with placebo in 4 subjects, with the remaining subject having equal challenge lengths while receiving montelukast and placebo. All challenges that were terminated early were due to either LRSx or a greater than 50% fall in FEV1. Fig 2 represents the median percentage change in FEV1 in the challenges after active and placebo treatment. The overall change in FEV1 was significantly reduced with montelukast (P = .02) and remained significant after adjusting for allergen level (P = .01). The median decreases in FEV1 at 15, 30, 45, and 60 minutes were 11%, 15%, 15%, and 15% with montelukast and 21%, 21%, 21%, and 21% with placebo. At 15 and 30 minutes, there were significant differences in favor of montelukast (P = .005 and .043, respectively), although not at 45 and 60 minutes (P = .08 and .098, respectively). The maximum fall in FEV1 was reduced with montelukast, although these differences were not significant (median, 15% vs 21.2%, P = .065; P = .38 after adjustment for allergen level). FEV1 results were also analyzed with regard to the time it took for subjects reach their maximum fall in FEV1; significant differences were detected in favor of montelukast in the unadjusted analysis (P = .01), although not in the allergenadjusted analysis (P = .08). Median LRSx scores were significantly reduced with montelukast treatment compared with placebo (montelukast range, 0-1.7; montelukast median, 0.5; placebo range, 0-2, placebo median, 1.07; P = .007; Fig 3 and
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FIG 3. Median change in LRSx scores over time. Median scores were 0.4, 0.5, 0.5, and 0.5 with montelukast and 0.87, 1.08, 1.21, and 1.21 with placebo. Statistically significant differences were detected at the 15-, 30-, 45-, and 60-minute time points (P < .05) without adjustment for differences in allergen exposure.
TABLE II. Comparison of challenge outcome measures Montelukast
Challenge length (min) Mean change in FEV1 (%) Maximum change in FEV1 (%) Mean LRSx score Coughs/min Mean URSx score Sneezes/min Maximum change in MCA (%) Fel d 1 (ng/m3)
15 (3-60) 15 (0-51) 15 (0-55) 0.5 (0-1.7) 0.04 (0-0.47) 1.33 (0.33-2.83) 0.13 (0-0.54) 19.7 (0-76) 4487 (1073-16,480)
Placebo
10 (3-45) 21.2 (8-63) 21.2 (5.3-63) 1.07 (0-2) 0.06 (0-1.25) 1.36 (0.67-2.67) 0.33 (0-1.4) 33.2 (0-55) 7764 (1463-89,537)
P value
<.001 .02 .065 .007 .075 .43 .007 .078 .04
Adjusted P value*
.019 .012 .38 .16 .08 .49 .039 .082 NA
Values are given as median (range). NA, Not applicable. *Adjusted for allergen level.
Table II), although this difference was no longer significant after adjusting for allergen levels (P = .16). The median LRSx scores at 15, 30, 45, and 60 minutes were 0.4, 0.5, 0.5, and 0.5 with montelukast and 0.87, 1.08, 1.21, and 1.21 with placebo and were significantly different at all time points (P < .03). The number of coughs per minute ranged from 0 to 0.47 (median, 0.04) with montelukast and from 0 to 1.25 with placebo (median, 0.06), which approached significance (P = .075), with similar differences after adjusting for allergen level (P = .08). Median URSx scores were not significantly different between active and placebo treatment overall (P = .43) or at any specific time point. The median URSx scores at 15, 30, 45, and 60 minutes were 1.25, 1.33, 1.38, and 1.5 with montelukast and 1.33, 1.41, 1.42, and 1.41 with placebo. The number of sneezes per minute ranged from 0 to 0.54 (median, 0.13) with montelukast and from 0 to 1.4 (medi-
an, 0.33) with placebo and were significantly different at 15 minutes (P = .036) and over the whole challenge (P = .007; P = .039 after adjusting for allergen level). The overall change in MCA was reduced with montelukast but did not reach significance (P = .078; adjusted P = .083). At 15, 30, 45, and 60 minutes, changes in MCA were 18.6%, 15.3%, 15.3%, and 11.3% for montelukast and 31.7%, 24.9%, 25.1%, and 25.1% for placebo (P = .058, .21, .20, and .11 at 15, 30, 45, and 60 minutes, respectively). The mean maximum percentage change in MCA ranged from 0% to 76% (median, 17.6%) for those receiving montelukast and from 0% to 55% (median, 33.2%) for those receiving placebo, which was not significantly different (P = .09). Data were also reanalyzed to adjust for baseline FEV1 and for treatment order, which revealed no appreciable differences in the results for any outcome measure.
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Three subjects had mild adverse effects during treatment with montelukast, including dry mouth in one subject, somnolence in another subject, and headache in another subject. Two subjects had mild adverse effects during placebo treatment, with nasal congestion in one subject and nausea for 3 days in another subject. None of these effects caused prolonged harm or discomfort, and all resolved without medical intervention. None of the subjects were withdrawn from the study as a result of adverse events or noncompliance.
DISCUSSION This study, the first to specifically evaluate the efficacy of montelukast on allergic asthma in children, demonstrated that montelukast significantly reduces lower respiratory tract responses to intense cat exposure. Montelukast produced an overall attenuation in FEV1 change, even after adjusting for differences in allergen levels, and allowed these cat-sensitive children to tolerate longer exposures to cat allergen. LRSx scores were significantly different in favor of montelukast, but this effect was no longer evident after adjusting for allergen level. We did not find significant effects on upper respiratory tract responses in terms of symptom scores or changes in nasal anatomy, as measured by means of acoustic rhinometry, aside from a significant difference in the number of sneezes per minute. These findings indicate that montelukast is more helpful for treatment of lower airway responses than upper airway responses after intense allergen exposure. Despite the positive results for lower airway responses, the effects of montelukast might have been underestimated in this study. Allergen levels in the cat room are between 10- and 100-fold higher than those found in typical homes with cats (10-200 ng/m3),15 and it is possible that this intense exposure overwhelmed some of the effects of the drug. Furthermore, many of the subjects were unable to tolerate the challenges for longer than even 15 minutes, and complete data were only available on 3 subjects past 30 minutes. This perhaps explains why we saw a greater effect of montelukast on FEV1 changes during the first half of the challenge. The fact that montelukast showed any significant effect with such intense allergen exposure is encouraging, and it is likely that with lower levels of allergen, the effects would be even more apparent. Further studies at lower antigen levels would therefore be useful. Although there have not been other studies evaluating the effect of montelukast on cat allergen–induced asthma, previous studies have examined the effects of another leukotriene antagonist, zafirlukast, on cat allergen challenge. Findlay et al16 evaluated cat-sensitive adult asthmatic patients and found that zafirlukast was effective in increasing the predicted dose of inhaled cat allergen to induce a 20% decrease in FEV1 by 10-fold. In addition, we have studied adults with cat-induced asthma by using the same cat challenge model with zafirlukast and found significant preservation of pulmonary function and a
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modest benefit in symptom scores.17 Corren et al18 studied 18 adults with cat-induced asthma by using a similar cat challenge model with zafirlukast and found protective effects on LRSx scores and pulmonary function tests but no significant effect on markers of sputum inflammatory cells after sputum induction. With regard to montelukast and allergen-induced asthma, Diamant et al4 evaluated a group of adult dust mite–sensitive asthmatic patients and found that montelukast was effective in attenuating early and late asthmatic responses to inhaled dust mite allergen but did not find a significant difference in allergeninduced changes in sputum eosinophils. Our results for montelukast in children generally agree with the results of these studies and confirm that leukotriene antagonists are effective in attenuating lower airway responses to acute allergen exposure in susceptible subjects. We did not demonstrate any significant benefit with montelukast on upper airway responses. Less is known about the effect of leukotriene antagonists on nasal responses, with previous studies providing somewhat conflicting results. Pullertis et al19 studied 33 grasssensitive adolescents and adults with allergic rhinitis during the grass pollen season and found no significant difference between zafirlukast and placebo in symptoms or numbers of activated eosinophils in nasal tissue. However, Donnelly et al20 did find a significant difference in nasal symptoms among subjects with ragweed-induced rhinitis who received zafirlukast. Our previous study with adults receiving zafirlukast found some reduction in nasal responses, as assessed by acoustic rhinometry, without any effect on symptom scores.17 Similarly, the study by Corren et al18 did not find significant differences in URSx scores but did see some reduction in inflammatory cells in nasal lavage fluid. With regard to montelukast, Meltzer et al21 analyzed a group of adults with tree pollen allergy during the pollen season with montelukast and loratadine and found that monotherapy with either medication did not improve nasal symptom scores over those seen with placebo but that combined therapy did improve symptoms. Because our challenges involved intense allergen exposure and shorter challenges caused by significant lower airway responses, it is not surprising that we did not find a reduction in nasal responses. It is possible that the intense allergen levels overwhelmed the medication’s effect on the nose or that the subject’s acute and often intense lower respiratory tract responses masked the perception of an improvement in URSx scores. The degree of upper respiratory tract obstruction, as measured by means of acoustic rhinometry, did approach significance, and perhaps greater effects on this measure would have been seen with longer challenges. Additional studies with lower allergen levels and subjects with primarily catinduced rhinitis might be useful to better appreciate the effects of montelukast on URSx. In conclusion, the results of this study show that montelukast provides a significant benefit for cat-sensitive children with mild persistent asthma on lower respiratory tract responses after challenges with high levels of cat allergen. It also allowed these children to tolerate the
challenges for longer periods of time. Although the true clinical role of the leukotriene antagonists in allergic asthma is not yet completely clear, this study does provide encouraging information as to their potential benefit. REFERENCES 1. Reiss TF, Chervisnky P, Dockhorn RJ, Shingo S, Seidenberg BC, Edwards TB, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med 1998;11:1232-9. 2. Noonan MJ, Chervinsky P, Brandon M, Zhang J, Kundu S, McBurney J, et al. Montelukast, a potent leukotriene receptor antagonist, causes doserelated improvements in chronic asthma. Eur Respir J 1998;11:1232-9. 3. Knorr B, Mtz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, et al. Montelukast for chronic asthma in 6 to 14 year old children: a randomized double-blind trial. JAMA 1998;279:1181-6. 4. Diamant Z, Grootendorst DC, Veselic-Charvat M, Timmers MC, De Smet M, Leff JA, et al. The effect of montelukast (MK-0476), a cysteinyl leukotriene receptor antagonist, on allergen-induced airway responses and sputum cell counts in asthma. Clin Exp Allergy 1999;29:42-51. 5. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med 1998;339:147-52. 6. Kemp JP, Dockborn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, et al. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6-to 14-year-old children with asthma. J Pediatr 1998;133:424-8. 7. Niemeijer NR, de Monchy JGR. Age-dependency of sensitization to aero-allergens in asthmatics. Allergy 1992;47:431-5. 8. Ingram JM, Sporik R, Rose G, Hosinger R, Chapman MD, Platts-Mills TAE. Quantitative assessment of exposure to dog (Can f 1) and cat (Fel d 1) allergens: relationship to sensitization and asthma among children living in Los Alamos, New Mexico. J Allergy Clin Immunol 1995;96:449-56. 9. Sporik R, Ingram JM, Price W, Sussman JH, Honsinger RW, Platts-Mills TAE. Association of asthma with serum IgE and skin-test reactivity to allergens among children living at high altitude: tickling the dragon’s breath. Am J Respir Crit Care Med 1995;151:1388-92.
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