|Ratio of leukotriene e(4) to exhaled nitric oxide and the therapeutic response in children with exercise-induced bronchoconstriction.|
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|PMID: 23277875 Owner: NLM Status: PubMed-not-MEDLINE|
|PURPOSE: This study assessed the association between the ratio of leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) in the response of children with exercise-induced bronchoconstriction (EIB) enrolled in a therapeutic trial with montelukast or inhaled corticosteroid (fluticasone propionate [FP]).
METHODS: Children aged 6 to 18 years with EIB were randomized in a 4-week, placebo-controlled, double-blinded trial with montelukast or FP. Before and after treatment, treadmill exercise challenges were performed. The LTE(4) levels in the induced sputum and urine and the FE(NO) levels were measured in subjects before and 30 minutes after the exercise challenges. The same tests were conducted after treatment.
RESULTS: A total of 24 patients completed the study: 12 in the montelukast group and 12 in FP group. Both study groups displayed a similar postexercise maximum decrease in forced expiratory volume in one second (FEV1) before treatment as well as after treatment. However, there were significant differences in the magnitude of change between the two (Δ; -18.38±14.53% vs. -4.67±8.12% for the montelukast and FP groups, respectively; P=0.021). The Δ logarithmic sputum baseline and postexercise LTE(4)/FE(NO) ratio were significantly lower in the montelukast group than in the FP group (baseline; -0.09±0.21 vs. -0.024±0.03, P=0.045; postexercise, -0.61±0.33 vs. -0.11±0.28, P=0.023).
CONCLUSIONS: These data indicate that the efficacy of montelukast for preventing a maximum decrease in FEV1 after exercise is significantly higher than that of FP, and the high LTE(4)/FE(NO) ratio is associated with a greater response to montelukast than to FP for EIB therapy. These results suggest that LTE(4) may play an important role in EIB.
|Hey-Sung Baek; Juhwan Cho; Joo-Hwa Kim; Jae-Won Oh; Ha-Baik Lee|
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|Type: Journal Article Date: 2012-10-10|
|Title: Allergy, asthma & immunology research Volume: 5 ISSN: 2092-7355 ISO Abbreviation: Allergy Asthma Immunol Res Publication Date: 2013 Jan|
|Created Date: 2013-01-01 Completed Date: 2013-01-02 Revised Date: 2013-05-30|
Medline Journal Info:
|Nlm Unique ID: 101518382 Medline TA: Allergy Asthma Immunol Res Country: Korea (South)|
|Languages: eng Pagination: 26-33 Citation Subset: -|
|Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Korea.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): Allergy Asthma Immunol Res
Journal ID (iso-abbrev): Allergy Asthma Immunol Res
Journal ID (publisher-id): AAIR
Publisher: The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease
Copyright © 2013 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease
Received Day: 21 Month: 7 Year: 2011
Revision Received Day: 16 Month: 4 Year: 2012
Accepted Day: 16 Month: 5 Year: 2012
Print publication date: Month: 1 Year: 2013
Electronic publication date: Day: 10 Month: 10 Year: 2012
Volume: 5 Issue: 1
First Page: 26 Last Page: 33
PubMed Id: 23277875
|Ratio of Leukotriene E4 to Exhaled Nitric Oxide and the Therapeutic Response in Children With Exercise-Induced Bronchoconstriction|
1Department of Pediatrics, Kangdong Sacred Heart Hospital, Hallym University School of Medicine, Seoul, Korea.
2Department of Biochemistry and Molecular Biology, Hanyang University School of Medicine, Seoul, Korea.
3Department of Pediatrics, Hanyang University School of Medicine, Seoul, Korea.
Correspondence to: Ha-Baik Lee, MD, PhD, Department of Pediatrics, Hanyang University School of Medicine, 17 Haengdang-dong, Seongdong-gu, Seoul 133-792, Korea. Tel: +82-2-2290-8385; Fax: +82-2-2297-2380; firstname.lastname@example.org
Exercise-induced bronchoconstriction (EIB) is associated with vigorous physical exertion in 45%-85% of children with asthma.1 EIB is a highly prevalent but discrete clinical phenotype that shares common features with other measures of indirect bronchial hyperresponsiveness (BHR).2 The presence of EIB as a distinct pathophysiology in children may precede the development of other features of asthma, representing an early stage of the disease.3
Exercise causes asthma attacks due to the loss of water from the surface of the airways by evaporation when inspired air is exposed to conditions inside the body.4 This loss of water increases airway osmolarity, which initiates the activation of epithelial and mast cells and releases inflammatory mediators into the airways, leading to bronchoconstriction.5-8 The pathogenesis of EIB involves the release of cysteinyl leukotrienes (CysLTs), demonstrated by the release of CysLTs into the airways,9,10 an increase in leukotriene E4 (LTE4; a marker of CysLTs production and elimination) in the urine,11 and the inhibition of EIB pharmacologically by drugs that antagonize CysLTs.12
Clinicians currently have two main options for the initiation of pharmacotherapy in children with mild-to-moderate persistent asthma. These include inhaled corticosteroids (ICSs) or leukotriene modifiers such as montelukast. Regular antiasthma treatments with ICSs and leukotriene modifiers alleviate EIB.13-15 Clinical trials have shown that ICSs improve asthma control more effectively in both children and adults than leukotriene modifiers.16 However, there is a subset of patients who appear to respond better to leukotriene modifiers with greater improvement in lung function and asthma control.17-19 Two recent studies suggested that high LTE4 levels relative to fractional exhaled nitric oxide (FENO) were associated with a better response to montelukast compared to ICS therapy in the attenuation of albuterol usage20 and a greater forced expiratory volume in one second (FEV1).19
FENO and urinary LTE4 have been used as noninvasive markers of airway inflammation in children with asthma.21-23 The involvement of CysLT and eosinophilic inflammation can be measured by urinary LTE4 and FENO, respectively. In the present study, we investigated the association between the ratio of LTE4 to FENO and the response of therapeutic trials with montelukast or inhaled corticosteroids (fluticasone propionate [FP]) in asthmatic children with EIB.
Subjects were recruited from outpatient clinics of Hanyang University Hospital and screened with an exercise bronchoprovocation test under an approved study protocol by the Hanyang University Hospital Institutional Review Board. All subjects provided written informed consent. The study participants consisted of 24 children with asthma between the ages of 6 and 18 years. Participants with ≥15% postexercise maximum decrease in FEV1 were enrolled. Asthma was defined as the presence of symptoms, either an increased FEV1≥12% after bronchodilator treatment, or ≤16.0 mg/mL, if inhaled methacholine induced a 20% decrease in FEV1.24 The classification of asthma severity was based on the guidelines of the Global Initiative for Asthma using an algorithm including the medication dose and adherence, FEV1, and the symptom levels.25 Asthma was stable in all asthmatic patients at the time of the study. The exclusion criteria included acute exacerbation of asthma within the previous 6 months and parenchymal lung disease apparent on chest radiography within 4 weeks. Participants were excluded if they had used an ICS, leukotriene modifier, long-acting antihistamine, or long-acting β2-agonist 30 days before the study, and those with an FEV1 below 70% of the predicted values were also disqualified. Skin prick tests (SPTs) for common inhalant and food allergens including Dermatophagoides farinae, D. pteronyssinus, cat dander, dog dander, Alternaria alternata, cow milk, egg white, peanut, wheat, and soybean (Allergopharma, Reinbek, Germany), together with negative (saline) and positive (histamine) controls, were performed. A positive response was defined as a mean wheal diameter equal to or greater than one-half of the positive control. Specific IgE against the same common allergens that were used in the SPTs were measured with the Immuno-CAP system (Phadia AB, Uppsala, Sweden). For this analysis, atopy was defined as the presence of at least one positive allergen-specific IgE test result (IgE≥0.35 kU/L) or SPT finding. The spirometry, methacholine, and exercise challenge tests were performed by a trained technician.
This study was a randomized, double-blind, placebo-controlled trial comparing the effects of FP to those of montelukast in children with EIB. Children were randomized to receive either 5 or 10 mg montelukast (Singulair®; Merck/MSD, Whitehouse Station, NJ, USA) with a fluticasone placebo (from training diskus) or fluticasone (Seretide® diskus; GlaxoSmithKline, London, UK) with a montelukast placebo for a 4-week period. The participants had a total of four visits. Two studies were performed prior to treatment at baseline and 30 minutes after exercise challenge on separate days (4-day interval). Two studies were performed after treatment at baseline and 30 minutes after exercise challenge on separate days (4-day intervals). Blood tests were performed for the measurement of eosinophils, serum IgE, eosinophilic cationic protein (ECP), and cytokines. FENO-induced sputum was used to measure LTE4, cytokines, eosinophils, and ECP. Urine was used to measure LTE4. Samples were collected at baseline and 30 minutes after exercise challenge on separate days during a 4-day characterization period prior to treatment. Children were treated for 4 weeks. Following treatment, blood, FENO-induced sputum, and urine were collected at baseline and 30 minutes after exercise challenge on separate days during a 4-day characterization period following treatment.
Spirometry and methacholine challenges were conducted in accordance with the American Thoracic Society guidelines.24 Spirometry was performed with a Masterlab® spirometer (Jaeger Co., Freiburg, Germany).26 The bronchodilator response was calculated as the percentage change in FEV1 from baseline 15 minutes after inhaling 0.2 mg salbutamol sulfate (Ventolin®; GlaxoSmithKline) via a metered dose inhaler. Methacholine challenges were performed using a modified Chai procedure.26
Exercise challenges were conducted in accordance with the American Thoracic Society guidelines.24 An exercise challenge test was performed by running with the nose clipped on a treadmill (LE 200 CE; Jaeger Co., Hoechberg, Germany) using a standardized protocol. During the test, the heart rate was continuously monitored by a radiographic device (electronic electrocardiogram [ECG] monitor, BCI Autocorr). The ambient temperature in the air-conditioned laboratory was kept constant at 22℃, and the humidity was 40%-50% on each day of the study. The inspired air temperature and humidity were measured. The test began with running at a low speed on the treadmill with a 10% incline. The running speed of the treadmill was increased, raising the heart rate to approximately 85% of the predicted maximum [(220-age)×0.9]. This speed was maintained for a maximum of 6 minutes. Spirometry was conducted 20 and 5 minutes prior to each exercise challenge and repeated 0, 3, 6, 10, 15, and 20 minutes after the end of each exercise event. The better test sample of at least two FEV1 maneuvers within 5% of each other was recorded at each time point. The area under the FEV1-time curve (expressed as the percentage change from baseline values) over a 20-min period after exercise (AUC20)12 was used as an index of the severity of EIB. The AUC20 values were calculated using the trapezoidal rule.
Induced sputum was conducted with 4.5% hypertonic saline administered through an ultrasonic nebulizer (DeVilbiss, Somerset, PA, USA), as previously described.20 In 2-min intervals, the subjects were asked to clear saliva from their mouth and expectorate sputum. The sputum was collected over 12 minutes and pooled into a single sample container. The induced sputum was placed on ice and processed within 30 minutes of collection. Samples were coded with a subject number, visit number, and date. The link between the clinical characteristics of the participants and the coded label was maintained in a separate file by the principal investigator. The total and differential cell counts were performed by an investigator (MWM) who was blinded to the clinical characteristics of each participant. The levels of LTE4, ECP, interleukin (IL)-4, IL-5, IL-8, interferon (IFN)-γ, and IL-17 were determined in the induced sputum supernatants.
The concentrations of IL-4, IL-5, IL-8, IFN-γ, and IL-17 in the induced sputum and blood were determined using the cytokine multiplex assay. Enzyme immunoassay analyses of LTE4 were performed in crude urine samples and induced sputum supernatants using competitive enzyme immunoassays for LTE4 (Cayman Chemical Company, Ann Arbor, MI, USA) as described by O'Sullivan et al.27 The concentration of each sample was determined from a standard curve ranging from 7.8 to 1,000 pg/mL. The precision of the EIA for LTE428 was 17.6%. The urine LTE4 levels were reported in picograms and standardized per milligram of creatinine. Urine creatinine analyses were performed using a colorimetric assay (Sigma-Aldrich, St. Louis, MO, USA).
FENO levels were measured with a portable nitric oxide analyzer (NIOX MINO®; Aerocrine, Solna, Sweden) that provided measurements at a 50 mL/sec exhalation flow rate expressed in ppb.29 Determinations made with the device were within the clinically acceptable range with measurements provided by a stationary analyzer according to the guidelines of the American Thoracic Society.30
Data analysis was conducted using SPSS software (version 16.0; SPSS Inc., Chicago, IL, USA). The variables measured on a continuous scale are summarized as the mean±standard error (SE). To compare mean values, we used parametric Student's t-tests, or nonparametric Mann-Whitney U and Wilcoxon signed-rank tests where needed. The comparisons of categorical variables were evaluated using a chi-square test or Fisher's exact test.
This study included 24 patients, 12 in the montelukast group and 12 in the FP group. Of the 24 subjects with asthma, 8 displayed mild intermittent asthma (4 in the montelukast and 4 in the FP group), 10 had mild persistent asthma (6 in the montelukast and 4 in FP group), and 4 displayed moderate asthma (2 in the montelukast and 2 in the FP group). No significant differences in asthma severity, the mean values of age, sex distribution, the rates of atopy, or prior use of ICSs between the montelukast and FP groups were observed (Table 1). No significant differences were observed in the baseline values of postexercise maximum decrease in FEV1 and PC20 (Table 1). No significant differences in the induced sputum volume (1.46±0.97 mL vs. 1.53±1.05 mL, P=0.185) or the concentration of the lower airway cells in the induced sputum (1.18±0.98×106 cells/mL vs. 1.23±1.17×106 cells/mL, P=0.732) were evident between the two groups. There were no significant differences in the baseline values of the percentage of eosinophils and neutrophils between the montelukast and FP groups (Table 1). No significant differences were observed in the baseline levels of sputum LTE4, urinary LTE4, FENO, or serum and sputum ECP between the groups (Table 1).
No significant changes were observed in the sputum volume and concentration of the lower airway cells in the induced sputum at baseline and after exercise challenge in either group. No significant differences were detected in eosinophils, macrophages, lymphocytes, and neutrophils in the induced sputum between the baseline and post-exercise samples, or between the two groups (data not shown). The sputum LTE4 significantly increased in the airways after exercise challenge in the montelukast group (347.1±323.4 pg/mL vs. 1,109.5±841.1 pg/mL, P=0.027) and in the FP group (452.6±281.9 pg/mL vs. 1,447.5±921.1 pg/mL, P=0.032) compared to those at baseline, while the urinary LTE4 did not. The sputum LTE4/FENO significantly increased in the airways after exercise challenge in the montelukast group (20.59±15.26 vs. 44.53±39.85, P=0.027) and in the FP group (27.37±17.58 vs. 55.73±44.91, P=0.032) compared to those at baseline, while the urinary LTE4/FENO did not (Fig. 1). The baseline levels of ECP and IFN-γ in the serum and sputum did not differ compared to those after exercise challenge. The levels of IL-5, IL-10, and IL-17A in the airways and blood were below the levels of detection in both groups. No further significant differences were observed in the baseline and postexercise levels of sputum LTE4, urinary LTE4, serum and sputum ECP between the two groups (Table 1).
The postexercise maximum decrease in FEV1 and AUC20 decreased significantly following the 4-week treatment in both groups, but were significantly lower in the montelukast group than in the FP group (8.83±7.74% vs. 16.54±7.71%, P=0.024; 232.1±187.9 vs. 374.9±145.0, P=0.035; Table 2 and Fig. 2). There were significant differences in the magnitude of change between the two (Δ; -18.38±14.53% vs. -4.67±8.12% for the montelukast and FP groups, respectively; P=0.021; Fig. 3A). There were also significant differences in the Δ AUC20 between the groups (-21.23±17.53 vs. -3.72±3.81, P=0.028; Fig. 3B).
There were no significant differences in the percentage of eosinophils between treatments in the montelukast group (baseline, 2.11±0.54 vs. 1.34±0.41, P=0.077; postexercise, 2.05±2.59 vs. 2.19±0.82, P=0.643) or the FP group (baseline, 2.11±0.54 vs. 1.34±0.41, P=0.062; postexercise, 2.05±2.59 vs. 2.19±0.82, P=0.647). There were no significant differences in the percentage and concentrations of macrophages, lymphocytes, and neutrophils at baseline and postexercise between treatments (data not shown). A significant decrease in the levels of sputum LTE4 at baseline and postexercise after treatment compared to those before treatment was observed in the montelukast group (baseline, 347.1±323.4 pg/mL vs. 253.2±199.4 pg/mL, P=0.021; postexercise, 1,109.5±841.0 pg/mL vs. 554.5±281.9 pg/mL; P=0.018) and the FP group (baseline, 452.6±281.9 pg/mL vs. 203.1±213.7 pg/mL, P=0.038; postexercise, 1,447.5±921.1 pg/mL vs. 778.6±689.7 pg/mL, P=0.017), but there were no further significant differences in the Δbaseline sputum LTE4 or the Δpostexercise sputum LTE4 between the groups. There were no significant differences in the levels of urine LTE4 at baseline and postexercise after treatment compared to those before treatment in either group. The levels of sputum ECP at baseline and postexercise before treatment significantly decreased following treatment in the montelukast group (baseline, 41.28±38.83 ng/mL vs. 27.91±16.61 ng/mL, P=0.032; postexercise, 78.68±78.46 ng/mL vs. 29.38±21.41 ng/mL, P=0.009) and the FP group (baseline, 86.89±75.23 ng/mL vs. 38.56±24.45 ng/mL, P=0.014; postexercise, 87.16±87.73 ng/mL vs. 48.67±59.23 ng/mL, P=0.047). No significant differences were observed in the Δbaseline sputum ECP or the Δpostexercise sputum ECP between the groups. There were no significant differences in the levels of serum ECP at baseline and postexercise after treatment compared to those before treatment. A significant decrease in the levels of FENO at baseline and postexercise after treatment compared to those before treatment was observed in both the montelukast (baseline, 29.36±21.36 ppb vs. 19.00±9.12 ppb, P=0.037; postexercise, 28.09±24.48 ppb vs. 18.17±11.51 ppb, P=0.023) and FP groups (baseline, 31.58±24.46 ppb vs. 20.25±17.63 ppb, P=0.034; postexercise, 28.67±12.78 ppb vs. 18.50±11.37 ppb, P=0.039). There were no significant differences in the Δbaseline levels of FENO or in the Δpostexercise levels of FENO between the two treatment groups.
There were significant differences in the sputum LTE4/FENO ratio at baseline and postexercise after treatment compared to those before treatment in both the montelukast (baseline, 25.66±23.47 vs. 8.42±8.01, P=0.008; postexercise, 45.72±52.94 vs. 16.63±15.26, P=0.001) (Fig. 1A) and FP groups (baseline, 25.24±17.58 vs. 20.41±17.54, P=0.048; postexercise, 51.10±47.91 vs. 45.79±39.86, P=0.044) (Fig. 1B). There were significant differences in the urine LTE4/FENO ratio at baseline and postexercise between treatments in both the montelukast (baseline, 2.36±2.37 vs. 0.88±0.38, P=0.012; postexercise, 2.53±1.64 vs. 1.04±0.68, Fig. 1C) and FP groups (baseline, 2.23±2.01 vs. 1.60±1.48, P=0.038; postexercise, 2.28±1.75 vs. 1.71±1.39, P=0.043) (Fig. 1D).
The Δ logarithmic sputum baseline and postexercise LTE4/FENO ratio were both significantly lower in the montelukast group compared to those in the FP group (baseline, -0.09±0.21 vs. -0.024±0.03, P=0.045, Fig. 3C; postexercise, -0.61±0.33 vs. -0.11±0.28, P=0.023, Fig. 3D), as were the Δ logarithmic urinary baseline and postexercise LTE4/FENO ratio (baseline, -0.60±0.21 vs. -0.084±0.14, P=0.046, Fig. 3E; postexercise, -0.30±0.25 vs. -0.16±0.16, P=0.038, Fig. 3F).
Comparing the effects of oral montelukast and inhaled FP in patients with EIB, the postexercise maximum decrease in FEV1, and AUC20 were significantly lower in the montelukast group than in the FP group. These results are consistent with a recent study by Stelmach et al.,31 who observed that montelukast, in combination with budesonide or alone, provided the best protection against EIB compared to other therapeutic options. No differences were seen in the degree of EIB protection between the two groups receiving montelukast, suggesting a lack of additional effects of budesonide on EIB protection in combination therapy. Earlier studies reported that montelukast reduced the immediate and late phases of bronchoconstriction.32-34
This study was conducted using induced sputum, which provided a sample from the airways.35 We showed that the levels of sputum LTE4 significantly increased in the airways 30 minutes after exercise challenge in the montelukast and FP groups. The pathogenesis of EIB involves the release of CysLTs as demonstrated by the release of CysLTs into the airways9,10,36 and the pharmacological inhibition of EIB using drugs that antagonize CysLTs.12 Hallstrand et al.10 demonstrated that treatment with CysLT antagonists reduce the severity of EIB and decrease the release of CysLTs into the airways. The overproduction of CysLTs may increase the susceptibility to EIB through various pro-inflammatory mechanisms, as CysLTs mediate airway smooth muscle constriction, mucus release, and increased vascular permeability.37 Increased levels of CysLTs may be detected in the urine after exercise challenge in subjects with EIB,11,38 but this has not been observed in all studies.39 In the present study, the baseline urinary LTE4 displayed no significant differences compared to the post-exercise urinary LTE4.
Although previous reports have associated eosinophilic airway inflammation with the severity of EIB,40 we observed no significant differences in the eosinophils in the induced sputum between the baseline and post-exercise samples, or between the two treatment groups. Inflammation in asthma is usually associated with eosinophilia, whereas isolated EIB in elite athletes seems to be more associated with neutrophilic or mixed-type airway inflammation.41-45 Airway eosinophilia may not be essential for the development of EIB.9
We showed that the Δ sputum and urinary LTE4/FENO ratio were significantly higher in the montelukast group compared to those in the FP group in children with EIB (Fig. 3).
In the montelukast group, a greater improvement in EIB was observed following treatment compared to the FP group. Understanding the pathogenesis of EIB is key to effective treatment. The pathogenesis of EIB involves the release of LTE4.9,10,36 Thus, treatments that block the activity of LTE4 are logically used as effective therapies for controlling EIB.28,46 In addition, FENO might be considered a marker of allergen-driven, local eosinophilic inflammation (readily targeted by ICS therapy). The mechanisms that trigger EIB seem to involve neutrophilic or mixed-type airway inflammation.41-45 This inflammation is not consistently associated with BHR and does not respond to inhaled steroids as is characteristic of asthma.47,48 The results of the present study are similar to those of earlier studies that reported an association between LTE4/FENO ratios and greater FEV1, and that montelukast led to a better asthma control response than ICS therapy.19 Our results are also similar to another recent study on children with moderate-to-severe asthma who predominantly received ICS therapy, which suggested that increased albuterol usage among schoolchildren was associated with high LTE4 levels, relative to FENO, and was attenuated after randomization for treatment with montelukast.20
Due to the small sample size, the results of the present study have several limitations that must be considered when interpreting the data. As this study excluded patients with unstable asthma and subjects with frequent or unstable asthma exacerbations, we cannot specifically state how our findings relate to poor asthma control. Montelukast can provide significant protection against EIB having an onset within 2 hours following a single oral dose,49 whereas ICSs exert a maximum effect after a few months. As children were treated for 4 weeks in this study, we cannot state that improvement in EIB would extend beyond this study period. A greater improvement in EIB and Δ LTE4/FENO ratio were observed in children with asthma treated with montelukast compared to FP. We speculate that LTE4 is a more general indicator of the inflammatory response to exercise, while the allergic-type triggers eosinophilc inflammation and specifically increases the FENO levels.
These data indicate that the LTE4/FENO ratio is associated with a greater response to montelukast than FP for EIB therapy. These results suggest that LTE4 may play an important role in EIB.
There are no financial or other issues that might lead to conflict of interest.
Thies work was supported by the research finding fund of Hanyang University (HY-2010-MC).
|1.||Cabral AL,Conceição GM,Fonseca-Guedes CH,Martins MA. Exercise-induced bronchospasm in children: effects of asthma severityAm J Respir Crit Care MedYear: 19991591819182310351925|
|2.||Joos GF,O'Connor B,Anderson SD,Chung F,Cockcroft DW,Dahlén B,DiMaria G,Foresi A,Hargreave FE,Holgate ST,Inman M,Lötvall J,Magnussen H,Polosa R,Postma DS,Riedler J. ERS Task ForceIndirect airway challengesEur Respir JYear: 2003211050106812797503|
|3.||Jones A. Screening for asthma in childrenBr J Gen PractYear: 1994441791838185993|
|4.||Holgate ST,Lemanske RF Jr,O'Byrne PM,Kakumanu S,Busse WW. Adkinson NF,Yunginger JW,Busse WW,Bochner BS,Holgate ST,Simon FEAsthma pathogenesisMiddleton's allergy: principles and practiceYear: 20097th edPhiladelphiaMosby893|
|5.||O'Sullivan S,Roquet A,Dahlén B,Larsen F,Eklund A,Kumlin M,O'Byrne PM,Dahlén SE. Evidence for mast cell activation during exercise-induced bronchoconstrictionEur Respir JYear: 1998123453509727783|
|6.||Gauvreau GM,Ronnen GM,Watson RM,O'Byrne PM. Exercise-induced bronchoconstriction does not cause eosinophilic airway inflammation or airway hyperresponsiveness in subjects with asthmaAm J Respir Crit Care MedYear: 20001621302130711029335|
|7.||Carroll NG,Mutavdzic S,James AL. Distribution and degranulation of airway mast cells in normal and asthmatic subjectsEur Respir JYear: 20021987988512030728|
|8.||Karjalainen EM,Laitinen A,Sue-Chu M,Altraja A,Bjermer L,Laitinen LA. Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholineAm J Respir Crit Care MedYear: 20001612086209110852791|
|9.||Hallstrand TS,Moody MW,Aitken ML,Henderson WR Jr. Airway immunopathology of asthma with exercise-induced bronchoconstrictionJ Allergy Clin ImmunolYear: 200511658659316159628|
|10.||Hallstrand TS,Moody MW,Wurfel MM,Schwartz LB,Henderson WR Jr,Aitken ML. Inflammatory basis of exercise-induced bronchoconstrictionAm J Respir Crit Care MedYear: 200517267968615947280|
|11.||Reiss TF,Hill JB,Harman E,Zhang J,Tanaka WK,Bronsky E,Guerreiro D,Hendeles L. Increased urinary excretion of LTE4 after exercise and attenuation of exercise-induced bronchospasm by montelukast, a cysteinyl leukotriene receptor antagonistThoraxYear: 199752103010359516894|
|12.||Leff JA,Busse WW,Pearlman D,Bronsky EA,Kemp J,Hendeles L,Dockhorn R,Kundu S,Zhang J,Seidenberg BC,Reiss TF. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstrictionN Engl J MedYear: 19983391471529664090|
|13.||Waalkens HJ,van Essen-Zandvliet EE,Gerritsen J,Duiverman EJ,Kerrebijn KF,Knol K. Dutch CNSLD Study GroupThe effect of an inhaled corticosteroid (budesonide) on exercise-induced asthma in childrenEur Respir JYear: 199366526568519374|
|14.||Freezer NJ,Croasdell H,Doull IJ,Holgate ST. Effect of regular inhaled beclomethasone on exercise and methacholine airway responses in school children with recurrent wheezeEur Respir JYear: 19958148814938575573|
|15.||de Benedictis FM,del Giudice MM,Forenza N,Decimo F,de Benedictis D,Capristo A. Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in childrenEur Respir JYear: 20062829129516641126|
|16.||Busse WW,Lemanske RF Jr. Expert Panel Report 3: Moving forward to improve asthma careJ Allergy Clin ImmunolYear: 20071201012101417983868|
|17.||Szefler SJ,Phillips BR,Martinez FD,Chinchilli VM,Lemanske RF,Strunk RC,Zeiger RS,Larsen G,Spahn JD,Bacharier LB,Bloomberg GR,Guilbert TW,Heldt G,Morgan WJ,Moss MH,Sorkness CA,Taussig LM. Characterization of within-subject responses to fluticasone and montelukast in childhood asthmaJ Allergy Clin ImmunolYear: 200511523324215696076|
|18.||Zeiger RS,Szefler SJ,Phillips BR,Schatz M,Martinez FD,Chinchilli VM,Lemanske RF Jr,Strunk RC,Larsen G,Spahn JD,Bacharier LB,Bloomberg GR,Guilbert TW,Heldt G,Morgan WJ,Moss MH,Sorkness CA,Taussig LM. Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood InstituteResponse profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthmaJ Allergy Clin ImmunolYear: 2006117455216387583|
|19.||Rabinovitch N,Graber NJ,Chinchilli VM,Sorkness CA,Zeiger RS,Strunk RC,Bacharier LB,Martinez FD,Szefler SJ. Childhood Asthma Research and Education Network of the National Heart, Lung, and Blood InstituteUrinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthmaJ Allergy Clin ImmunolYear: 2010126545551.e1-420816189|
|20.||Rabinovitch N,Strand M,Stuhlman K,Gelfand EW. Exposure to tobacco smoke increases leukotriene E4-related albuterol usage and response to montelukastJ Allergy Clin ImmunolYear: 20081211365137118439662|
|21.||Kharitonov SA,Yates D,Robbins RA,Logan-Sinclair R,Shinebourne EA,Barnes PJ. Increased nitric oxide in exhaled air of asthmatic patientsLancetYear: 19943431331357904001|
|22.||Massaro AF,Gaston B,Kita D,Fanta C,Stamler JS,Drazen JM. Expired nitric oxide levels during treatment of acute asthmaAm J Respir Crit Care MedYear: 19951528008037633745|
|23.||Gogate S,Katial R. Pediatric biomarkers in asthma: exhaled nitric oxide, sputum eosinophils and leukotriene E4Curr Opin Allergy Clin ImmunolYear: 2008815415718317025|
|24.||Crapo RO,Casaburi R,Coates AL,Enright PL,Hankinson JL,Irvin CG,MacIntyre NR,McKay RT,Wanger JS,Anderson SD,Cockcroft DW,Fish JE,Sterk PJ. Guidelines for methacholine and exercise challenge testing-1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999Am J Respir Crit Care MedYear: 200016130932910619836|
|25.||Bateman ED,Hurd SS,Barnes PJ,Bousquet J,Drazen JM,FitzGerald M,Gibson P,Ohta K,O'Byrne P,Pedersen SE,Pizzichini E,Sullivan SD,Wenzel SE,Zar HJ. Global strategy for asthma management and prevention: GINA executive summaryEur Respir JYear: 20083114317818166595|
|26.||Chai H,Farr RS,Froehlich LA,Mathison DA,McLean JA,Rosenthal RR,Sheffer AL,Spector SL,Townley RG. Standardization of bronchial inhalation challenge proceduresJ Allergy Clin ImmunolYear: 1975563233271176724|
|27.||O'Sullivan S,Roquet A,Dahlén B,Dahlén S,Kumlin M. Urinary excretion of inflammatory mediators during allergen-induced early and late phase asthmatic reactionsClin Exp AllergyYear: 199828133213399824404|
|28.||Kumlin M,Stensvad F,Larsson L,Dahlén B,Dahlén SE. Validation and application of a new simple strategy for measurements of urinary leukotriene E4 in humansClin Exp AllergyYear: 1995254674797553251|
|29.||Menzies D,Nair A,Lipworth BJ. Portable exhaled nitric oxide measurement: Comparison with the "gold standard" techniqueChestYear: 200713141041417296641|
|30.||American Thoracic SocietyEuropean Respiratory SocietyATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005Am J Respir Crit Care MedYear: 200517191293015817806|
|31.||Stelmach I,Grzelewski T,Majak P,Jerzynska J,Stelmach W,Kuna P. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthmaJ Allergy Clin ImmunolYear: 200812138338917980416|
|32.||Melo RE,Solé D,Naspitz CK. Exercise-induced bronchoconstriction in children: montelukast attenuates the immediate-phase and late-phase responsesJ Allergy Clin ImmunolYear: 200311130130712589349|
|33.||Kim JH,Lee SY,Kim HB,Kim BS,Shim JY,Hong TJ,Hong SJ. Prolonged effect of montelukast in asthmatic children with exercise-induced bronchoconstrictionPediatr PulmonolYear: 20053916216615633203|
|34.||Kemp JP,Dockhorn RJ,Shapiro GG,Nguyen HH,Reiss TF,Seidenberg BC,Knorr B. Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthmaJ PediatrYear: 19981334244289738728|
|35.||Alexis NE,Hu SC,Zeman K,Alter T,Bennett WD. Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery techniqueAm J Respir Crit Care MedYear: 20011641964197011734453|
|36.||Freed AN,Wang Y,McCulloch S,Myers T,Suzuki R. Mucosal injury and eicosanoid kinetics during hyperventilation-induced bronchoconstrictionJ Appl PhysiolYear: 1999871724173310562615|
|37.||Hallstrand TS,Henderson WR Jr. Leukotriene modifiersMed Clin North AmYear: 20028610091033vi12428543|
|38.||Mickleborough TD,Murray RL,Ionescu AA,Lindley MR. Fish oil supplementation reduces severity of exercise-induced bronchoconstriction in elite athletesAm J Respir Crit Care MedYear: 20031681181118912904324|
|39.||Anderson SD,Brannan JD. Exercise-induced asthma: is there still a case for histamine?J Allergy Clin ImmunolYear: 200210977177311994697|
|40.||Yoshikawa T,Shoji S,Fujii T,Kanazawa H,Kudoh S,Hirata K,Yoshikawa J. Severity of exercise-induced bronchoconstriction is related to airway eosinophilic inflammation in patients with asthmaEur Respir JYear: 1998128798849817162|
|41.||Bonsignore MR,Morici G,Riccobono L,Insalaco G,Bonanno A,Profita M,Paternò A,Vassalle C,Mirabella A,Vignola AM. Airway inflammation in nonasthmatic amateur runnersAm J Physiol Lung Cell Mol PhysiolYear: 2001281L668L67611504695|
|42.||Helenius I,Lumme A,Haahtela T. Asthma, airway inflammation and treatment in elite athletesSports MedYear: 20053556557416026170|
|43.||Hermansen CL,Kirchner JT. Identifying exercise-induced bronchospasm. Treatment hinges on distinguishing it from chronic asthmaPostgrad MedYear: 20041151516212515216571|
|44.||Sadeh J,Israel E. Airway narrowing in athletes: a different kettle of fish?Am J Respir Crit Care MedYear: 20031681146114714607821|
|45.||Holzer K,Anderson SD,Douglass J. Exercise in elite summer athletes: Challenges for diagnosisJ Allergy Clin ImmunolYear: 200211037438012209082|
|46.||Oh JW,Lee HB,Kang IJ,Kim SW,Park KS,Kook MH,Kim BS,Baek HS,Kim JH,Kim JK,Lee DJ,Kim KR,Choi YJ. The revised edition of korean calendar for allergenic pollensAllergy Asthma Immunol ResYear: 2012451122211164|
|47.||Ahn SM,Rho HS,Baek HS,Joo YH,Hong YD,Shin SS,Park YH,Park SN. Inhibitory activity of novel kojic acid derivative containing trolox moiety on melanogenesisBioorg Med Chem LettYear: 2011217466746922071299|
|48.||Yoon SH,Cho T,Kim HJ,Kim SY,Ko JH,Baek HS,Lee HJ,Lee CH. IVS6+5G>A found in Wiskott-Aldrich syndrome and X-linked thrombocytopenia in a Korean familyPediatr Blood CancerYear: 20125829729922038941|
|49.||Pearlman DS,van Adelsberg J,Philip G,Tilles SA,Busse W,Hendeles L,Loeys T,Dass SB,Reiss TF. Onset and duration of protection against exercise-induced bronchoconstriction by a single oral dose of montelukastAnn Allergy Asthma ImmunolYear: 2006979810416892789|
Keywords: Exercise-induced bronchoconstriction, fractional exhaled nitric oxide, inhaled corticosteroid, leukotriene E4, montelukast.
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