- Email: [email protected]
Exercise-induced bronchospasm in children and adolescents with allergic rhinitis by treadmill and hyperventilation challenges
Accepted Manuscript Exercise-induced bronchospasm in children and adolescents with allergic rhinitis by treadmill and hyperventilation challenges Edil de Albuquerque Rodrigues Filho, José Ângelo Rizzo, Adriana Velozo Gonçalves, Marco Aurelio de Valois Correia, Jr., Emanuel Sávio Cavalcanti Sarinho, Décio Medeiros PII:
S0954-6111(18)30109-4
DOI:
10.1016/j.rmed.2018.04.001
Reference:
YRMED 5416
To appear in:
Respiratory Medicine
Received Date: 15 December 2017 Revised Date:
18 March 2018
Accepted Date: 1 April 2018
Please cite this article as: Albuquerque Rodrigues Filho Ed, Rizzo JoséÂ, Gonçalves AV, Valois Correia Jr. MAd, Sarinho EmanuelSáCavalcanti, Medeiros Dé, Exercise-induced bronchospasm in children and adolescents with allergic rhinitis by treadmill and hyperventilation challenges, Respiratory Medicine (2018), doi: 10.1016/j.rmed.2018.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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EXERCISE-INDUCED BRONCHOSPASM IN CHILDREN AND ADOLESCENTS WITH ALLERGIC RHINITIS BY TREADMILL AND HYPERVENTILATION CHALLENGES
Edil de Albuquerque Rodrigues Filho a,d
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José Ângelo Rizzo a, b, c,d *
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Adriana Velozo Gonçalves a
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Marco Aurelio de Valois Correia Jr a,c,d
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Emanuel Sávio Cavalcanti Sarinho a,c,d
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Décio Medeiros a,c,d
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b
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Health Sciences Postgraduate Course, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil Pneumology Department, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil
Center for Research in Allergy and Clinical Immunology, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil
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Child and Adolescent Health Postgraduate Course, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
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Running Title: EIB in young people with allergic rhinitis
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Keywords: Exercise-induced bronchospasm, bronchial provocation, allergic rhinitis, asthma, physical activity.
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* Author for correspondence
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José Ângelo Rizzo. Rua de apipucos 235/1901. Apipucos. City – Recife State – Pernambuco. Brazil. Zip code 52071-000 Fone 55 81 986994098 Fax – 55 81 21263819 Email - [email protected]
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Word count- Abstract : 245; Main Text: 3060
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Number of tables: 3
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Number of figures: 1
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INTRODUCTION
2 Respiratory symptoms during or after physical exercise are commonly reported
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by children and adolescents, more frequently in individuals with asthma, but also in
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those with rhinitis alone and even in some with neither condition1. In those with rhinitis
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but without asthma, these complaints are reported by 22% to 50%1,2. These symptoms
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may have a negative impact on engagement in physical activity and quality of life in
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these individuals1,3.
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One of the most widely studied causes of these complaints is exercise-induced
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bronchospasm (EIB), characterized by an acute transitory bronchial constriction during
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or shortly after vigorous physical activity4,5. Prevalence varies from 50 to 90% in
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asthmatic individuals6,7 and from zero to 47% in those with rhinitis but no symptoms of
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asthma8-11. This wide difference is probably a consequence of lack of uniformity in
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diagnostic methods and criteria employed.
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Airway inflammation and epithelial injury form the immunological basis for EIB
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in susceptible individuals, in whom hyperventilation during vigorous exercise induces
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mechanical, thermal and osmotic changes, with epithelial cells shedding and releasing
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inflammatory bronchoconstrictive mediators such as cysteinyl leukotrienes (CysLTs),
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prostaglandin D2, histamine and eosinophil cationic protein from airway mast cells and
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eosinophils. The relative reduction in the bronchoprotective prostaglandin E2 found in
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these individuals may also play a role in the pathogenesis of EIB. Sensorial nerve
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endings activated by the CysLTs and osmotic stimulus release tachykinins that also lead
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to bronchoconstriction and mucus release. Temperature and humidity, as well as
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allergens and pollutants in breathed air may substantially influence susceptibility to
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EIB, especially in athletes performing in dry/cold environments or in a noxious air
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environment (pool chlorine, fossil fuel air pollution)5,12.
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Respiratory complaints alone do not provide accurate diagnosis of EIB and
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objective tests are required for its correct recognition5. A series of evaluations of forced
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expiratory volume in the first second (FEV1) before and after treadmill running (TR) is
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the most commonly used diagnostic method4. The test is considered positive when there
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is a reduction > 10% in FEV1 after exercise compared to the baseline4,5.
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The eucapnic voluntary hyperventilation (EVH) challenge is an alternative
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method that enables better control of ventilation rates and ease of execution, since it
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dispenses with the need for physical effort as the trigger challenge5. It has the same
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physiopathological pathway for EIB as TR, namely the dehydration effect on the
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bronchial mucosa5. In this method, the patient hyperventilates breathing dry air enriched
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with 5% CO2 (to avoid respiratory alkalosis) at a rate greater than or equal to 60% of
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maximum voluntary ventilation (MVV)5. Respiratory complaints are frequent in young people with allergic rhinitis and EIB
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is a preventable but often unrecognized cause1,2. Previous studies report discrepant
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results regarding objectively diagnosed EIB prevalence in this population8-11. EVH
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could be an alternative and easier method for EIB diagnosis5 but it was not possible to
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find studies comparing this with the most commonly recommended treadmill running
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method in this population. The present study thus aimed to evaluate the prevalence of
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EIB in children and adolescents with allergic rhinitis, to examine its association with
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patients’ reported respiratory symptoms after physical activity and to compare the
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treadmill running and eucapnic voluntary hyperventilation challenge methods for
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diagnosis and measurement of the intensity of EIB.
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METHODS
A cross-sectional study was carried out at the pulmonary function testing
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laboratory of the Pulmonology Service of the Federal University of Pernambuco’s
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Hospital das Clínicas – Recife, Brazil. The study was approved by the institution’s
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Ethics Committee. All parents or guardians signed terms of informed consent and the
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adolescents signed terms of assent as requested by the Brazilian regulatory agency.
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- Study Population
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The sample included children and adolescents with a clinical diagnosis of
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allergic rhinitis, of both sexes, aged between 10 and 20 years seen for the first time at
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the hospital’s Allergy and Immunology outpatients unit between January and October
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2015 and not using regular medication.
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Excluded individuals were those who specifically reported asthma symptoms in
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the past 12 months (dyspnea, chest tightness or episodes of wheezing), those with
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respiratory infection in the previous six weeks, those with FEV1 lower than 60% of the
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predicted value5, those incapable of carrying out the spirometry or hyperventilation
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maneuvers and those unable to run on the treadmill for the time required by the
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protocol. Patients declared they had not used any kind of medication for rhinitis in the
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past four weeks. Rhinitis was classified according to the frequency and intensity of symptoms, using
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the ARIA criteria13 according to which ‘intermittent’ means that symptoms are present
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for less than 4 days a week or for less than 4 consecutive weeks and persistent
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symptoms are those that occur for more than 4 days a week and for more than 4
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consecutive weeks. Mild symptoms are those that do not disturb sleep, daily activities,
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school or work and that, although present, are not troublesome. Moderate/severe
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symptoms are those that cause some impairment of sleep, daily activities, school or
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work and are perceived as troublesome by patients.
All patients had a positive prick test for at least one of the mite aeroallergens tested (D. pteronyssinus, B. tropicalis)
and some also for the other tested allergens (A.
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alternata, A. fumigatus, dog and cat dander).
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- Procedures
Data were gathered on patients’ age, weight, height, and gender. The
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temperature and humidity of the ambient air were measured using a digital
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thermohygrometer (Incoterm, Porto Alegre, Brazil). Before any other procedure was
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carried out, the patients answered a question regarding their perception of respiratory
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symptoms after physical activity: have you noticed wheezing, shortness of breath,
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coughing, or tightness of the chest after exercise at any time in the last 12 months?14.
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The baseline FEV1 was determined using a spirometer (microQuark –
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COSMED, Rome, Italy) in accordance with international protocols15. It was
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subsequently measured in duplicate three, five, seven, 10, 15 and 30 minutes after
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treadmill running or after EVH. On each occasion, the highest value obtained was
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chosen4, 5.
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The two techniques (TR and EVH) were carried out with a minimum interval of
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24 hours and a maximum of 72 hours. Participants were randomly assigned in blocks of
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four to determine which test would be carried out first.
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The TR test lasted eight to nine minutes (ProAction BH Fitness treadmill –
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Vitoria, Spain). In the first two minutes, treadmill velocity was increased gradually for
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adaptation and to reach the target heart rate (HR) (between 80% and 90% of maximum;
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220-age) to be maintained for the final six minutes5,15 (Polar model RS300X - Kempele,
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Finland). Patients’ ventilation rate during TR was not measured.
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and 5% carbon dioxide (CO2) (White-Martins, Recife, PE - Brazil) collected in a
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Douglas balloon, through the mouth with nose clipped, using a one-way low-resistance
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valve (Laerdal, Copenhagen - Denmark). The test lasted six minutes and the target
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ventilation per minute was 21 times that of the baseline FEV1 for each individual5. The
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ventilation rate per minute was monitored using an analogic ventilometer (Wright Mark
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8 NSPIRE Health, Colorado - USA).
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The speed of the treadmill was adjusted by the examiner to maintain the target
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heart rate and, in the EVH test, the examiner encouraged the patients to maintain the
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target ventilation rate every 30 seconds. EIB was diagnosed when there was a > 10%
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reduction in FEV1 from the baseline at two consecutive evaluation points after the
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challenge (TR or EVH)5,6.
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Statistical Analysis
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The Shapiro Wilk test was applied and all continuous data showed a normal
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distribution. Categorical variables were compared using Fisher’s Exact Test and
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continuous variables using Student’s t test for paired samples. Multivariate analysis of
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variance (MANOVA) was used to compare the reduction in FEV1 from the baseline in
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EIB positive and negative groups at the time points between the challenge tests.
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Cohen’s kappa was used to assess the proportion of agreement and the positive and
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negative proportional agreement between challenge methods were calculated. The
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adopted probability of alpha error was 5%. The data were processed and analyzed using
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the GraphPad Instat program (GraphPad Inc., San Diego, USA, Release 3:06, 2003) and
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the Statistical Package for the Social Sciences (SPSS) for Windows version 16.
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RESULTS
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Eighty individuals were selected and 40 were excluded (30 for reporting
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symptoms of asthma in the past year, 8 owing to symptoms of acute respiratory
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infection in the six weeks prior to the test and 7 for having a baseline FEV1 < 60% of
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the predicted value). Of the 40 patients who underwent the first test, five were lost to
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follow-up for not attending the second day of the test within the stipulated timeframe
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(three after TR and two after EVH). Thirty-five individuals concluded the study and
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their data are presented in Table 1.
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EIB was diagnosed in 13 individuals (37%), by both methods in six (17%) and
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by only one in seven (20%) (three by treadmill running and four by EVH – kappa 0.486
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- Table 2). Figure 1 shows the means for maximum reduction in FEV1 at each evaluation
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point by the two methods in patients with and without EIB. There were no differences
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in FEV1 reduction from the baseline between the two challenge tests at any time, either
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among EIB positive [(F=2.33; p=0.13), times (F=1.59; p=0.17) and interaction (F=1.18;
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p=0.97)] or among EIB negative individuals [(tests, F=0.01, p=0.93; times, F=0.46,
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p=0.81; and interaction F=0.19, p=0.96) - MANOVA]. In only three individuals was
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there a reduction in FEV1 greater than or equal to 30% in relation to the baseline; one
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patient in both tests (30% after TR and 32% after EVH) and two in different tests (TR =
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45% and EVH = 35%).
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No differences were found in baseline FEV1 values as a percentage of predicted
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on either day of the test (TR: 97.1% + 14.8% vs. EVH: 96.6% + 14.4%, p=0.66,
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respectively). Comparison of individuals with and without EIB for each method showed
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that baseline FEV1 was lower for those testing positive (Table 3). This table also shows
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that no differences were found in maximum heart rate achieved between patients with
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and without EIB on TR, nor in the mean EVH respiratory minute volume. All
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individuals reached the target heart rate (>80% of maximum calculated heart rate: 220 –
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age). In the case of eucapnic voluntary hyperventilation, 29 individuals (83%) reached
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or surpassed 90% of the calculated target ventilation (21 times baseline FEV1) and six
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reached between 80% and 89%. In the latter group, four presented EIB and two did not.
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There was no association between EIB diagnosed by either or both methods and
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the severity of rhinitis, history of asthma symptoms or complaints of respiratory
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symptoms after exercise (Table 3).
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There was no significant difference in mean temperature and relative humidity
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of the air between the two days of the test (22.5 + 1.4 Cº and 56.9% + 4.4%
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respectively).
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In the case of patients in whom bronchoconstriction persisted until the thirtieth
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minute (four after EVH and four after TR), 400mcg of inhaled albuterol were
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administered. On no occasion was there a need for the sequence of tests to be
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interrupted.
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DISCUSSION
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treadmill running challenge with that using eucapnic voluntary hyperventilation in
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young people with allergic rhinitis found a prevalence of 37% (13/35) when both
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methods were considered – six by both methods, three by treadmill running alone and
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four by eucapnic voluntary hyperventilation alone. There was moderate agreement
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between the two methods (Cohen’s Kappa = 0.486). No associations were found
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between the presence of EIB and respiratory complaints on exercise, the severity of
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symptoms of rhinitis, or a past (> 1 year) history of asthma.
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The results for prevalence of EIB in patients with allergic rhinitis using treadmill
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running alone (25.7%) are similar to those found by Rakkhong et al.2 and Valdesoiro et
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al.9, who found a prevalence of 20.7% and 24% respectively in a similar group of
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individuals, but differ from those of Custovic et al.8, who used free running as a
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challenge and found no positive responses for EIB in any of the 17 children with rhinitis
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investigated. These differences are probably due to the number of individuals studied
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and the methodology used in the last study.
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Caillaud et al.11, in an epidemiological study in France, tested 902
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schoolchildren with symptoms of rhinitis in the previous year using free running and
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peak expiratory flow and found a mean EIB prevalence of 7%. Different from the
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present study, in which the patients were not taking medication for rhinitis, the French
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study patients were using a nasal corticoid11, which may influence the bronchial
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reactivity of these individuals16. Another striking feature of this French study is the low
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prevalence (10%) of EIB in patients with asthma, indicating the low sensitivity of the
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diagnostic method employed. These differences in prevalence indicate the need to use
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standardized methodologies for challenge tests to evaluate EIB.
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The only study found in the literature that examined EVH in patients with
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rhinitis but no symptoms of asthma aimed to investigate the association between EIB
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and respiratory symptoms in elite athletes and also included symptomless asthmatic
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individuals. However, the results are not presented separately and it is not possible to
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calculate the prevalence of EIB using this method in patients with rhinitis alone17.
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An overall agreement of 80% between the two methods was found, although
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with a modest kappa index (0.486), which may be explained by the proportional
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negative agreement between the tests (86% - Table 1)18. The two tests were both
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positive in only six individuals; in the others, EIB was diagnosed by TR alone in three
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and by EVH alone in four. Similar results have been found in adolescents with asthma
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when comparing the two challenge methods7. This discrepancy may be explained by the
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intrinsic variability of each method when tests are repeated in the same subject within a
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short time period19,20. In concordance with the data in the literature, no association was found between
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clinical complaints of respiratory symptoms and diagnosis of EIB14,2. Neither was there
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any association between EIB and the severity of symptoms of rhinitis (Table 3). In the
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case of the latter, our results differ from those of Rakkhong et al.2 that found a higher
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EIB prevalence in individuals with persistent symptoms. However, there was an
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association with lower baseline FEV1 rate, expressed as a percentage of the expected,
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and EIB prevalence (Table 3). Such an association has also been found in previous
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studies of asthmatics7,21 and patients with rhinitis alone22. This is probably associated
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with a higher degree of inflammation and hence bronchial hyperresponsiveness23.
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Three individuals had baseline FEV1 values between 60% and 80% of predicted,
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two without and one with a history of asthma symptoms one year before the study. All
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three had EIB diagnosed by both methods. Low lung function detected in some
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adolescents without current asthma symptoms may be a consequence of wheezing
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phenotypes in early childhood24 and may be associated with other concomitant factors,
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such as maternal asthma or smoking during pregnancy and atopic sensitization or
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respiratory viral infections after birth25. This was not investigated in these three patients.
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In patients with rhinitis, the presence of bronchial hyperreactivity and EIB
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indicate increased likelihood of developing asthma in the future26-28, which means that
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the tests used for this diagnosis — including EVH — may also be important for
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prognosis and recommendation of preventive measures.
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a past history of symptoms of asthma (more than one year). Baseline FEV1 values were
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no different from those measured in individuals without a history of asthma (p = 0.79),
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neither were there differences in the proportion of individuals with EIB, when
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comparing both groups (5/15 and 8/20 respectively; Chi-square p=0.686). Asthma and
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rhinitis often coexist in the same youngsters. In many, the asthma fades away leaving
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only rhinitis symptoms13 and it was deemed more representative of the real world not to
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exclude these individuals. Another limitation is the recall bias of patients answering the
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question about respiratory symptoms after exercise in the past 12 months.
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As we chose to analyze the results as categorical variables (EIB positive or
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negative), we did not adopt the Bland-Altman method for evaluating limits of
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agreement between the challenges, although we found no differences in the magnitude
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of FEV1 reduction from the baseline between the challenge tests at any evaluation time,
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either among EIB positive or EIB negative individuals (Figure 1). The tests were carried out in an air-conditioned laboratory, which enabled
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uniformity of temperature and humidity of the air breathed during the treadmill running
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test. There was no difference in heart rate during TR or ventilation rate on EVH
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between patients testing positive and those testing negative (Table 3). All theese factors
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may interfere with EIB diagnosis5,11,29, 30.
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It is worth pointing out that the present study followed the guidelines laid out by
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Weiler et al.6, which only considered the test to be positive if a reduction of FEV1 >
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10% from the baseline was observed on at least two consecutive measurements. Had a
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reduction in FEV1 in only one measurement been considered, the prevalence would
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have increased to 51% when both tests are included. Although this would increase
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diagnostic sensitivity, it would not substantially alter agreement (kappa = 0.440).
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The EVH test proved to be safe and easy to apply. No patient failed to execute
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the hyperventilation maneuver appropriately and all easily reached the established
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ventilation rates. No individual experienced symptoms of severe dyspnea or a severe
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reduction in FEV1 (>50%)5, which would have required suspension of the test. This has
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also been reported by other authors29.
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The data of the present study suggest that the results of both methods should be
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interpreted with caution when the intention is to compare them or even to consider them
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interchangeably. As there is no the gold standard method for diagnosis of EIB 29 and, on
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the basis of the present study and other studies of the diagnostic accuracy of EVH 31 and
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TR tests20, we can agree with Price et al.19 that a negative test on only one occasion is
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not sufficient to rule out diagnosis of EIB, especially in individuals with complaints that
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interfere with their physical activities. Furthermore, it should be emphasized that
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objective methods should be employed for EIB diagnosis32 and that the EVH test may
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be a safe and easy to execute alternative for this purpose.
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Acknowledgements
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We are thankful to Mr. Peter Ratcliffe for language revision.
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20. Anderson SD, Pearlman DS, Rundell KW, Perry CP, Boushey H, Sorkness CA, et
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al. Reproducibility of the airway response to an exercise protocol standardized for
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intensity, duration, and inspired air conditions, in subjects with symptoms suggestive of
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asthma. Respiratory Research 2010; 1: 110 – 120.
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21. Cabral AL, Conceição GM, Fonseca-Guedes CH, Martins MA. Exercise induced
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bronchospasm in children: effects of asthma severity. Am J Respir Crit Care Med 1999;
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159(6):1819 – 23.
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ACCEPTED MANUSCRIPT 22. Kim SW, Han DH, Lee SJ, Lee CH, Rhee CS. Bronchial hyperresponsiveness in
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pediatric rhinitis patients: the difference between allergic and nonallergic rhinitis. Am J
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Rhinol Allergy 2013; 27(3):63 – 8.
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23. Braunstahl GJ, Fokkens WJ, Overbeek SE, KleinJan A, Hoogsteden HC, Prins JB.
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Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a
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comparison between upper and lower airways. Clin Exp Allergy 2003; 33(5):579 – 87.
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24. Lodge CJ, Lowe AJ, Allen KJ, Zaloumis S, Gurrin LC, Matheson MC, et al.
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Childhood wheeze phenotypes show less than expected growth in FEV1 across
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adolescence. Am J Respir Crit Care Med. 2014;89(11):1351-8.
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25. Turner S, Fielding S, Mullane D, Cox DW, Goldblatt J, Landau L, le Souef P. A
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longitudinal study of lung function from 1 month to 18 years of age. Thorax. 2014;
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69(11):1015-20.
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26. Townley RG, Ryo UY, Kolotkin BM, Kang B. Bronchial sensitivity to
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methacholine in current and former asthmatic and allergic rhinitis patients and control
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subjects. J Allergy Clin Immunol 1975; 56(6):429 – 442.
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27. Porsbjerg C, Von Linstow ML, Ulrik CS, Nepper-Christensen SC, Backer V.
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Outcome in adulthood of asymptomatic airway hyperresponsiveness to histamine and
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exercise-induced bronchospasm in childhood. Ann Allergy Asthma Immunol 2005;
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95(2):137 – 42.
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28. Cirillo I, Vizzaccaro A, Tosca MA, Negrini S, Negrini AC, Marseglia G, et al.
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Bronchial hyperreactivity and spirometric impairment in patients with allergic rhinitis.
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Monaldi Arch Chest Dis 2005; 63(2):79 – 83.
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29. Brummel NE, Mastronarde JG, Rittinger D, et al. The clinical utility of eucapnic
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voluntary hyperventilation testing for the diagnosis of exercise-induced bronchospasm.
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J Asthma. 2009;46(7):683–6.
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30. Parsons JP, Cosmar D, Phillips G, Kaeding C, Best TM, Mastronarde JG. Screening
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for exercise-induced bronchoconstriction in college athletes. J Asthma 2012;49(2):153-
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7.
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31. Stickland MK, Rowe BH, Spooner CH, Vandermeer B, Dryden DM. Accuracy of
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eucapnic hyperpnea or mannitol to diagnose exercise-induced bronchoconstriction: a
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systematic review. Ann Allergy Asthma Immunol 2011;107(3):229 – 34.
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32. Sánchez-García S, Rodríguez del Río P, Escudero C, García-Fernández C, Ibáñez
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MD. Exercise-induced bronchospasm diagnosis in children. Utility of combined lung
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function tests. Pediatr Allergy Immunol. 2015;26(1):73-9.
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ACCEPTED MANUSCRIPT 369 Table 1. General Patient Data. RESULTS (n = 35)
GENDER: Male/Female
22/13
AGE (Mean in years, percentile 25-75)
16.3, 13-20
WEIGHT (Mean + SD in kg)
58.5 + 15.9
HEIGHT (Mean + SD in m)
1.60 + 0.12
BMI* (Mean + SD in kg/m2)
22.5 + 4.5
Initial Test: TR or EVH**
18/17
FEV1*** baseline at l/sec (Mean + SD)
3.12 + 0.85
FEV1 baseline (Mean + SD of % predicted)
91.2 + 14.5
Asthma in past****
15 (43%)
Respiratory symptoms after exercise
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PARAMETERS
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Classification of rhinitis (intermittent/persistent)
20 (57%) 20/15
* BMI = Body Mass Index, ** TR = treadmill running, **EVH = eucapnic voluntary
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hyperventilation, ** Forced expiratory volume in the first second **** Reported
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compatible symptoms occurring more than one year previously.
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Table 2. Results obtained for both challenges. EVH
Negative
Total
Positive
6
3
9
Negative
4
22
26
Total
10
25
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Kappa
0.486
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EVH = Eucapnic voluntary hyperventilation. TR = Treadmill running. Positive = Reduction in FEV1 > 10% in relation to baseline at two points in the evaluation. Negative = Reduction in FEV1 < 10% in relation to baseline or > 10% on only one occasion. General agreement = 80%. Proportional positive agreement = 63%; Proportional negative agreement = 86%.
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Positive
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ACCEPTED MANUSCRIPT Table 3. Comparison of individuals with and without EIB for each challenge method Treadmill Running
Eucapnic Voluntary Hyperventilation
Positive (9)
Negative (26)
p
Positive (10)
Negative (25)
p
FEV1 baseline (% of predicted) Mean SD 95% CI
85% 16.2% 72%-97%
101% 11.7% 97%-106%
0.02*
85% 15.7 79%-92%
101% 11.2% 97%-106%
0.001*
HR¥ reached (% of maximum predicted: 220-age) Mean SD 95% CI
85% 3.8% 82%-88%
87% 4.3% 85%-89%
0.16*
-
-
V¥¥ achieved (% calculated: 21 times baseline FEV1) Mean SD 95% CI
-
-
4(44%) 6/3
Rhinitis severity (intermittent/persistent)
5(55%)
Respiratory complaints on exercise (%)
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99% 11.1% 94%-104%
101% 10.7% 97%- 105%
0.64*
11(42%)
1,0**
4(40%)
11(44%)
1.0**
14/12
0,7**
6/4
14/11
1.0**
15(58%)
1,00**
7(70%)
13(52%)
0.46**
*Student’s t test, ** Fisher’s exact test, ¥HR = Heart rate, ¥¥V = Ventilation rate. SD =
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Standard deviation. 95%CI = 95% confidence interval.
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' 30
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Time of measurement ( minutes after challenge)
Figure 1. Mean (+ SEM) variation in FEV1 as a percentage of the baseline at each evaluation point in individuals with and without exercise induced bronchospasm (EIB+, EIB-) after the challenge tests. There were no differences between tests in the EIB+ group (p=0.13), nor in the EIB- group (p=0.93), (MANOVA).
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FEV1 reduction (as % of basal value)
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*TR+ = treadmill running in individuals with EIB. TR- = treadmill running in individuals without EIB. EVH+ = eucapnic voluntary hyperventilation in individuals with EIB. EVH- = eucapnic voluntary hyperventilation in individuals without EIB. SEM = Standard error of the mean.
ACCEPTED MANUSCRIPT Highlights
Respiratory symptoms after exercise were reported by 57% of studied rhinitis patients These symptoms may limit a subject’s ability to be physically active We found no association between exercise-related respiratory complaints and EIB
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Eucapnic voluntary hyperventilation may be a safe challenge method for EIB diagnosis
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A negative challenge test on only one occasion may be insufficient to rule out EIB
S0954-6111(18)30109-4
DOI:
10.1016/j.rmed.2018.04.001
Reference:
YRMED 5416
To appear in:
Respiratory Medicine
Received Date: 15 December 2017 Revised Date:
18 March 2018
Accepted Date: 1 April 2018
Please cite this article as: Albuquerque Rodrigues Filho Ed, Rizzo JoséÂ, Gonçalves AV, Valois Correia Jr. MAd, Sarinho EmanuelSáCavalcanti, Medeiros Dé, Exercise-induced bronchospasm in children and adolescents with allergic rhinitis by treadmill and hyperventilation challenges, Respiratory Medicine (2018), doi: 10.1016/j.rmed.2018.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 2 3
EXERCISE-INDUCED BRONCHOSPASM IN CHILDREN AND ADOLESCENTS WITH ALLERGIC RHINITIS BY TREADMILL AND HYPERVENTILATION CHALLENGES
Edil de Albuquerque Rodrigues Filho a,d
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José Ângelo Rizzo a, b, c,d *
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Adriana Velozo Gonçalves a
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Marco Aurelio de Valois Correia Jr a,c,d
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Emanuel Sávio Cavalcanti Sarinho a,c,d
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Décio Medeiros a,c,d
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b
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c
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Health Sciences Postgraduate Course, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil Pneumology Department, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil
Center for Research in Allergy and Clinical Immunology, Clinical Hospital, Federal University of Pernambuco, Recife, Brazil
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Child and Adolescent Health Postgraduate Course, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil
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Running Title: EIB in young people with allergic rhinitis
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Keywords: Exercise-induced bronchospasm, bronchial provocation, allergic rhinitis, asthma, physical activity.
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* Author for correspondence
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José Ângelo Rizzo. Rua de apipucos 235/1901. Apipucos. City – Recife State – Pernambuco. Brazil. Zip code 52071-000 Fone 55 81 986994098 Fax – 55 81 21263819 Email - [email protected]
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Word count- Abstract : 245; Main Text: 3060
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Number of tables: 3
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Number of figures: 1
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INTRODUCTION
2 Respiratory symptoms during or after physical exercise are commonly reported
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by children and adolescents, more frequently in individuals with asthma, but also in
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those with rhinitis alone and even in some with neither condition1. In those with rhinitis
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but without asthma, these complaints are reported by 22% to 50%1,2. These symptoms
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may have a negative impact on engagement in physical activity and quality of life in
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these individuals1,3.
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One of the most widely studied causes of these complaints is exercise-induced
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bronchospasm (EIB), characterized by an acute transitory bronchial constriction during
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or shortly after vigorous physical activity4,5. Prevalence varies from 50 to 90% in
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asthmatic individuals6,7 and from zero to 47% in those with rhinitis but no symptoms of
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asthma8-11. This wide difference is probably a consequence of lack of uniformity in
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diagnostic methods and criteria employed.
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Airway inflammation and epithelial injury form the immunological basis for EIB
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in susceptible individuals, in whom hyperventilation during vigorous exercise induces
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mechanical, thermal and osmotic changes, with epithelial cells shedding and releasing
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inflammatory bronchoconstrictive mediators such as cysteinyl leukotrienes (CysLTs),
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prostaglandin D2, histamine and eosinophil cationic protein from airway mast cells and
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eosinophils. The relative reduction in the bronchoprotective prostaglandin E2 found in
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these individuals may also play a role in the pathogenesis of EIB. Sensorial nerve
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endings activated by the CysLTs and osmotic stimulus release tachykinins that also lead
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to bronchoconstriction and mucus release. Temperature and humidity, as well as
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allergens and pollutants in breathed air may substantially influence susceptibility to
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EIB, especially in athletes performing in dry/cold environments or in a noxious air
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environment (pool chlorine, fossil fuel air pollution)5,12.
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Respiratory complaints alone do not provide accurate diagnosis of EIB and
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objective tests are required for its correct recognition5. A series of evaluations of forced
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expiratory volume in the first second (FEV1) before and after treadmill running (TR) is
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the most commonly used diagnostic method4. The test is considered positive when there
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is a reduction > 10% in FEV1 after exercise compared to the baseline4,5.
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The eucapnic voluntary hyperventilation (EVH) challenge is an alternative
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method that enables better control of ventilation rates and ease of execution, since it
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dispenses with the need for physical effort as the trigger challenge5. It has the same
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physiopathological pathway for EIB as TR, namely the dehydration effect on the
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bronchial mucosa5. In this method, the patient hyperventilates breathing dry air enriched
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with 5% CO2 (to avoid respiratory alkalosis) at a rate greater than or equal to 60% of
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maximum voluntary ventilation (MVV)5. Respiratory complaints are frequent in young people with allergic rhinitis and EIB
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is a preventable but often unrecognized cause1,2. Previous studies report discrepant
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results regarding objectively diagnosed EIB prevalence in this population8-11. EVH
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could be an alternative and easier method for EIB diagnosis5 but it was not possible to
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find studies comparing this with the most commonly recommended treadmill running
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method in this population. The present study thus aimed to evaluate the prevalence of
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EIB in children and adolescents with allergic rhinitis, to examine its association with
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patients’ reported respiratory symptoms after physical activity and to compare the
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treadmill running and eucapnic voluntary hyperventilation challenge methods for
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diagnosis and measurement of the intensity of EIB.
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METHODS
A cross-sectional study was carried out at the pulmonary function testing
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laboratory of the Pulmonology Service of the Federal University of Pernambuco’s
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Hospital das Clínicas – Recife, Brazil. The study was approved by the institution’s
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Ethics Committee. All parents or guardians signed terms of informed consent and the
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adolescents signed terms of assent as requested by the Brazilian regulatory agency.
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- Study Population
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The sample included children and adolescents with a clinical diagnosis of
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allergic rhinitis, of both sexes, aged between 10 and 20 years seen for the first time at
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the hospital’s Allergy and Immunology outpatients unit between January and October
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2015 and not using regular medication.
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Excluded individuals were those who specifically reported asthma symptoms in
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the past 12 months (dyspnea, chest tightness or episodes of wheezing), those with
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respiratory infection in the previous six weeks, those with FEV1 lower than 60% of the
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predicted value5, those incapable of carrying out the spirometry or hyperventilation
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maneuvers and those unable to run on the treadmill for the time required by the
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protocol. Patients declared they had not used any kind of medication for rhinitis in the
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past four weeks. Rhinitis was classified according to the frequency and intensity of symptoms, using
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the ARIA criteria13 according to which ‘intermittent’ means that symptoms are present
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for less than 4 days a week or for less than 4 consecutive weeks and persistent
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symptoms are those that occur for more than 4 days a week and for more than 4
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consecutive weeks. Mild symptoms are those that do not disturb sleep, daily activities,
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school or work and that, although present, are not troublesome. Moderate/severe
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symptoms are those that cause some impairment of sleep, daily activities, school or
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work and are perceived as troublesome by patients.
All patients had a positive prick test for at least one of the mite aeroallergens tested (D. pteronyssinus, B. tropicalis)
and some also for the other tested allergens (A.
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alternata, A. fumigatus, dog and cat dander).
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- Procedures
Data were gathered on patients’ age, weight, height, and gender. The
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temperature and humidity of the ambient air were measured using a digital
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thermohygrometer (Incoterm, Porto Alegre, Brazil). Before any other procedure was
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carried out, the patients answered a question regarding their perception of respiratory
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symptoms after physical activity: have you noticed wheezing, shortness of breath,
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coughing, or tightness of the chest after exercise at any time in the last 12 months?14.
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The baseline FEV1 was determined using a spirometer (microQuark –
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COSMED, Rome, Italy) in accordance with international protocols15. It was
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subsequently measured in duplicate three, five, seven, 10, 15 and 30 minutes after
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treadmill running or after EVH. On each occasion, the highest value obtained was
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chosen4, 5.
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The two techniques (TR and EVH) were carried out with a minimum interval of
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24 hours and a maximum of 72 hours. Participants were randomly assigned in blocks of
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four to determine which test would be carried out first.
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The TR test lasted eight to nine minutes (ProAction BH Fitness treadmill –
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Vitoria, Spain). In the first two minutes, treadmill velocity was increased gradually for
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adaptation and to reach the target heart rate (HR) (between 80% and 90% of maximum;
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220-age) to be maintained for the final six minutes5,15 (Polar model RS300X - Kempele,
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Finland). Patients’ ventilation rate during TR was not measured.
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and 5% carbon dioxide (CO2) (White-Martins, Recife, PE - Brazil) collected in a
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Douglas balloon, through the mouth with nose clipped, using a one-way low-resistance
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valve (Laerdal, Copenhagen - Denmark). The test lasted six minutes and the target
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ventilation per minute was 21 times that of the baseline FEV1 for each individual5. The
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ventilation rate per minute was monitored using an analogic ventilometer (Wright Mark
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8 NSPIRE Health, Colorado - USA).
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The speed of the treadmill was adjusted by the examiner to maintain the target
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heart rate and, in the EVH test, the examiner encouraged the patients to maintain the
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target ventilation rate every 30 seconds. EIB was diagnosed when there was a > 10%
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reduction in FEV1 from the baseline at two consecutive evaluation points after the
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challenge (TR or EVH)5,6.
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Statistical Analysis
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The Shapiro Wilk test was applied and all continuous data showed a normal
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distribution. Categorical variables were compared using Fisher’s Exact Test and
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continuous variables using Student’s t test for paired samples. Multivariate analysis of
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variance (MANOVA) was used to compare the reduction in FEV1 from the baseline in
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EIB positive and negative groups at the time points between the challenge tests.
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Cohen’s kappa was used to assess the proportion of agreement and the positive and
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negative proportional agreement between challenge methods were calculated. The
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adopted probability of alpha error was 5%. The data were processed and analyzed using
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the GraphPad Instat program (GraphPad Inc., San Diego, USA, Release 3:06, 2003) and
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the Statistical Package for the Social Sciences (SPSS) for Windows version 16.
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RESULTS
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Eighty individuals were selected and 40 were excluded (30 for reporting
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symptoms of asthma in the past year, 8 owing to symptoms of acute respiratory
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infection in the six weeks prior to the test and 7 for having a baseline FEV1 < 60% of
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the predicted value). Of the 40 patients who underwent the first test, five were lost to
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follow-up for not attending the second day of the test within the stipulated timeframe
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(three after TR and two after EVH). Thirty-five individuals concluded the study and
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their data are presented in Table 1.
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EIB was diagnosed in 13 individuals (37%), by both methods in six (17%) and
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by only one in seven (20%) (three by treadmill running and four by EVH – kappa 0.486
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- Table 2). Figure 1 shows the means for maximum reduction in FEV1 at each evaluation
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point by the two methods in patients with and without EIB. There were no differences
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in FEV1 reduction from the baseline between the two challenge tests at any time, either
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among EIB positive [(F=2.33; p=0.13), times (F=1.59; p=0.17) and interaction (F=1.18;
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p=0.97)] or among EIB negative individuals [(tests, F=0.01, p=0.93; times, F=0.46,
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p=0.81; and interaction F=0.19, p=0.96) - MANOVA]. In only three individuals was
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there a reduction in FEV1 greater than or equal to 30% in relation to the baseline; one
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patient in both tests (30% after TR and 32% after EVH) and two in different tests (TR =
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45% and EVH = 35%).
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No differences were found in baseline FEV1 values as a percentage of predicted
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on either day of the test (TR: 97.1% + 14.8% vs. EVH: 96.6% + 14.4%, p=0.66,
150
respectively). Comparison of individuals with and without EIB for each method showed
151
that baseline FEV1 was lower for those testing positive (Table 3). This table also shows
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that no differences were found in maximum heart rate achieved between patients with
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and without EIB on TR, nor in the mean EVH respiratory minute volume. All
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individuals reached the target heart rate (>80% of maximum calculated heart rate: 220 –
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age). In the case of eucapnic voluntary hyperventilation, 29 individuals (83%) reached
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or surpassed 90% of the calculated target ventilation (21 times baseline FEV1) and six
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reached between 80% and 89%. In the latter group, four presented EIB and two did not.
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There was no association between EIB diagnosed by either or both methods and
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the severity of rhinitis, history of asthma symptoms or complaints of respiratory
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symptoms after exercise (Table 3).
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There was no significant difference in mean temperature and relative humidity
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of the air between the two days of the test (22.5 + 1.4 Cº and 56.9% + 4.4%
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respectively).
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In the case of patients in whom bronchoconstriction persisted until the thirtieth
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minute (four after EVH and four after TR), 400mcg of inhaled albuterol were
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administered. On no occasion was there a need for the sequence of tests to be
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interrupted.
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DISCUSSION
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treadmill running challenge with that using eucapnic voluntary hyperventilation in
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young people with allergic rhinitis found a prevalence of 37% (13/35) when both
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methods were considered – six by both methods, three by treadmill running alone and
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four by eucapnic voluntary hyperventilation alone. There was moderate agreement
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between the two methods (Cohen’s Kappa = 0.486). No associations were found
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between the presence of EIB and respiratory complaints on exercise, the severity of
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symptoms of rhinitis, or a past (> 1 year) history of asthma.
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The results for prevalence of EIB in patients with allergic rhinitis using treadmill
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running alone (25.7%) are similar to those found by Rakkhong et al.2 and Valdesoiro et
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al.9, who found a prevalence of 20.7% and 24% respectively in a similar group of
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individuals, but differ from those of Custovic et al.8, who used free running as a
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challenge and found no positive responses for EIB in any of the 17 children with rhinitis
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investigated. These differences are probably due to the number of individuals studied
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and the methodology used in the last study.
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Caillaud et al.11, in an epidemiological study in France, tested 902
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schoolchildren with symptoms of rhinitis in the previous year using free running and
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peak expiratory flow and found a mean EIB prevalence of 7%. Different from the
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present study, in which the patients were not taking medication for rhinitis, the French
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study patients were using a nasal corticoid11, which may influence the bronchial
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reactivity of these individuals16. Another striking feature of this French study is the low
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prevalence (10%) of EIB in patients with asthma, indicating the low sensitivity of the
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diagnostic method employed. These differences in prevalence indicate the need to use
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standardized methodologies for challenge tests to evaluate EIB.
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The only study found in the literature that examined EVH in patients with
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rhinitis but no symptoms of asthma aimed to investigate the association between EIB
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and respiratory symptoms in elite athletes and also included symptomless asthmatic
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individuals. However, the results are not presented separately and it is not possible to
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calculate the prevalence of EIB using this method in patients with rhinitis alone17.
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An overall agreement of 80% between the two methods was found, although
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with a modest kappa index (0.486), which may be explained by the proportional
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negative agreement between the tests (86% - Table 1)18. The two tests were both
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positive in only six individuals; in the others, EIB was diagnosed by TR alone in three
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and by EVH alone in four. Similar results have been found in adolescents with asthma
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when comparing the two challenge methods7. This discrepancy may be explained by the
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intrinsic variability of each method when tests are repeated in the same subject within a
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short time period19,20. In concordance with the data in the literature, no association was found between
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clinical complaints of respiratory symptoms and diagnosis of EIB14,2. Neither was there
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any association between EIB and the severity of symptoms of rhinitis (Table 3). In the
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case of the latter, our results differ from those of Rakkhong et al.2 that found a higher
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EIB prevalence in individuals with persistent symptoms. However, there was an
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association with lower baseline FEV1 rate, expressed as a percentage of the expected,
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and EIB prevalence (Table 3). Such an association has also been found in previous
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studies of asthmatics7,21 and patients with rhinitis alone22. This is probably associated
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with a higher degree of inflammation and hence bronchial hyperresponsiveness23.
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Three individuals had baseline FEV1 values between 60% and 80% of predicted,
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two without and one with a history of asthma symptoms one year before the study. All
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three had EIB diagnosed by both methods. Low lung function detected in some
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adolescents without current asthma symptoms may be a consequence of wheezing
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phenotypes in early childhood24 and may be associated with other concomitant factors,
222
such as maternal asthma or smoking during pregnancy and atopic sensitization or
223
respiratory viral infections after birth25. This was not investigated in these three patients.
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In patients with rhinitis, the presence of bronchial hyperreactivity and EIB
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indicate increased likelihood of developing asthma in the future26-28, which means that
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the tests used for this diagnosis — including EVH — may also be important for
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prognosis and recommendation of preventive measures.
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a past history of symptoms of asthma (more than one year). Baseline FEV1 values were
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no different from those measured in individuals without a history of asthma (p = 0.79),
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neither were there differences in the proportion of individuals with EIB, when
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comparing both groups (5/15 and 8/20 respectively; Chi-square p=0.686). Asthma and
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rhinitis often coexist in the same youngsters. In many, the asthma fades away leaving
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only rhinitis symptoms13 and it was deemed more representative of the real world not to
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exclude these individuals. Another limitation is the recall bias of patients answering the
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question about respiratory symptoms after exercise in the past 12 months.
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As we chose to analyze the results as categorical variables (EIB positive or
238
negative), we did not adopt the Bland-Altman method for evaluating limits of
239
agreement between the challenges, although we found no differences in the magnitude
240
of FEV1 reduction from the baseline between the challenge tests at any evaluation time,
241
either among EIB positive or EIB negative individuals (Figure 1). The tests were carried out in an air-conditioned laboratory, which enabled
243
uniformity of temperature and humidity of the air breathed during the treadmill running
244
test. There was no difference in heart rate during TR or ventilation rate on EVH
245
between patients testing positive and those testing negative (Table 3). All theese factors
246
may interfere with EIB diagnosis5,11,29, 30.
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It is worth pointing out that the present study followed the guidelines laid out by
248
Weiler et al.6, which only considered the test to be positive if a reduction of FEV1 >
249
10% from the baseline was observed on at least two consecutive measurements. Had a
250
reduction in FEV1 in only one measurement been considered, the prevalence would
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have increased to 51% when both tests are included. Although this would increase
252
diagnostic sensitivity, it would not substantially alter agreement (kappa = 0.440).
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The EVH test proved to be safe and easy to apply. No patient failed to execute
254
the hyperventilation maneuver appropriately and all easily reached the established
255
ventilation rates. No individual experienced symptoms of severe dyspnea or a severe
256
reduction in FEV1 (>50%)5, which would have required suspension of the test. This has
257
also been reported by other authors29.
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The data of the present study suggest that the results of both methods should be
259
interpreted with caution when the intention is to compare them or even to consider them
260
interchangeably. As there is no the gold standard method for diagnosis of EIB 29 and, on
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the basis of the present study and other studies of the diagnostic accuracy of EVH 31 and
262
TR tests20, we can agree with Price et al.19 that a negative test on only one occasion is
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not sufficient to rule out diagnosis of EIB, especially in individuals with complaints that
264
interfere with their physical activities. Furthermore, it should be emphasized that
265
objective methods should be employed for EIB diagnosis32 and that the EVH test may
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be a safe and easy to execute alternative for this purpose.
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267 268
Acknowledgements
269
We are thankful to Mr. Peter Ratcliffe for language revision.
ACCEPTED MANUSCRIPT REFERENCES – IV
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ACCEPTED MANUSCRIPT 369 Table 1. General Patient Data. RESULTS (n = 35)
GENDER: Male/Female
22/13
AGE (Mean in years, percentile 25-75)
16.3, 13-20
WEIGHT (Mean + SD in kg)
58.5 + 15.9
HEIGHT (Mean + SD in m)
1.60 + 0.12
BMI* (Mean + SD in kg/m2)
22.5 + 4.5
Initial Test: TR or EVH**
18/17
FEV1*** baseline at l/sec (Mean + SD)
3.12 + 0.85
FEV1 baseline (Mean + SD of % predicted)
91.2 + 14.5
Asthma in past****
15 (43%)
Respiratory symptoms after exercise
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PARAMETERS
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Classification of rhinitis (intermittent/persistent)
20 (57%) 20/15
* BMI = Body Mass Index, ** TR = treadmill running, **EVH = eucapnic voluntary
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hyperventilation, ** Forced expiratory volume in the first second **** Reported
373
compatible symptoms occurring more than one year previously.
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Table 2. Results obtained for both challenges. EVH
Negative
Total
Positive
6
3
9
Negative
4
22
26
Total
10
25
35
Kappa
0.486
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EVH = Eucapnic voluntary hyperventilation. TR = Treadmill running. Positive = Reduction in FEV1 > 10% in relation to baseline at two points in the evaluation. Negative = Reduction in FEV1 < 10% in relation to baseline or > 10% on only one occasion. General agreement = 80%. Proportional positive agreement = 63%; Proportional negative agreement = 86%.
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376 377 378 379 380 381
Positive
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TR
Cohen’s
382
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ACCEPTED MANUSCRIPT Table 3. Comparison of individuals with and without EIB for each challenge method Treadmill Running
Eucapnic Voluntary Hyperventilation
Positive (9)
Negative (26)
p
Positive (10)
Negative (25)
p
FEV1 baseline (% of predicted) Mean SD 95% CI
85% 16.2% 72%-97%
101% 11.7% 97%-106%
0.02*
85% 15.7 79%-92%
101% 11.2% 97%-106%
0.001*
HR¥ reached (% of maximum predicted: 220-age) Mean SD 95% CI
85% 3.8% 82%-88%
87% 4.3% 85%-89%
0.16*
-
-
V¥¥ achieved (% calculated: 21 times baseline FEV1) Mean SD 95% CI
-
-
4(44%) 6/3
Rhinitis severity (intermittent/persistent)
5(55%)
Respiratory complaints on exercise (%)
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Asthma in past (%)
RI PT
384 385
99% 11.1% 94%-104%
101% 10.7% 97%- 105%
0.64*
11(42%)
1,0**
4(40%)
11(44%)
1.0**
14/12
0,7**
6/4
14/11
1.0**
15(58%)
1,00**
7(70%)
13(52%)
0.46**
*Student’s t test, ** Fisher’s exact test, ¥HR = Heart rate, ¥¥V = Ventilation rate. SD =
387
Standard deviation. 95%CI = 95% confidence interval.
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ACCEPTED MANUSCRIPT 391 392 TR TR+ EVHEVH+
5
RI PT SC
-5
' 30
' 15
EP
Time of measurement ( minutes after challenge)
Figure 1. Mean (+ SEM) variation in FEV1 as a percentage of the baseline at each evaluation point in individuals with and without exercise induced bronchospasm (EIB+, EIB-) after the challenge tests. There were no differences between tests in the EIB+ group (p=0.13), nor in the EIB- group (p=0.93), (MANOVA).
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393 394 395 396 397 398 399 400 401 402 403
5'
3'
-25
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-20
10
-15
'
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-10
7'
FEV1 reduction (as % of basal value)
0
*TR+ = treadmill running in individuals with EIB. TR- = treadmill running in individuals without EIB. EVH+ = eucapnic voluntary hyperventilation in individuals with EIB. EVH- = eucapnic voluntary hyperventilation in individuals without EIB. SEM = Standard error of the mean.
ACCEPTED MANUSCRIPT Highlights
Respiratory symptoms after exercise were reported by 57% of studied rhinitis patients These symptoms may limit a subject’s ability to be physically active We found no association between exercise-related respiratory complaints and EIB
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Eucapnic voluntary hyperventilation may be a safe challenge method for EIB diagnosis
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A negative challenge test on only one occasion may be insufficient to rule out EIB