Effect of ingested H1 antihistamines on methacholine challenge

Effect of ingested H1 antihistamines on methacholine challenge

LETTERS TO THE EDITOR 579 J ALLERGY CLIN IMMUNOL VOLUME 135, NUMBER 2 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. polyps is associated with comorbid ...

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LETTERS TO THE EDITOR 579

J ALLERGY CLIN IMMUNOL VOLUME 135, NUMBER 2

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polyps is associated with comorbid asthma. J Allergy Clin Immunol 2010;126: 962-8, 968.e1-6. Cao PP, Li HB, Wang BF, Wang SB, You XJ, Cui YH, et al. Distinct immunopathologic characteristics of various types of chronic rhinosinusitis in adult Chinese. J Allergy Clin Immunol 2009;124:478-84, 484.e1-2. Kim SJ, Lee KH, Kim SW, Cho JS, Park YK, Shin SY. Changes in histological features of nasal polyps in a Korean population over a 17-year period. Otolaryngol Head Neck Surg 2013;149:431-7. Nakayama T, Yoshikawa M, Asaka D, Okushi T, Matsuwaki Y, Otori N, et al. Mucosal eosinophilia and recurrence of nasal polyps—new classification of chronic rhinosinusitis. Rhinology 2011;49:392-6. Tikaram A, Prepageran N. Asian nasal polyps: a separate entity? Med J Malaysia 2013;68:445-7. Hu Y, Cao PP, Liang GT, Cui YH, Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults. Laryngoscope 2012;122:498-503. Zhang N, Van Zele T, Perez-Novo C, Van Bruaene N, Holtappels G, DeRuyck N, et al. Different types of T-effector cells orchestrate mucosal inflammation in chronic sinus disease. J Allergy Clin Immunol 2008;122:961-8. Katotomichelakis M, Tantilipikorn P, Holtappels G, De Ruyck N, Feng L, Van Zele T, et al. Inflammatory patterns in upper airway disease in the same geographical area may change over time. Am J Rhinol Allergy 2013;27:354-60. Shi LL, Xiong P, Zhang L, Cao PP, Liao B, Lu X, et al. Features of airway remodeling in different types of Chinese chronic rhinosinusitis are associated with inflammation patterns. Allergy 2013;68:101-9. Sakuma Y, Ishitoya J, Komatsu M, Shiono O, Hirama M, Yamashita Y, et al. New clinical diagnostic criteria for eosinophilic chronic rhinosinusitis. Auris Nasus Larynx 2011;38:583-8. Peric A, Vojvodic D, Matkovic-Jozin S. Effect of long-term, low-dose clarithromycin on T helper 2 cytokines, eosinophilic cationic protein and the ‘regulated on activation, normal T cell expressed and secreted’ chemokine in the nasal secretions of patients with nasal polyposis. J Laryngol Otol 2012;126:495-502. Available online October 11, 2014. http://dx.doi.org/10.1016/j.jaci.2014.08.031

Effect of ingested H1 antihistamines on methacholine challenge To the Editor: Current guidelines recommend withholding H1 antihistamines before methacholine challenge.1 There does not appear to be much evidence to support this recommendation. We performed a double-blind random-order study comparing single-dose diphenhydramine, desloratadine, and cetirizine to placebo on the airway response to methacholine. Twelve mild well-controlled atopic asthmatic subjects completed the study. The subjects (7 women) were 29 6 3.8 years old and 66.3 6 1.4 inches tall. All had an FEV1 value of greater than 70% predicted (89% 6 3.1%) and a screening 2minute tidal breathing1 provocation concentration (of methacholine) causing a 20% FEV1 fall (PC20) of less than 16 mg/mL (geometric mean, 2.9 mg/mL). Pregnant and lactating women were excluded. Subjects had no other chronic diseases. Two of the 12 were using low-dose budesonide in stable dose; the remainder used only infrequent as needed albuterol. No subject had any allergen exposure, respiratory infection, or exacerbation for more than 4 weeks. The study was approved by the University of Saskatchewan Biomedical Research Ethics Committee and was registered at clinicaltrials.gov (no. NCT01985789); signed informed consent was obtained. Following screening, subjects attended the laboratory on 4 occasions at the same time of day 7 or more days apart. At each visit, after a 30-minute rest, methacholine PC20 was measured; airflow obstruction was not reversed. Blinded medication was administered (placebo, diphenhydramine 50 mg, desloratadine 5 mg, or cetirizine 10 mg). Two hours later, the methacholine PC20 was measured again. At that point, single prick

skin tests were done with diluent, histamine, and a relevant allergen: The wheal and flare diameter of the allergen and histamine skin test (greater than any diluent response) was measured in 2 perpendicular directions at 15 minutes and the mean value was recorded. Subjects were queried regarding sleepiness at the completion of the day. The primary end point, change in log PC20, as well as mean wheal and flare diameters were analyzed with a 2-way ANOVA (subject, treatment). Drowsiness (yes, no) was assessed using the x2 test applied to a 4 3 2 table. All 12 subjects completed the study without any adverse event. There was no significant difference in FEV1 pretreatment, 2-hour posttreatment, or for the change in FEV1 between pre- and posttreatment. The mean changes in FEV1 were small and ranged from 20.05 to 0.07 L (21.5% to 2%). Methacholine PC20 (n 5 96) values are shown pre- and posttreatments in Fig 1. There was no significant treatment effect (ANOVA; P 5 .29). The mean changes in log PC20 were 0.19 6 0.07, 0.14 6 0.11, 0.11 6 0.07, and 20.006 6 0.08 for placebo, diphenhydramine, cetirizine, and desloratadine, respectively. The histamine wheal diameters were 4.2 6 0.32, 3.0 6 0.39, 2.7 6 0.35, and 3.3 6 0.18 mm (P 5 .018), respectively, for the 4 treatments; wheal diameters for diphenhydramine and cetirizine were significantly smaller than that for placebo. The histamine flare diameters were 20.9 6 2.0, 8.66 6 2.15, 8.05 6 2.33, and 12.9 6 1.87 mm, respectively (P 5 .0007); flare diameters for all active treatments were significantly smaller than that for placebo. The allergen wheal (P 5 .0006) diameter was significantly reduced only by cetirizine and the flare diameter (P 5 .0025) by diphenhydramine and cetirizine. Eight of the 12 subjects reported drowsiness, 5 markedly so, after diphenhydramine compared with 2 after placebo, 2 after desloratadine, and 1 after cetirizine, all mild (x2 5 12.9; P 5 .005). These data demonstrate that pharmacologically active single doses of 3 H1 antihistamines fail to have any effect on the methacholine inhalation test. The largest mean change in PC20, about one-half doubling concentration, occurred after the administration of placebo. Although not significant, this is possibly attributable to the known tendency to develop tolerance to inhaled methacholine, a feature limited to subjects with normal2 and possibly very mild asthma. The inclusion screening PC20 value was 16 mg/mL or less (1 subject had a screening PC20 value of 16.8); however, a few of the subjects had substantially higher PC20 values during the study. Data from our laboratory and from the literature show that with 12 subjects there is greater than 95% power to detect a one-half doubling concentration and a 99% power to detect a minimal clinically significant difference of one doubling concentration in methacholine PC20. H1 antihistamines inhibit airway response to inhaled histamine (as expected) as well as airway response to indirect stimuli3 which is due to histamine and other mediators released from inflammatory cells. The intrinsic H1-blocking effect should not affect methacholine; the concerns regarding H1 blockers and methacholine testing likely relate to their recognized antimuscarinic effects.4 We chose a relatively high dose (double the standard dose) of the first-generation H1-blocker diphenhydramine as a potential positive control. Although this induced both significant drowsiness and significant antihistaminic effect in subjects who underwent the skin tests, there was no effect on airway response to methacholine.

580 LETTERS TO THE EDITOR

J ALLERGY CLIN IMMUNOL FEBRUARY 2015

FIG 1. Methacholine PC20 before (left) and after (right) each treatment. The methacholine PC20 (mg/mL) is on the vertical axis (log scale) and the time points on the horizontal axis.

We were able to identify only a few previous studies addressing this issue. A relatively high single dose of inhaled chlorpheniramine, a first-generation H1 blocker, produced a small (less than one doubling dose) increase in methacholine PC20.5 The clinical significance of these findings is uncertain. In contrast, inhaled clemastine,6 oral terfenadine,7 oral ketotifen,8 and oral cetirizine9 have been shown to have no effect on the methacholine challenge. Antihistamines are frequently used in subjects with atopic disease including those in whom asthma is a potential diagnosis. These data along with other published reports suggest that it is not necessary to withhold these H1 blockers before performing a methacholine challenge. We thank Jacquie Bramley for assisting in the preparation of this article. Donald W. Cockcroft, MD, FRCP(C), FAAAAIa,b Beth E. Davis, PhDa Yeonju Roh, BScb Joe-Ann Lourens, BScb From athe Division of Respirology, Critical Care and Sleep Medicine, Department of Medicine and bthe Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. REFERENCES 1. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, et al. Guidelines for methacholine and exercise challenge testing-1989. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000; 161:309-29. 2. Stevens WH, Manning PJ, Watson RM, O’Byrne PM. Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects. J Appl Physiol (1985) 1990; 69:875-9. 3. Holgate ST, Finnerty JP. Antihistamines in asthma. J Allergy Clin Immunol 1989; 83:537-47. 4. Orzechowski RF, Currie DS, Valancius CA. Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models. Eur J Pharmacol 2005;506:257-64. 5. O’Byrne PM, Thomson NC, Morris M, Roberts RS, Daniel EE, Hargreave FE. The protective effect of inhaled chlorpheniramine and atropine on bronchoconstriction stimulated by airway cooling. Am Rev Respir Dis 1983;128:611-7. 6. Nogrady SG, Bevan C. Inhaled antihistamines—bronchodilatation and effects on histamine- and methacholine-induced bronchoconstriction. Thorax 1978;33: 700-4. 7. Ruffin RE, Latimer KM. Lack of effect of 4 weeks of oral H1 antagonist on bronchial responsiveness. Eur Respir J 1991;4:575-9.

8. Graff-Lonnevig V, Hedlin G. The effect of ketotifen on bronchial hyperreactivity in childhood asthma. J Allergy Clin Immunol 1985;76:59-63. 9. Aubier M, Neukirch C, Peiffer C, Melac M. Effect of cetirizine on bronchial hyperresponsiveness in patients with seasonal allergic rhinitis and asthma. Allergy 2001; 56:35-42. Available online October 24, 2014. http://dx.doi.org/10.1016/j.jaci.2014.09.013

Changes in peanut allergy prevalence in different ethnic groups in 2 time periods To the Editor: Peanut allergy (PA) is one of the most serious of the food hypersensitivities and appears to be increasing in prevalence. The prevalence of PA in industrialized countries, such as the United States and United Kingdom (UK),1 appears to be higher than in the developing world, even among atopic children.2 There is recent evidence of ethnic variations in skin and respiratory allergy3 and that patterns of sensitization to foods differ among ethnic groups within the same geographic population,4 with such sensitization being more common in nonwhite minorities in the United States.5 However, there is also evidence that food allergy in North America is more prevalent in white than nonwhite groups, but the increase in food allergies over a 10-year period (based on hospital discharge diagnoses) was 3-fold higher in nonwhite groups.6 It has also been our impression that the proportion of children given a diagnosis of PA from nonwhite backgrounds has increased in our clinic over the past 15 years. Apart from the observation that Chinese American children appear to have a prevalence of PA similar to that of the general US population,7 relatively little attention has been paid to the ethnicity of those with PA in the context of the diverse populations found in urban Western settings. Data from our recent food allergy work8 indicate that the household peanut consumption of nonwhite families is higher than that of white families, usually as a consequence of traditional dietary patterns. The influence of the recently withdrawn 1998 UK Department of Health guidance for mothers aimed at reducing PA on traditional patterns of peanut consumption in nonwhite families is unknown. The guidance stated, ‘‘Pregnant women who are atopic or have an atopic partner may wish to avoid eating peanuts during pregnancy and lactation, whilst