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Clinical phenotypes of bronchial hyperresponsiveness in school-aged children
Accepted Manuscript
Clinical phenotypes of bronchial hyperresponsiveness in school-aged children Eun Lee MD, PhD , Young-Ho Kim MD , Hyun-Ju Cho MD , Ji-Sun Yoon MD , Sungsu Jung MD , Song-I Yang MD, PhD , Hyung Young Kim MD , Ji-Won Kwon MD, PhD , Ju-Hee Seo MD, PhD , Hyo Bin Kim MD, PhD , So Yeon Lee MD, PhD , Soo-Jong Hong MD, PhD PII: DOI: Reference:
S1081-1206(18)30420-4 10.1016/j.anai.2018.05.033 ANAI 2576
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
17 February 2018 19 May 2018 29 May 2018
Please cite this article as: Eun Lee MD, PhD , Young-Ho Kim MD , Hyun-Ju Cho MD , Ji-Sun Yoon MD , Sungsu Jung MD , Song-I Yang MD, PhD , Hyung Young Kim MD , Ji-Won Kwon MD, PhD , Ju-Hee Seo MD, PhD , Hyo Bin Kim MD, PhD , So Yeon Lee MD, PhD , Soo-Jong Hong MD, PhD , Clinical phenotypes of bronchial hyperresponsiveness in school-aged children, Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.05.033
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Clinical phenotypes of bronchial hyperresponsiveness in school-aged children
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Eun Lee, MD, PhD*, Young-Ho Kim, MD†, Hyun-Ju Cho, MD‡, Ji-Sun Yoon, MD†, Sungsu
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Jung, MD †, Song-I Yang, MD, PhD§, Hyung Young Kim, MD∥, Ji-Won Kwon, MD, PhD¶,
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Ju-Hee Seo, MD, PhD**, Hyo Bin Kim, MD, PhD††, So Yeon Lee, MD, PhD†, Soo-Jong
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Hong, MD, PhD†
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University Medical School, Gwangju, Korea,
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Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
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ncheon, Korea,
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Seoul, Korea.
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Department of Pediatrics, Chonnam National University Hospital, Chonnam National
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Department of Pediatrics, Childhood Asthma Atopy Center, Environmental Health Center,
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Department of Pediatrics, International St. Mary's hospital, Catholic Kwandong University, I
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Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang, Korea, Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Korea,
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Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea, Department of Pediatrics, Dankuk University Hospital, Cheonan, Korea,
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Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine,
Lee E and Kim YH equally contributed to this work.
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Correspondence: Soo-Jong Hong, MD, PhD
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Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health
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Center, Asan Medical Center, University of Ulsan
College of Medicine, 88 Olympic-ro 43-
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gil, Songpa-gu, Seoul 05505, Korea
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Tel: 82-2-3010-3379; Fax: 82-2-473-3725; E-mail: [email protected]
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Funding sources: This research was supported by Basic Science Research Program through
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the National Research Foundation of Korea (NRF) funded by the Ministry of Education
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(2017R1D1A1B03033576).
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Word count for text: 3,767
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Number of figures: 4
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Number of tables: 4
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Potential conflict of interest: The authors declare no conflicts of interest in relation to this
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study.
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Author’s contribution: conception and design of the study-Lee E, Kim YH, Lee SY, Hong
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SJ. Data generation: Kim YH, Lee SY, Cho HJ, Yoon JS, Jung SU, Yang SI, Kim HY, Kwon
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JW, Seo SH, Kim HB, Lee SY, Hong SJ.
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Abstract
Background: Bronchial hyperresponsiveness (BHR), one of the key features of asthma, shows a
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diverse natural course in school-aged children, but, studies on BHR phenotypes are lacking.
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Objective: We classified BHR phenotypes according to onset age and persistence in children a
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nd investigated the characteristics and factors associated with each phenotype in a longitudin
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al study.
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Methods: We analyzed 1,305 elementary school children from the Children's HEalth and Enviro
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nmental Research (CHEER) study, a 4-year prospective follow-up study with 2-year intervals sta
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rting at a mean age of 7 years. Total serum IgE levels and blood eosinophils (%) were measu
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red, and allergy work-up including methacholine challenge tests with ISSAC questionnaire were
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performed at each survey. Results: We classified the four BHR phenotypes as non-BHR (n=942, 72.2%), early-onset transi
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ent BHR (n=201, 15.4%), late-onset BHR (n=87, 6.7%), and early-onset persistent BHR (n=75, 5
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.7%). Early-onset persistent BHR is characterized by an increased eosinophils (%), total serum I
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gE level, sensitization rate, a decreased lung function and an increased risk of newly diagnose
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d asthma during follow-up (aOR, 3.89; 95% CI, 1.70-8.88). The two early-onset phenotypes we
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re associated with peripheral airway dysfunction. The late-onset BHR phenotype related with i
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ncreased risks of AR symptoms at baseline and later sensitization against inhalant allergens.
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Conclusion: The early-onset persistent BHR phenotype in school-aged children is associated wi
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th high atopic burden and increased risk of newly diagnosed asthma, whereas the late-onset
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BHR phenotype related with later sensitization and AR symptoms. Diverse BHR phenotypes in
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children have specific characteristics that require targeted follow-ups.
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Keywords: asthma; bronchial hyperresponsiveness; children; phenotype; sensitization.
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INTRODUCTION
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Bronchial hyperresponsiveness (BHR) is associated with airway inflammation, even in
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asymptomatic individuals, and with abnormalities of airway smooth muscle cells.1,2 BHR is
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one of the key characteristics of asthma and is correlated with its severity. In previous general
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population based studies, the prevalence of BHR was reported to be about 14 – 33% in
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children and to decrease in prevalence with age, particularly in relation to severity.3,4
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Airway caliber, sex, and age have impacts on the degree of BHR.4-8 In addition, asthma,
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combined allergic diseases, atopy, exposure to gas cooking, and high levels of total serum IgE
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have an identified association with BHR.9 In our previous study, atopy was found to be
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related to BHR in boys, whereas sexual maturation showed an association with BHR in girls.4
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In a report from another group, atopic asthmatic school-aged children showed greater BHR
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compared to non-atopic asthmatic children, whereas atopic and non-atopic asthmatic
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preschool children showed a similar BHR.9 Further epidemiologic studies have reported that
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the severity of BHR is associated with the symptoms and persistence of BHR.10,11 The
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findings from the previous studies have thus suggested that BHR has heterogeneous features
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with a variety of prognoses, irrespective of the presence of asthma. Notably however, studies
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on BHR phenotypes are lacking, even though these phenotypes would necessarily contribute
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to the understanding of pattern variations in childhood BHR and to the identification of
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modifiable factors related to its onset.
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Further investigation of clinical BHR phenotypes is essential to a better prediction of
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prognosis and increased understanding of the associated factors for each clinical phenotype of
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BHR. Although the natural course of asthma in children has not yet been fully elucidated,12
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much detailed research has contributed to our understanding of the diversity of asthma
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phenotypes and their underlying pathophysiologic differences.13,14 In children with asthma,
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onset age and persistency of symptoms are important prognostic indicators of lung function
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outcomes in later life.13 Similar to asthma, onset age and persistency of BHR may play an
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important role in the prognosis of BHR and its comorbidities.
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In our present study, we have classified four clinical phenotypes of BHR in accordance with
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onset age and persistence over its natural course in 7 year old children. We investigated the
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characteristics and factors associated with each clinical phenotype of BHR in a prospective
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longitudinal study.
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METHODS
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Study population
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This study was performed as a part of the Children‟s Health and Environment Research
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(CHEER) study, conducted in 27 randomly selected elementary schools in 10 areas across the
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Republic of Korea.14-17 The participants were followed-up for 4 years with 2-year intervals
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starting at 6-8 years of age. Each survey comprised a parent-completed questionnaire on
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allergic diseases, blood tests including total serum IgE levels and eosinophil count, skin prick
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tests (SPT), pulmonary function test (PFT), and methacholine challenge test (MCT). Among
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the total population of 2,423 elementary school-aged children in the CHEER study, we
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enrolled 1,305 children for whom MCT results at each of the three surveys were available.
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Written consent was obtained from all parents or guardians. The present study was approved
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by the Institutional Review Board of Ulsan University College of Medicine (IRB No. 2006-
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0081).
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Definitions
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We classified four clinical phenotypes of BHR in accordance with onset age and persistence.
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No evidence of BHR at either the baseline or final survey indicated a „non-BHR‟ phenotype.
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Children with positive BHR at baseline but no BHR at the final study were classified as
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„early-onset transient BHR‟. The „early-onset persistent BHR‟ phenotype included children
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who were positive for BHR at both the baseline and final surveys. The „late-onset BHR‟
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phenotype was defined as no BHR at baseline survey but positive BHR at the final survey.
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MCT can be performed in children from 6 years of age according to the cooperation of the
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patients and we assigned „early-onset BHR‟ to children with positive MCT results at 6-7
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years, which was the enrollment age in the present study as well as enforceable age with good
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performance. Although four-year follow-up might not be sufficient to define the „persistent‟
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phenotype, BHR persisting for 4 years including the puberty period is meaningful in the
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prediction of persistence of BHR.4 By applying a strict definition of BHR as less than 8
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mg/mL methacholine, we excluded ambiguous cases of positive BHR. We classified children
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with positive BHR both enrollment and follow-up surveys as “persistent BHR”, considering
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the high possibility of persistence of BHR in children aged 11-12 years old at the time of 3rd
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survey. We did not consider the results of MCTs on the 2nd survey in the classification of
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clinical BHR phenotypes, because a 2-year interval for the follow-up of BHR was not
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sufficient to define the clinical phenotypes of BHR.
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Questionnaire
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The International Studies of Asthma Allergic diseases in Childhood (ISAAC) questionnaire
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has been previously validated in Korean children and was utilized in our current study to
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evaluate the presence of allergic diseases including atopic dermatitis (AD), allergic rhinitis
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(AR) and asthma, and factors associated with allergic diseases at the time of each survey.18,19
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Asthma at the time of enrollment was defined by an affirmative response to the questions in
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the ISAAC questionnaire: “Have you ever been diagnosed with asthma by a physician?”. The
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presence of asthma symptoms in the preceding 12 months was assessed using the question,
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“Have you ever had symptoms of asthma, such as wheezing or whistling in the chest, during
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the last 12 months?”. A participant was designated as having AR at the time of enrollment if
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there was an affirmative response in the ISAAC questionnaire to the following question:
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“Have you ever been diagnosed with AR by a physician?” The presence of AR symptoms in
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the preceding 12 months was assessed by the question, “Have you ever had nasal symptoms,
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such as watery rhinorrhea, nasal obstruction, nasal itching or sneezing unrelated to cold,
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during the last 12 months?”. The prevalence of AD was defined by a positive response to the
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“Has your child been diagnosed with AD by a physician (lifetime AD diagnosis)”.
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Methacholine challenge test (MCT)
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For the methacholine challenge test (MCT), we used a modified five-breath dosimeter
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method in accordance with the American Thoracic Society (ATS) guideline.20 Spirometry
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(Jaeger APS; CareFusion Respiratory Care, San Diego, CA) was conducted using a Hans-
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Rudolph nonrebreathing valve (Hand Rudolph Inc., Kansas City, MO) and a Misty-Neb
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Medication nebulizer set (CareFusion Respiratory Care) with the flow meter set at 0.009 mL
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± 10% of the solution per 0.6 s of actuation during inhalation. Subjects were excluded from
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the analysis if they had a history of upper or lower respiratory tract infection during the three
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weeks prior to MCT or had received inhaled corticosteroid therapy at least four weeks before
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MCT. Normal saline was used as a baseline and was followed by stepwise concentrations of
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methacholine concentrations (0.625 1.25, 2.5, 5, 12.5, and 25 mg/mL). The forced expiratory
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volume in 1 second (FEV1) was measured at 30 and 90 s after the nebulization was completed
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and the next dosing schedule then proceeded within 5 minutes. The MCTs in the CHEER
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study were performed within a few days in the same season to exclude the possible effects of
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confounding factors on BHR. Subjects with a history of upper or lower respiratory infection
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during the preceeding four weeks or who received inhaled corticosteroid therapy were not
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given an MCT. We defined BHR positivity as a 20% decrease in the FEV1 (PC20) caused by a
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provocative methacholine concentration of less than 8 mg/mL.
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Skin prick tests (SPTs)
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Skin prick tests (SPTs) were performed for 14 common inhalant and 4 food allergens
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(Allergopharma GmbH & Co, Reinbek, Germany). The inhalant allergens included house
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dust mites (Dermatophagoides pteronyssinus [Der p] and Dermatophagoides farina [Der f]), cat epithelium, dog dander, cockroaches, molds (Alternaria alternata and Aspergillus
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fumigatus), tree mix I (alder, elm, hazel, and poplar), tree mix II (beech, birch, oak, and plane
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tree), ragweed, mugwort, alder, oak, and a grass pollen mixture. The four food allergens were
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peanuts, egg whites, cow‟s milk, and soybeans. Histamine (10 mg/mL) and normal saline
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were used as positive and negative controls, respectively. We defined atopy as the presence of
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one or more positive results on an SPT. A positive SPT was defined as a mean wheal diameter
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of equal or greater than 3 mm and positive control.
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Pulmonary function tests (PFTs)
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Pulmonary function tests (PFTs) were performed according to the ATS (American Thoracic
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Society)/ERS (European Respiratory Society) guidelines.21 A portable micro-spirometer
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(Microspiro HI-298; Chest Corporation, Tokyo, Japan) was used to measure the forced vital
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capacity (FVC), FEV1, forced expiratory flow at 25% to 75% of FVC (FEF25-75%), and
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FEV1/FVC ratio.
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Statistical analysis
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The data are presented as a mean ± standard deviation. Logistic regression analysis was
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conducted to investigate associated factors and compare the odds of allergic outcomes across
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the four clinical BHR phenotypes. Multiple comparisons between two groups were
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counteracted with Bonferroni correction. SAS 9.4 software (IBM SAS, Chicago, IL) was
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used for the statistical analysis. A p value of 0.05 or less was considered to be significant.
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RESULTS
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Characteristics of the study population and BHR phenotypes
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A comparison of the characteristics of each BHR phenotype revealed significant differences
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in the living area and monthly income across the four clinical phenotypes (Table 1).
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Approximately half (50.9%) of the study population were boys and there was no significant
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difference in the proportion of boys and girls across the four BHR phenotypes. The
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distribution of the total study population across the four clinical phenotypes of BHR was as
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follows: non-BHR (n=942, 72.2%), early-onset transient BHR (n=201, 15.4%), late-onset
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BHR (n=87, 6.7%), and early-onset persistent BHR (n=75, 5.7%). We observed that 37.9% of
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the study population had a family history of allergic diseases without significant differences
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across the four phenotypes.
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The prevalence of exposure to environmental tobacco smoke (ETS), antibiotics and pets in
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infancy was highest among the early-onset persistent BHR phenotype cases, although this
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was not statistically significant. The prevalence of prematurity and bronchiolitis history in
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infancy was highest for the early-onset transient BHR phenotype, also without statistical
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significance.
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Atopic burden among the four BHR phenotypes
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The blood eosinophil count and total serum IgE levels were highest in the children with
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early-onset persistent BHR phenotype both at the time of enrollment and at follow-up (Fig.
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1). Based on the SPT results, the prevalence of sensitization against common allergens was
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also highest for the early-onset persistent BHR phenotype at the time of enrollment and
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follow-up (Fig. 2A and 2B). The sensitization rate, including the multiple sensitization rate,
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i.e. more than 2 allergens, was also highest among the early-onset persistent BHR phenotype
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subjects (Fig 2C). However, the new sensitization rate and number of newly sensitized
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allergens during the follow-up period was highest for the late-onset BHR phenotype (Fig. 2D
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and 2F). Sensitization to house dust mites and diverse pollen was increased during follow-up
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(Tables 2 and 3).
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Comorbidities with each BHR phenotype
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The prevalence of parental-reported, physician-diagnosed asthma, AD, and AR during the
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lifetime of each subject was highest in the early-onset persistent BHR phenotype (Table 4 and
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Supplementary Figures 1-3). The prevalence of parental-reported, physician-diagnosed AD in
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lifetime and current AD was higher in the early-onset transient BHR group than in the late-
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onset subjects (Table 4 and Supplementary Figure 1). The prevalence of AR symptoms and
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AR treatment in the preceding 12 months was highest for the late-onset BHR phenotype
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(Table 4 and Supplementary Figure 2). The risk of asthma symptoms and asthma treatment in
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the preceding 12 months at the time of enrollment was significantly increased in the subjects
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with the two early-onset BHR phenotypes (Supplementary Figure 3).
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Baseline and follow-up pulmonary function in clinical BHR phenotype
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The level of FEV1 % predicted at baseline was lowest in the early-onset persistent BHR
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phenotype subjects (P < 0.001), which accorded with the findings of the follow-up study (Fig.
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3A and 3B). At the time of enrollment, the levels of FVC % predicted in the early-onset
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transient BHR phenotype was significantly lower than that found for the non-BHR phenotype
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(Fig. 3C). In the follow-up study, the level of FVC % predicted was lowest in the early-onset
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persistent BHR phenotype, followed by the late-onset BHR, early-onset transient BHR, and
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non-BHR phenotypes (Fig. 3D). The FEV1/FVC was significantly lower among the three
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BHR phenotypes compared to the non-BHR phenotype at the time of enrollment (Fig. 3E).
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The same pattern was observed in the follow-up study (Fig. 3F). The levels of FEF25-75% %
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predicted were significantly lower among the children with the early-onset transient and
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early-onset persistent BHR phenotypes compared to those with the non-BHR phenotype both
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at the time of enrollment and follow-up (Fig. 3G and 3H).
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Prognosis for each clinical phenotype of BHR
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The odds ratio for newly diagnosed asthma by physicians during follow-up was increased
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(aOR, 3.89; 95% CIs, 1.70-8.88; Fig. 4A), as was that of asthma symptoms during the
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preceding 12 months during follow-up (aOR, 2.06; 95% CIs, 1.05-4.07; Fig. 4B), in the
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subjects with the early-onset persistent BHR phenotype. However, there were no significant
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differences found in the risk of newly diagnosed AR and AD across the four BHR phenotypes
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(Fig. 4C and 4D).
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DISCUSSION We have identified four clinical phenotypes of BHR in school-aged children and characterized some of the diverse factors and prognoses associated with each clinical BHR phenotype. The clinical phenotypes of BHR were defined as non-BHR, early-onset transient BHR, late-onset BHR, and early-onset persistent BHR in accordance with onset age and
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persistence. The early-onset persistent phenotype is characterized by high atopic burden (high sensitization rate, increased total serum IgE levels and higher eosinophil count), decreased lung function, and increased risks of newly developed asthma and asthma symptoms during
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follow-up. The two early-onset phenotypes were found to be associated with decreased peripheral airway function at baseline and during follow-up, suggesting the need for longterm follow-up of lung function in children with these phenotypes. The late-onset BHR phenotype is characterized by a new sensitization to diverse inhalant allergens including
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house dust mite and multiple pollens and an increased risk of AR symptoms. Although diverse studies on the phenotypes of asthma, AD, and AR have been undertaken, our present
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study is, to our knowledge, the first prospective report to classify distinct clinical phenotypes
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of BHR and identify their associated factors in school-aged children. Moreover, the results of our present study suggest the need to evaluate the presence of BHR in children showing a
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high atopic burden with new sensitization during follow-up and with decreased lung function. In a previous 4-year prospective follow-up epidemiologic study of BHR in 380 school-aged
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children, starting at 8-10 years old,3 BHR was categorized as mild or slight, moderate and severe according to its severity at each survey. Respiratory symptoms, atopy, and medication usage were assessed in that study and an association of these factors with moderate to severe BHR was reported. By contrast, we here classified four clinical phenotypes of BHR in accordance with onset age and persistence in a larger cohort of children starting at 7 years of age. We evaluated the factors associated with these phenotypes including serologic results,
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such as blood eosinophil count and total serum IgE levels, pulmonary function, and atopy on SPTs. By classifying the clinical phenotypes of BHR in this way, the clinical and pathophysiological heterogeneity of BHR was better characterized than by the previous use of severity.3 Our current findings thus provide useful new insights that can help to explain and predict the onset and persistence of BHR in real clinical situations.
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We found in our current analysis that the early-onset BHR phenotypes, including both the transient and persistent phenotypes, were characterized by a high eosinophil count and total serum IgE levels and a decreased lung function at the time of enrollment. Notably, the FEF25which is a measure of small airway function and can reflect the severity of BHR, 22 was
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decreased at the time of enrollment as well as during the follow-up survey in the children with these early-onset BHR phenotypes. These findings may suggest that BHR in early life affects lung function and the natural course of lung development in later life. Further long-
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term follow-up studies are thus needed to evaluate the effects of BHR on lung function and its long-term prognosis.
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Sensitization to allergens may play an important role on the natural course of BHR. At
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baseline, the most commonly sensitized allergen across the four BHR phenotypes were house dust mites including Der f and Der p. During the follow-up period, significant differences
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were observed in the sensitization rates for tree pollens, Alternaria, and Der f and Der p across the four phenotypes. Sensitization to fungal allergens, including Alternaria, is known
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to be related to the development and persistence of asthma and its exacerbation or severity.23 There have been no previous demonstrations of the clinical relevance of specific fungal sensitization to the clinical phenotypes of BHR, but our present findings indicate that it plays a role in determining these phenotypes. Our previous study identified that early sensitization to outdoor allergens, including Alternaria, and later sensitization to indoor allergens, including Aspergillus, was related to new-onset BHR,17 consistent with our current results.
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In addition, the prevalence of poly-sensitization was highest in the early-onset persistent BHR phenotype, whereas the newly sensitized rate and number of new sensitizations to common allergens during follow-up was highest in the late-onset BHR phenotype. These results suggest that changes in sensitization pattern are associated with the prognosis of BHR, although the role of sensitization in both the induction and maintenance of BHR remains to
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be elucidated.
The full spectrum of clinical implications and prognosis of BHR in children has remained, although several studies have reported an increased risk of asthma and a positive association
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between more severe BHR and symptomatic BHR.10,11,24 In our present investigation, we found no significant differences between the baseline BHR levels in the two early-onset BHR phenotypes (Supplementary Figure 4), although the prevalence of sensitization in combination with the blood eosinophil count, and total serum IgE levels were higher in
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children with the early-onset persistent BHR phenotype compared to those in the early-onset transient BHR phenotype. These findings suggest that the atopic burden, rather than the
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severity of BHR in early life, might play an important role in the persistence of BHR.
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The bronchial provocation test in children is performed to evaluate the degree of BHR in patients with asthma or to diagnose asthma when the symptoms are vague or the diagnosis is
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uncertain using spirometry.20 However, BHR can be accompanied by allergic diseases other than asthma.25 In patients with AR, the combined presence of BHR is indicative of a lower
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chance of remission of AR, except in patients treated for AR.25 A previous study has reported that asymptomatic BHR without any allergic symptoms was not associated with the increased risk of asthma. In another report, adolescents with respiratory symptoms in combination with BHR showed an increased risk of asthma.26 Taken together, the evidence to date suggests that the presence of BHR may predict the persistence of not only asthma but also allergic diseases including AR. Hence, the measurement of BHR may be very helpful in making a
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personalized therapeutic plan and predicting the prognosis in patients with severe and persistent AR or allergic symptoms. We further found in our current analysis that there was a higher prevalence of a lifetime diagnosis of AD among the children in the two early-onset BHR phenotypes, although the statistical power of these observations was notably weak. Among the subjects in the two
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early-onset BHR phenotypes, the persistence of BHR showed a relationship with sensitization and might therefore relate to the progression of decreased lung function. These findings suggest that the early-onset BHR phenotypes may be associated with allergic march and
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therefore that a long-term follow-up is needed in these children.27
Prematurity and a bronchiolitis history in infancy were found to be more prevalent among the children in the early-onset transient BHR phenotype, although this was not a significant difference. The lack of a significant difference between these two factors across the four BHR
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phenotypes may suggest that they do not play an important role in the development and persistency of BHR in school-aged children. This possibility is supported by the findings of a
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previous study, which indicated that the majority of wheezing symptoms in infants are
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transient and are not associated with the risk of asthma or allergic diseases in later life.28 A primary strength of our present analyses was the enrollment of subjects from a nation-wide
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and longitudinal general population of children. This allowed us to identify the clinical phenotypes of BHR and the factors associated with each phenotype. In addition, our detailed
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evaluations using objective PFT, SPTs, and MCT, and our assessment of serologic marker levels including total serum IgE and blood eosinophil counts, enabled us to further elucidate the characteristics of each phenotype. Nonetheless, our current study had several limitations of note. The follow-up period was relatively short, and the long-term prognosis associated with each BHR phenotype could therefore not be fully evaluated. However, our study was strengthened by the repeat BHR measurements as well as our use of other allergic work-ups
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including SPTs to assess more diverse allergens and also the PFTs we conducted at regular intervals. We also artificially classified the four BHR phenotypes in accordance with onset age and persistence. It must be noted however that cluster analysis, such as latent class analysis, which is commonly used in the identification of small sets of phenotypes in diverse diseases, also has limitations such as the lack of examinations for higher-order interactions.29
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Since the aim of our present study was to identify associated factors for each BHR phenotype depending on onset age and persistence, the arbitrary classification we used is itself meaningful in a clinical setting and provides a very useful prediction method for the
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prognosis of BHR. Further studies on BHR phenotypes using diverse cluster analysis are still needed however to identify the heterogeneous pathophysiologies and underlying diverse clinical phenotypes of BHR. We used the ISAAC questionnaire to evaluate the presence of allergic diseases, which had the potential to misclassify these allergic diseases. However, this
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questionnaire is widely used and has been previously validated in a large epidemiologic study.30
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In summary, we have classified four clinical phenotypes of BHR in accordance with its onset
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age and persistence and further evaluated the factors associated with each phenotype. High eosinophil counts and total serum IgE levels, sensitization, sensitization patterns, and
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decreased lung function were found to be associated with the onset age and persistence of BHR. Peripheral airway function was decreased in the children of the two early-onset
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phenotypes, and a further reduction in lung function was observed in the early-onset persistent BHR phenotype. Sensitization in early life as well as during follow-up may play an important role in determining the new-onset and persistence of BHR. Early-onset persistent BHR was associated with an increased risk of asthma at the time of enrollment as well as the new development of asthma during follow-up. The late-onset BHR phenotype showed a relationship with increased risks of AR symptoms at baseline and later sensitization against
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inhalant allergens. We conclude from our present findings that targeted follow-ups for children with BHR, based on their BHR phenotype, are needed for more effective management of combined allergic diseases and improvement of lung function outcomes in these cases. Through the identification of specific clinical BHR phenotypes and their associated factors, the results of our present study may be a foundation for the future
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development of preventive and therapeutic strategies for allergic diseases.
[1]
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rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351:1225-
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Figure legends
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1232.
Fig. 1. Comparison of the blood eosinophil counts (/mm3) and total serum IgE levels (Ku/L)
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at the baseline and follow-up surveys according to BHR phenotypes. (A) Blood eosinophil counts (/mm3) at baseline. (B) Blood eosinophil counts (/mm3) at follow-up. (C) Total serum IgE levels (Ku/L) at baseline. (D) Total serum IgE levels (Ku/L) at follow-up.
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Fig. 2. Comparison of the sensitization rate determined by skin prick tests at baseline and
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follow-up according to the BHR phenotypes. (A) Sensitization rates at baseline. (B) Sensitization rates at follow-up. (C) Prevalence of number of sensitized allergens at baseline.
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follow-up.
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(D) New sensitization rate during follow-up. (E) Number of newly sensitized allergens during
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Fig. 3. Results of pulmonary function tests at baseline and follow-up. (A) FEV1 % predicted
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at baseline. (B) FEV1 % predicted at follow-up. (C) FVC % predicted at baseline. (D) FVC % predicted at follow-up. (E) FEV1/FVC at baseline. (F) FEV1/FVC at follow-up. (G) FEF25% predicted at baseline. (H) FEF25-75% % predicted at follow-up.
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75%
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Fig. 4. Prognosis for each BHR phenotype. (A) Odds ratio and 95% CI for newly diagnosed asthma by physicians during the follow-up period. (B) Odds ratio and 95% CI for AR symptoms during the preceding 12 months at the final survey. (C) Odds ratio and 95% CI for newly diagnosed allergic rhinitis by physicians during the follow-up period. (D) Odds ratio and 95% CI for newly diagnosed atopic dermatitis by physicians during the follow-up period.
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*aOR, adjusted odds ratio; 95% CI, confidence intervals. **Adjusted for region, sex, parental history of allergic diseases, income, maternal education
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level.
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Table 1. Characteristics of the study subjects at the baseline survey Variables,
Non-BHR
AC
n (%) or mean ± SD
Early-onset
Late-onset
Early-onset
transient
BHR
persistent
BHR
P value
BHR
Number (%)
942 (72.2)
201 (15.4)
87 (6.7)
75 (5.7)
Age, years
7.37 ± 0.14
7.32 ± 0.03
7.26 ± 0.05
7.32 ± 0.05
0.081
Sex, male
479 (50.8)
101 (50.2)
44 (50.6)
40 (53.3)
0.977
Body mass index, kg/m2
16.80 ± 0.08
16.71 ± 0.18
16.12 ± 0.22
16.71 ± 0.27
0.097
Parental history of allergic
344 (37.0)
70 (35.9)
39 (45.3)
34 (45.9)
0.195
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<0.001
City
360 (38.2)
101 (50.2)
18 (20.7)
29 (38.7)
Industrial areas
375 (39.8)
48 (23.9)
54 (62.1)
27 (36.0)
Farming areas
207 (22.0)
52 (25.9)
15 (17.2)
19 (25.3)
Maternal educational level
0.260 530 (62.4)
120 (64.9)
58 (73.4)
44 (65.7)
> University
319 (37.6)
65 (35.1)
21 (26.6)
23 (34.3)
Monthly income
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≤ High school
0.041
646 (69.5)
153 (78.1)
53 (63.9)
53 (74.6)
> 3,000 $
283 (30.5)
43 (21.9)
30 (36.1)
18 (25.4)
Vaginal delivery
345/894 (38.6)
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≤ 3,000 $
86/188
29/82 (35.4)
26/73 (35.6)
0.221
31/77 (40.3)
35/66 (53.0)
0.323
13/182 (7.1)
3/76 (3.9)
2/64 (3.1)
0.486
56/181
21/74 (28.4)
23/65 (35.4)
0.764
3/198 (1.5)
2/85 (2.4)
4/75 (5.3)
0.355
22/185
7/73 (8.8)
4/61 (6.2)
0.541
71/82 (86.6)
58/72 (80.6)
0.292
50/78 (64.1)
46/64 (71.9)
0.672
(45.7)
ETS
391/856 (45.7)
75/181 (41.4)
41/849 (4.8)
Antibiotics in infancy
250/843 (29.7)
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Prematurity
31/932 (3.3)
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Pets in infancy
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Bronchiolitis in infancy
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Having any sibling
Breast milk feeding, yes
78/861 (9.1)
720/916 (78.6)
(30.9)
(11.9) 161/196 (82.1)
538/837 (64.3)
117/179 (65.4)
Abbreviations: ETS, Environmental tobacco smoke; SD, Standard deviation. The student‟s t-test, Fisher‟s exact test, or Kruskal–Wallis test was used as appropriate.
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Table 2. Sensitization rate for common allergens among the four clinical phenotypes of BHR at baseline Sensitized
Non-BHR
Early-onset
allergens, n (%)
Late-onset BHR
transient BHR
Early-onset
P value
persistent BHR
153/941 (16.3)
54/201 (26.9)
26/86 (30.2)
37/75 (49.3)
< 0.001
Der f, n (%)
129/941 (13.7)
50/201 (24.9)
19/86 (22.1)
34/75 (45.3)
< 0.001
Cockroach, n
20/942 (2.1)
5/201 (2.5)
3/86 (3.5)
8/941 (0.9)
2/201 (1.0)
2/86 (2.3)
6/941 (0.6)
3/201 (1.5)
1/86 (1.2)
7/941 (0.7)
3/201 (1.5)
2/86 (2.3)
2/75 (2.7)
0.226
Mugwort, n (%)
9/941 (1.0)
2/201 (1.0)
1/86 (1.2)
0/75 (0.0)
0.855
Ragweed, n (%)
4/941 (0.4)
2/201 (1.0)
1/86 (1.2)
1/75 (1.3)
0.554
Dog, n (%)
8/942 (0.8)
6/201 (3.0)
1/86 (1.2)
1/75 (1.3)
0.100
Cat, n (%)
8/941 (0.9)
3/201 (1.5)
3/86 (3.5)
2/75 (2.7)
0.106
Alternaria, n
29/941 (3.1)
9/201 (4.5)
7/86 (8.1)
5/75 (6.7)
0.055
4/201 (2.0)
1/86 (1.2)
2/75 (2.7)
0.042
(%) Grasses, n (%) †
Trees mix I, n
§
Trees mix II, n
†
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tree mix I: alder, elm, hazel, poplar, willow. tree mix II: beech, birch, oak, plane tree.
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§
4/941 (0.4)
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(%)
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Aspergillus, n
M
(%)
(%)
Abbreviations: NA, not applicable.
5/75 (6.7)
0.104
1/75 (1.3)
0.609
1/75 (1.3)
0.613
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(%)
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Der p, n (%)
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1
Table 3. Sensitization rate for common allergens among the four clinical phenotypes of BHR
2
at follow-up. Sensitized
Non-BHR
allergens, n (%)
Early-onset
Late-onset
Early-onset
transient BHR
BHR
persistent BHR
263/941 (27.9)
70/200 (35.0)
46/87 (52.9)
43/74 (58.1)
< 0.001
Der f, n (%)
240/941 (25.5)
65/200 (32.5)
45/87 (51.7)
44/74 (59.5)
< 0.001
Cockroach, n
23/941 (2.4)
3/200 (1.5)
2/87 (2.3)
17/941 (1.8)
8/200 (4.0)
5/87 (5.7)
29/941 (3.1)
9/200 (4.5)
7/87 (8.0)
34/941 (3.6)
9/200 (4.5)
6/87 (6.9)
8/74 (10.8)
0.019
Mugwort, n (%)
23/941 (2.4)
6/200 (3.0)
7/87 (8.0)
1/74 (1.4)
0.021
Ragweed, n (%)
5/941 (0.5)
3/200 (1.5)
1/87 (1.1)
2/74 (2.7)
0.153
Dog, n (%)
25/941 (2.7)
11/200 (5.5)
6/87 (6.9)
4/74 (5.4)
0.045
Cat, n (%)
39/941 (4.1)
9/200 (4.5)
8/87 (9.2)
5/74 (6.8)
0.151
Alternaria, n
39/941 (4.1)
12/200 (6.0)
11/87 (12.6)
7/74 (9.5)
0.002
2/200 (1.0)
0/87 (0.0)
0/74 (0.0)
0.697
†
Trees mix I, n
(%) §
Trees mix II, n
5 6 7 8
0.871
3/74 (4.1)
0.044
7/74 (9.5)
0.009
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Alder, n (%)
14/573 (2.4)
5/81 (6.2)
4/72 (5.6)
4/42 (9.5)
0.030
Oak, n (%)
16/573 (2.8)
3/81 (3.7)
4/72 (5.6)
2/42 (4.8)
0.582
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4
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(%)
7/941 (0.7)
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Aspergillus, n
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(%)
(%)
2/74 (2.7)
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Grasses, n (%)
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Der p, n (%)
(%)
3
P value
†
§
tree mix I: alder, elm, hazel, poplar, willow. tree mix II: beech, birch, oak, plane tree.
Abbreviations: NA, not applicable.
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Table 4. Comorbidities of allergic diseases at the baseline survey for each clinical phenotype of BHR Variables
Non-BHR
Early-onset
Late-onset
Early-onset
transient BHR
BHR
persistent
P value
BHR Wheeze, ever, n (%)
88/895 (9.8)
33/193 (17.1)
10/82 (12.2)
Wheeze, last 12 months, n
88/895 (9.8)
33/193 (17.1)
10/82 (12.2)
16/70 (22.9)
0.001
77/894 (8.6)
30/191 (15.7)
8/81 (9.9)
17/70 (24.3)
<0.001
31/895 (3.5)
14/193 (7.3)
6/82 (7.3)
10/70 (14.3)
<0.001
37/895 (4.1)
16/193 (8.3)
5/81 (6.2)
12/70 (17.1)
<0.001
Itchy eczema, ever, n (%)
314/881 (35.6)
75/194 (38.7)
31/80 (38.8)
37/71 (52.1)
0.048
Itchy eczema, last 12
196/881 (22.2)
50/194 (25.8)
18/80 (22.5)
23/71 (32.4)
0.212
270/880 (20.7)
69/193 (35.8)
22/80 (27.5)
32/71 (45.1)
0.041
111/877 (12.7)
29/186 (15.6)
14/79 (17.7)
12/71 (16.9)
0.381
158/880 (18.0)
45/193 (23.3)
14/80 (17.5)
19/71 (26.8)
0.126
AR symptoms, ever, n (%)
377/886 (42.6)
103/195 (52.8)
45/81 (55.6)
41/70 (58.6)
0.002
AR symptoms, last 12
290/328 (88.4)
70/82 (85.4)
33/35 (94.3)
30/33 (90.9)
0.545
AR diagnosis, ever, n (%)
194/885 (21.9)
56/195 (27.8)
25/81 (30.9)
23/70 (32.9)
0.023
AR treatment, last 12
164/886 (18.5)
47/194 (24.2)
23/81 (28.4)
18/70 (25.7)
0.044
179/886 (20.2)
49/195 (25.1)
22/81 (27.2)
18/70 (25.7)
0.204
12 months, n (%)
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Current asthma, n (%)
Diagnosis of AD, ever, n (%)
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Current AD, n (%)
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Treatment of AD, last 12
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months, n (%)
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n (%) Treatment of asthma, last
0.001
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16/70 (22.9)
months, n (%)
months, n (%) Current AR, n (%) 11
Abbreviations:
AD,
atopic
dermatitis;
AR,
allergic
rhinitis;
BHR,
bronchial
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hyperresponsiveness.
AC
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Clinical phenotypes of bronchial hyperresponsiveness in school-aged children Eun Lee MD, PhD , Young-Ho Kim MD , Hyun-Ju Cho MD , Ji-Sun Yoon MD , Sungsu Jung MD , Song-I Yang MD, PhD , Hyung Young Kim MD , Ji-Won Kwon MD, PhD , Ju-Hee Seo MD, PhD , Hyo Bin Kim MD, PhD , So Yeon Lee MD, PhD , Soo-Jong Hong MD, PhD PII: DOI: Reference:
S1081-1206(18)30420-4 10.1016/j.anai.2018.05.033 ANAI 2576
To appear in:
Annals of Allergy, Asthma Immunology
Received date: Revised date: Accepted date:
17 February 2018 19 May 2018 29 May 2018
Please cite this article as: Eun Lee MD, PhD , Young-Ho Kim MD , Hyun-Ju Cho MD , Ji-Sun Yoon MD , Sungsu Jung MD , Song-I Yang MD, PhD , Hyung Young Kim MD , Ji-Won Kwon MD, PhD , Ju-Hee Seo MD, PhD , Hyo Bin Kim MD, PhD , So Yeon Lee MD, PhD , Soo-Jong Hong MD, PhD , Clinical phenotypes of bronchial hyperresponsiveness in school-aged children, Annals of Allergy, Asthma Immunology (2018), doi: 10.1016/j.anai.2018.05.033
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Clinical phenotypes of bronchial hyperresponsiveness in school-aged children
2
Eun Lee, MD, PhD*, Young-Ho Kim, MD†, Hyun-Ju Cho, MD‡, Ji-Sun Yoon, MD†, Sungsu
4
Jung, MD †, Song-I Yang, MD, PhD§, Hyung Young Kim, MD∥, Ji-Won Kwon, MD, PhD¶,
5
Ju-Hee Seo, MD, PhD**, Hyo Bin Kim, MD, PhD††, So Yeon Lee, MD, PhD†, Soo-Jong
6
Hong, MD, PhD†
7 8
*
9
University Medical School, Gwangju, Korea,
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3
10
†
11
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea,
12
‡
13
ncheon, Korea,
14
§
15
∥
16
¶
17
**
18
††
19
Seoul, Korea.
20
AC
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Department of Pediatrics, Chonnam National University Hospital, Chonnam National
21
Department of Pediatrics, Childhood Asthma Atopy Center, Environmental Health Center,
M
Department of Pediatrics, International St. Mary's hospital, Catholic Kwandong University, I
ED
Department of Pediatrics, Hallym University Sacred Heart Hospital, Anyang, Korea, Department of Pediatrics, Pusan National University Yangsan Hospital, Yangsan, Korea,
PT
Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea, Department of Pediatrics, Dankuk University Hospital, Cheonan, Korea,
CE
Department of Pediatrics, Sanggye Paik Hospital, Inje University College of Medicine,
Lee E and Kim YH equally contributed to this work.
22 23
Correspondence: Soo-Jong Hong, MD, PhD
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Department of Pediatrics, Childhood Asthma and Atopy Center, Environmental Health
25
Center, Asan Medical Center, University of Ulsan
College of Medicine, 88 Olympic-ro 43-
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gil, Songpa-gu, Seoul 05505, Korea
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Tel: 82-2-3010-3379; Fax: 82-2-473-3725; E-mail: [email protected]
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Funding sources: This research was supported by Basic Science Research Program through
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the National Research Foundation of Korea (NRF) funded by the Ministry of Education
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(2017R1D1A1B03033576).
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Word count for text: 3,767
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Number of figures: 4
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Number of tables: 4
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Potential conflict of interest: The authors declare no conflicts of interest in relation to this
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study.
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Author’s contribution: conception and design of the study-Lee E, Kim YH, Lee SY, Hong
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SJ. Data generation: Kim YH, Lee SY, Cho HJ, Yoon JS, Jung SU, Yang SI, Kim HY, Kwon
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JW, Seo SH, Kim HB, Lee SY, Hong SJ.
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Abstract
Background: Bronchial hyperresponsiveness (BHR), one of the key features of asthma, shows a
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diverse natural course in school-aged children, but, studies on BHR phenotypes are lacking.
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Objective: We classified BHR phenotypes according to onset age and persistence in children a
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nd investigated the characteristics and factors associated with each phenotype in a longitudin
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al study.
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Methods: We analyzed 1,305 elementary school children from the Children's HEalth and Enviro
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nmental Research (CHEER) study, a 4-year prospective follow-up study with 2-year intervals sta
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rting at a mean age of 7 years. Total serum IgE levels and blood eosinophils (%) were measu
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red, and allergy work-up including methacholine challenge tests with ISSAC questionnaire were
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performed at each survey. Results: We classified the four BHR phenotypes as non-BHR (n=942, 72.2%), early-onset transi
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ent BHR (n=201, 15.4%), late-onset BHR (n=87, 6.7%), and early-onset persistent BHR (n=75, 5
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.7%). Early-onset persistent BHR is characterized by an increased eosinophils (%), total serum I
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gE level, sensitization rate, a decreased lung function and an increased risk of newly diagnose
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d asthma during follow-up (aOR, 3.89; 95% CI, 1.70-8.88). The two early-onset phenotypes we
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re associated with peripheral airway dysfunction. The late-onset BHR phenotype related with i
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ncreased risks of AR symptoms at baseline and later sensitization against inhalant allergens.
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Conclusion: The early-onset persistent BHR phenotype in school-aged children is associated wi
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th high atopic burden and increased risk of newly diagnosed asthma, whereas the late-onset
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BHR phenotype related with later sensitization and AR symptoms. Diverse BHR phenotypes in
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children have specific characteristics that require targeted follow-ups.
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Keywords: asthma; bronchial hyperresponsiveness; children; phenotype; sensitization.
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INTRODUCTION
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Bronchial hyperresponsiveness (BHR) is associated with airway inflammation, even in
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asymptomatic individuals, and with abnormalities of airway smooth muscle cells.1,2 BHR is
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one of the key characteristics of asthma and is correlated with its severity. In previous general
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population based studies, the prevalence of BHR was reported to be about 14 – 33% in
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children and to decrease in prevalence with age, particularly in relation to severity.3,4
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Airway caliber, sex, and age have impacts on the degree of BHR.4-8 In addition, asthma,
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combined allergic diseases, atopy, exposure to gas cooking, and high levels of total serum IgE
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have an identified association with BHR.9 In our previous study, atopy was found to be
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related to BHR in boys, whereas sexual maturation showed an association with BHR in girls.4
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In a report from another group, atopic asthmatic school-aged children showed greater BHR
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compared to non-atopic asthmatic children, whereas atopic and non-atopic asthmatic
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preschool children showed a similar BHR.9 Further epidemiologic studies have reported that
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the severity of BHR is associated with the symptoms and persistence of BHR.10,11 The
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findings from the previous studies have thus suggested that BHR has heterogeneous features
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with a variety of prognoses, irrespective of the presence of asthma. Notably however, studies
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on BHR phenotypes are lacking, even though these phenotypes would necessarily contribute
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to the understanding of pattern variations in childhood BHR and to the identification of
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modifiable factors related to its onset.
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Further investigation of clinical BHR phenotypes is essential to a better prediction of
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prognosis and increased understanding of the associated factors for each clinical phenotype of
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BHR. Although the natural course of asthma in children has not yet been fully elucidated,12
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much detailed research has contributed to our understanding of the diversity of asthma
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phenotypes and their underlying pathophysiologic differences.13,14 In children with asthma,
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onset age and persistency of symptoms are important prognostic indicators of lung function
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outcomes in later life.13 Similar to asthma, onset age and persistency of BHR may play an
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important role in the prognosis of BHR and its comorbidities.
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In our present study, we have classified four clinical phenotypes of BHR in accordance with
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onset age and persistence over its natural course in 7 year old children. We investigated the
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characteristics and factors associated with each clinical phenotype of BHR in a prospective
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longitudinal study.
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METHODS
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Study population
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This study was performed as a part of the Children‟s Health and Environment Research
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(CHEER) study, conducted in 27 randomly selected elementary schools in 10 areas across the
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Republic of Korea.14-17 The participants were followed-up for 4 years with 2-year intervals
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starting at 6-8 years of age. Each survey comprised a parent-completed questionnaire on
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allergic diseases, blood tests including total serum IgE levels and eosinophil count, skin prick
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tests (SPT), pulmonary function test (PFT), and methacholine challenge test (MCT). Among
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the total population of 2,423 elementary school-aged children in the CHEER study, we
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enrolled 1,305 children for whom MCT results at each of the three surveys were available.
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Written consent was obtained from all parents or guardians. The present study was approved
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by the Institutional Review Board of Ulsan University College of Medicine (IRB No. 2006-
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Definitions
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We classified four clinical phenotypes of BHR in accordance with onset age and persistence.
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No evidence of BHR at either the baseline or final survey indicated a „non-BHR‟ phenotype.
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Children with positive BHR at baseline but no BHR at the final study were classified as
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„early-onset transient BHR‟. The „early-onset persistent BHR‟ phenotype included children
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who were positive for BHR at both the baseline and final surveys. The „late-onset BHR‟
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phenotype was defined as no BHR at baseline survey but positive BHR at the final survey.
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MCT can be performed in children from 6 years of age according to the cooperation of the
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patients and we assigned „early-onset BHR‟ to children with positive MCT results at 6-7
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years, which was the enrollment age in the present study as well as enforceable age with good
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performance. Although four-year follow-up might not be sufficient to define the „persistent‟
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phenotype, BHR persisting for 4 years including the puberty period is meaningful in the
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prediction of persistence of BHR.4 By applying a strict definition of BHR as less than 8
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mg/mL methacholine, we excluded ambiguous cases of positive BHR. We classified children
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with positive BHR both enrollment and follow-up surveys as “persistent BHR”, considering
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the high possibility of persistence of BHR in children aged 11-12 years old at the time of 3rd
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survey. We did not consider the results of MCTs on the 2nd survey in the classification of
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clinical BHR phenotypes, because a 2-year interval for the follow-up of BHR was not
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sufficient to define the clinical phenotypes of BHR.
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Questionnaire
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The International Studies of Asthma Allergic diseases in Childhood (ISAAC) questionnaire
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has been previously validated in Korean children and was utilized in our current study to
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evaluate the presence of allergic diseases including atopic dermatitis (AD), allergic rhinitis
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(AR) and asthma, and factors associated with allergic diseases at the time of each survey.18,19
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Asthma at the time of enrollment was defined by an affirmative response to the questions in
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the ISAAC questionnaire: “Have you ever been diagnosed with asthma by a physician?”. The
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presence of asthma symptoms in the preceding 12 months was assessed using the question,
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“Have you ever had symptoms of asthma, such as wheezing or whistling in the chest, during
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the last 12 months?”. A participant was designated as having AR at the time of enrollment if
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there was an affirmative response in the ISAAC questionnaire to the following question:
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“Have you ever been diagnosed with AR by a physician?” The presence of AR symptoms in
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the preceding 12 months was assessed by the question, “Have you ever had nasal symptoms,
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such as watery rhinorrhea, nasal obstruction, nasal itching or sneezing unrelated to cold,
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during the last 12 months?”. The prevalence of AD was defined by a positive response to the
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“Has your child been diagnosed with AD by a physician (lifetime AD diagnosis)”.
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Methacholine challenge test (MCT)
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For the methacholine challenge test (MCT), we used a modified five-breath dosimeter
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method in accordance with the American Thoracic Society (ATS) guideline.20 Spirometry
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(Jaeger APS; CareFusion Respiratory Care, San Diego, CA) was conducted using a Hans-
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Rudolph nonrebreathing valve (Hand Rudolph Inc., Kansas City, MO) and a Misty-Neb
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Medication nebulizer set (CareFusion Respiratory Care) with the flow meter set at 0.009 mL
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± 10% of the solution per 0.6 s of actuation during inhalation. Subjects were excluded from
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the analysis if they had a history of upper or lower respiratory tract infection during the three
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weeks prior to MCT or had received inhaled corticosteroid therapy at least four weeks before
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MCT. Normal saline was used as a baseline and was followed by stepwise concentrations of
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methacholine concentrations (0.625 1.25, 2.5, 5, 12.5, and 25 mg/mL). The forced expiratory
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volume in 1 second (FEV1) was measured at 30 and 90 s after the nebulization was completed
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and the next dosing schedule then proceeded within 5 minutes. The MCTs in the CHEER
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study were performed within a few days in the same season to exclude the possible effects of
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confounding factors on BHR. Subjects with a history of upper or lower respiratory infection
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during the preceeding four weeks or who received inhaled corticosteroid therapy were not
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given an MCT. We defined BHR positivity as a 20% decrease in the FEV1 (PC20) caused by a
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provocative methacholine concentration of less than 8 mg/mL.
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Skin prick tests (SPTs)
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Skin prick tests (SPTs) were performed for 14 common inhalant and 4 food allergens
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(Allergopharma GmbH & Co, Reinbek, Germany). The inhalant allergens included house
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dust mites (Dermatophagoides pteronyssinus [Der p] and Dermatophagoides farina [Der f]), cat epithelium, dog dander, cockroaches, molds (Alternaria alternata and Aspergillus
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fumigatus), tree mix I (alder, elm, hazel, and poplar), tree mix II (beech, birch, oak, and plane
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tree), ragweed, mugwort, alder, oak, and a grass pollen mixture. The four food allergens were
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peanuts, egg whites, cow‟s milk, and soybeans. Histamine (10 mg/mL) and normal saline
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were used as positive and negative controls, respectively. We defined atopy as the presence of
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one or more positive results on an SPT. A positive SPT was defined as a mean wheal diameter
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of equal or greater than 3 mm and positive control.
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Pulmonary function tests (PFTs)
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Pulmonary function tests (PFTs) were performed according to the ATS (American Thoracic
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Society)/ERS (European Respiratory Society) guidelines.21 A portable micro-spirometer
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(Microspiro HI-298; Chest Corporation, Tokyo, Japan) was used to measure the forced vital
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capacity (FVC), FEV1, forced expiratory flow at 25% to 75% of FVC (FEF25-75%), and
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FEV1/FVC ratio.
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Statistical analysis
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The data are presented as a mean ± standard deviation. Logistic regression analysis was
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conducted to investigate associated factors and compare the odds of allergic outcomes across
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the four clinical BHR phenotypes. Multiple comparisons between two groups were
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counteracted with Bonferroni correction. SAS 9.4 software (IBM SAS, Chicago, IL) was
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used for the statistical analysis. A p value of 0.05 or less was considered to be significant.
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RESULTS
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Characteristics of the study population and BHR phenotypes
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A comparison of the characteristics of each BHR phenotype revealed significant differences
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in the living area and monthly income across the four clinical phenotypes (Table 1).
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Approximately half (50.9%) of the study population were boys and there was no significant
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difference in the proportion of boys and girls across the four BHR phenotypes. The
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distribution of the total study population across the four clinical phenotypes of BHR was as
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follows: non-BHR (n=942, 72.2%), early-onset transient BHR (n=201, 15.4%), late-onset
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BHR (n=87, 6.7%), and early-onset persistent BHR (n=75, 5.7%). We observed that 37.9% of
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the study population had a family history of allergic diseases without significant differences
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across the four phenotypes.
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The prevalence of exposure to environmental tobacco smoke (ETS), antibiotics and pets in
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infancy was highest among the early-onset persistent BHR phenotype cases, although this
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was not statistically significant. The prevalence of prematurity and bronchiolitis history in
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infancy was highest for the early-onset transient BHR phenotype, also without statistical
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significance.
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Atopic burden among the four BHR phenotypes
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The blood eosinophil count and total serum IgE levels were highest in the children with
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early-onset persistent BHR phenotype both at the time of enrollment and at follow-up (Fig.
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1). Based on the SPT results, the prevalence of sensitization against common allergens was
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also highest for the early-onset persistent BHR phenotype at the time of enrollment and
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follow-up (Fig. 2A and 2B). The sensitization rate, including the multiple sensitization rate,
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i.e. more than 2 allergens, was also highest among the early-onset persistent BHR phenotype
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subjects (Fig 2C). However, the new sensitization rate and number of newly sensitized
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allergens during the follow-up period was highest for the late-onset BHR phenotype (Fig. 2D
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and 2F). Sensitization to house dust mites and diverse pollen was increased during follow-up
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(Tables 2 and 3).
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Comorbidities with each BHR phenotype
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The prevalence of parental-reported, physician-diagnosed asthma, AD, and AR during the
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lifetime of each subject was highest in the early-onset persistent BHR phenotype (Table 4 and
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Supplementary Figures 1-3). The prevalence of parental-reported, physician-diagnosed AD in
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lifetime and current AD was higher in the early-onset transient BHR group than in the late-
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onset subjects (Table 4 and Supplementary Figure 1). The prevalence of AR symptoms and
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AR treatment in the preceding 12 months was highest for the late-onset BHR phenotype
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(Table 4 and Supplementary Figure 2). The risk of asthma symptoms and asthma treatment in
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the preceding 12 months at the time of enrollment was significantly increased in the subjects
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with the two early-onset BHR phenotypes (Supplementary Figure 3).
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Baseline and follow-up pulmonary function in clinical BHR phenotype
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The level of FEV1 % predicted at baseline was lowest in the early-onset persistent BHR
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phenotype subjects (P < 0.001), which accorded with the findings of the follow-up study (Fig.
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3A and 3B). At the time of enrollment, the levels of FVC % predicted in the early-onset
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transient BHR phenotype was significantly lower than that found for the non-BHR phenotype
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(Fig. 3C). In the follow-up study, the level of FVC % predicted was lowest in the early-onset
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persistent BHR phenotype, followed by the late-onset BHR, early-onset transient BHR, and
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non-BHR phenotypes (Fig. 3D). The FEV1/FVC was significantly lower among the three
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BHR phenotypes compared to the non-BHR phenotype at the time of enrollment (Fig. 3E).
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The same pattern was observed in the follow-up study (Fig. 3F). The levels of FEF25-75% %
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predicted were significantly lower among the children with the early-onset transient and
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early-onset persistent BHR phenotypes compared to those with the non-BHR phenotype both
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at the time of enrollment and follow-up (Fig. 3G and 3H).
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Prognosis for each clinical phenotype of BHR
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The odds ratio for newly diagnosed asthma by physicians during follow-up was increased
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(aOR, 3.89; 95% CIs, 1.70-8.88; Fig. 4A), as was that of asthma symptoms during the
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preceding 12 months during follow-up (aOR, 2.06; 95% CIs, 1.05-4.07; Fig. 4B), in the
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subjects with the early-onset persistent BHR phenotype. However, there were no significant
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differences found in the risk of newly diagnosed AR and AD across the four BHR phenotypes
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(Fig. 4C and 4D).
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DISCUSSION We have identified four clinical phenotypes of BHR in school-aged children and characterized some of the diverse factors and prognoses associated with each clinical BHR phenotype. The clinical phenotypes of BHR were defined as non-BHR, early-onset transient BHR, late-onset BHR, and early-onset persistent BHR in accordance with onset age and
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persistence. The early-onset persistent phenotype is characterized by high atopic burden (high sensitization rate, increased total serum IgE levels and higher eosinophil count), decreased lung function, and increased risks of newly developed asthma and asthma symptoms during
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follow-up. The two early-onset phenotypes were found to be associated with decreased peripheral airway function at baseline and during follow-up, suggesting the need for longterm follow-up of lung function in children with these phenotypes. The late-onset BHR phenotype is characterized by a new sensitization to diverse inhalant allergens including
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house dust mite and multiple pollens and an increased risk of AR symptoms. Although diverse studies on the phenotypes of asthma, AD, and AR have been undertaken, our present
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study is, to our knowledge, the first prospective report to classify distinct clinical phenotypes
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of BHR and identify their associated factors in school-aged children. Moreover, the results of our present study suggest the need to evaluate the presence of BHR in children showing a
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high atopic burden with new sensitization during follow-up and with decreased lung function. In a previous 4-year prospective follow-up epidemiologic study of BHR in 380 school-aged
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children, starting at 8-10 years old,3 BHR was categorized as mild or slight, moderate and severe according to its severity at each survey. Respiratory symptoms, atopy, and medication usage were assessed in that study and an association of these factors with moderate to severe BHR was reported. By contrast, we here classified four clinical phenotypes of BHR in accordance with onset age and persistence in a larger cohort of children starting at 7 years of age. We evaluated the factors associated with these phenotypes including serologic results,
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such as blood eosinophil count and total serum IgE levels, pulmonary function, and atopy on SPTs. By classifying the clinical phenotypes of BHR in this way, the clinical and pathophysiological heterogeneity of BHR was better characterized than by the previous use of severity.3 Our current findings thus provide useful new insights that can help to explain and predict the onset and persistence of BHR in real clinical situations.
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We found in our current analysis that the early-onset BHR phenotypes, including both the transient and persistent phenotypes, were characterized by a high eosinophil count and total serum IgE levels and a decreased lung function at the time of enrollment. Notably, the FEF25which is a measure of small airway function and can reflect the severity of BHR, 22 was
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decreased at the time of enrollment as well as during the follow-up survey in the children with these early-onset BHR phenotypes. These findings may suggest that BHR in early life affects lung function and the natural course of lung development in later life. Further long-
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term follow-up studies are thus needed to evaluate the effects of BHR on lung function and its long-term prognosis.
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Sensitization to allergens may play an important role on the natural course of BHR. At
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baseline, the most commonly sensitized allergen across the four BHR phenotypes were house dust mites including Der f and Der p. During the follow-up period, significant differences
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were observed in the sensitization rates for tree pollens, Alternaria, and Der f and Der p across the four phenotypes. Sensitization to fungal allergens, including Alternaria, is known
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to be related to the development and persistence of asthma and its exacerbation or severity.23 There have been no previous demonstrations of the clinical relevance of specific fungal sensitization to the clinical phenotypes of BHR, but our present findings indicate that it plays a role in determining these phenotypes. Our previous study identified that early sensitization to outdoor allergens, including Alternaria, and later sensitization to indoor allergens, including Aspergillus, was related to new-onset BHR,17 consistent with our current results.
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In addition, the prevalence of poly-sensitization was highest in the early-onset persistent BHR phenotype, whereas the newly sensitized rate and number of new sensitizations to common allergens during follow-up was highest in the late-onset BHR phenotype. These results suggest that changes in sensitization pattern are associated with the prognosis of BHR, although the role of sensitization in both the induction and maintenance of BHR remains to
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be elucidated.
The full spectrum of clinical implications and prognosis of BHR in children has remained, although several studies have reported an increased risk of asthma and a positive association
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between more severe BHR and symptomatic BHR.10,11,24 In our present investigation, we found no significant differences between the baseline BHR levels in the two early-onset BHR phenotypes (Supplementary Figure 4), although the prevalence of sensitization in combination with the blood eosinophil count, and total serum IgE levels were higher in
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children with the early-onset persistent BHR phenotype compared to those in the early-onset transient BHR phenotype. These findings suggest that the atopic burden, rather than the
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severity of BHR in early life, might play an important role in the persistence of BHR.
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The bronchial provocation test in children is performed to evaluate the degree of BHR in patients with asthma or to diagnose asthma when the symptoms are vague or the diagnosis is
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uncertain using spirometry.20 However, BHR can be accompanied by allergic diseases other than asthma.25 In patients with AR, the combined presence of BHR is indicative of a lower
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chance of remission of AR, except in patients treated for AR.25 A previous study has reported that asymptomatic BHR without any allergic symptoms was not associated with the increased risk of asthma. In another report, adolescents with respiratory symptoms in combination with BHR showed an increased risk of asthma.26 Taken together, the evidence to date suggests that the presence of BHR may predict the persistence of not only asthma but also allergic diseases including AR. Hence, the measurement of BHR may be very helpful in making a
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personalized therapeutic plan and predicting the prognosis in patients with severe and persistent AR or allergic symptoms. We further found in our current analysis that there was a higher prevalence of a lifetime diagnosis of AD among the children in the two early-onset BHR phenotypes, although the statistical power of these observations was notably weak. Among the subjects in the two
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early-onset BHR phenotypes, the persistence of BHR showed a relationship with sensitization and might therefore relate to the progression of decreased lung function. These findings suggest that the early-onset BHR phenotypes may be associated with allergic march and
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therefore that a long-term follow-up is needed in these children.27
Prematurity and a bronchiolitis history in infancy were found to be more prevalent among the children in the early-onset transient BHR phenotype, although this was not a significant difference. The lack of a significant difference between these two factors across the four BHR
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phenotypes may suggest that they do not play an important role in the development and persistency of BHR in school-aged children. This possibility is supported by the findings of a
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previous study, which indicated that the majority of wheezing symptoms in infants are
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transient and are not associated with the risk of asthma or allergic diseases in later life.28 A primary strength of our present analyses was the enrollment of subjects from a nation-wide
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and longitudinal general population of children. This allowed us to identify the clinical phenotypes of BHR and the factors associated with each phenotype. In addition, our detailed
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evaluations using objective PFT, SPTs, and MCT, and our assessment of serologic marker levels including total serum IgE and blood eosinophil counts, enabled us to further elucidate the characteristics of each phenotype. Nonetheless, our current study had several limitations of note. The follow-up period was relatively short, and the long-term prognosis associated with each BHR phenotype could therefore not be fully evaluated. However, our study was strengthened by the repeat BHR measurements as well as our use of other allergic work-ups
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including SPTs to assess more diverse allergens and also the PFTs we conducted at regular intervals. We also artificially classified the four BHR phenotypes in accordance with onset age and persistence. It must be noted however that cluster analysis, such as latent class analysis, which is commonly used in the identification of small sets of phenotypes in diverse diseases, also has limitations such as the lack of examinations for higher-order interactions.29
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Since the aim of our present study was to identify associated factors for each BHR phenotype depending on onset age and persistence, the arbitrary classification we used is itself meaningful in a clinical setting and provides a very useful prediction method for the
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prognosis of BHR. Further studies on BHR phenotypes using diverse cluster analysis are still needed however to identify the heterogeneous pathophysiologies and underlying diverse clinical phenotypes of BHR. We used the ISAAC questionnaire to evaluate the presence of allergic diseases, which had the potential to misclassify these allergic diseases. However, this
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questionnaire is widely used and has been previously validated in a large epidemiologic study.30
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In summary, we have classified four clinical phenotypes of BHR in accordance with its onset
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age and persistence and further evaluated the factors associated with each phenotype. High eosinophil counts and total serum IgE levels, sensitization, sensitization patterns, and
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decreased lung function were found to be associated with the onset age and persistence of BHR. Peripheral airway function was decreased in the children of the two early-onset
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phenotypes, and a further reduction in lung function was observed in the early-onset persistent BHR phenotype. Sensitization in early life as well as during follow-up may play an important role in determining the new-onset and persistence of BHR. Early-onset persistent BHR was associated with an increased risk of asthma at the time of enrollment as well as the new development of asthma during follow-up. The late-onset BHR phenotype showed a relationship with increased risks of AR symptoms at baseline and later sensitization against
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inhalant allergens. We conclude from our present findings that targeted follow-ups for children with BHR, based on their BHR phenotype, are needed for more effective management of combined allergic diseases and improvement of lung function outcomes in these cases. Through the identification of specific clinical BHR phenotypes and their associated factors, the results of our present study may be a foundation for the future
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development of preventive and therapeutic strategies for allergic diseases.
[1]
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hyperresponsiveness to 4.5% saline and its relation to asthma and allergy symptoms
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to allergic rhinitis and asthma. Allergy Asthma Immunol Res. 2011;3:67-73.
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[30]
Worldwide
variation
in
prevalence
of
symptoms
of
asthma,
allergic
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rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351:1225-
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Figure legends
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Fig. 1. Comparison of the blood eosinophil counts (/mm3) and total serum IgE levels (Ku/L)
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at the baseline and follow-up surveys according to BHR phenotypes. (A) Blood eosinophil counts (/mm3) at baseline. (B) Blood eosinophil counts (/mm3) at follow-up. (C) Total serum IgE levels (Ku/L) at baseline. (D) Total serum IgE levels (Ku/L) at follow-up.
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Fig. 2. Comparison of the sensitization rate determined by skin prick tests at baseline and
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follow-up according to the BHR phenotypes. (A) Sensitization rates at baseline. (B) Sensitization rates at follow-up. (C) Prevalence of number of sensitized allergens at baseline.
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follow-up.
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(D) New sensitization rate during follow-up. (E) Number of newly sensitized allergens during
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Fig. 3. Results of pulmonary function tests at baseline and follow-up. (A) FEV1 % predicted
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at baseline. (B) FEV1 % predicted at follow-up. (C) FVC % predicted at baseline. (D) FVC % predicted at follow-up. (E) FEV1/FVC at baseline. (F) FEV1/FVC at follow-up. (G) FEF25% predicted at baseline. (H) FEF25-75% % predicted at follow-up.
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Fig. 4. Prognosis for each BHR phenotype. (A) Odds ratio and 95% CI for newly diagnosed asthma by physicians during the follow-up period. (B) Odds ratio and 95% CI for AR symptoms during the preceding 12 months at the final survey. (C) Odds ratio and 95% CI for newly diagnosed allergic rhinitis by physicians during the follow-up period. (D) Odds ratio and 95% CI for newly diagnosed atopic dermatitis by physicians during the follow-up period.
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*aOR, adjusted odds ratio; 95% CI, confidence intervals. **Adjusted for region, sex, parental history of allergic diseases, income, maternal education
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level.
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Table 1. Characteristics of the study subjects at the baseline survey Variables,
Non-BHR
AC
n (%) or mean ± SD
Early-onset
Late-onset
Early-onset
transient
BHR
persistent
BHR
P value
BHR
Number (%)
942 (72.2)
201 (15.4)
87 (6.7)
75 (5.7)
Age, years
7.37 ± 0.14
7.32 ± 0.03
7.26 ± 0.05
7.32 ± 0.05
0.081
Sex, male
479 (50.8)
101 (50.2)
44 (50.6)
40 (53.3)
0.977
Body mass index, kg/m2
16.80 ± 0.08
16.71 ± 0.18
16.12 ± 0.22
16.71 ± 0.27
0.097
Parental history of allergic
344 (37.0)
70 (35.9)
39 (45.3)
34 (45.9)
0.195
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<0.001
City
360 (38.2)
101 (50.2)
18 (20.7)
29 (38.7)
Industrial areas
375 (39.8)
48 (23.9)
54 (62.1)
27 (36.0)
Farming areas
207 (22.0)
52 (25.9)
15 (17.2)
19 (25.3)
Maternal educational level
0.260 530 (62.4)
120 (64.9)
58 (73.4)
44 (65.7)
> University
319 (37.6)
65 (35.1)
21 (26.6)
23 (34.3)
Monthly income
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≤ High school
0.041
646 (69.5)
153 (78.1)
53 (63.9)
53 (74.6)
> 3,000 $
283 (30.5)
43 (21.9)
30 (36.1)
18 (25.4)
Vaginal delivery
345/894 (38.6)
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≤ 3,000 $
86/188
29/82 (35.4)
26/73 (35.6)
0.221
31/77 (40.3)
35/66 (53.0)
0.323
13/182 (7.1)
3/76 (3.9)
2/64 (3.1)
0.486
56/181
21/74 (28.4)
23/65 (35.4)
0.764
3/198 (1.5)
2/85 (2.4)
4/75 (5.3)
0.355
22/185
7/73 (8.8)
4/61 (6.2)
0.541
71/82 (86.6)
58/72 (80.6)
0.292
50/78 (64.1)
46/64 (71.9)
0.672
(45.7)
ETS
391/856 (45.7)
75/181 (41.4)
41/849 (4.8)
Antibiotics in infancy
250/843 (29.7)
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Prematurity
31/932 (3.3)
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Pets in infancy
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Bronchiolitis in infancy
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Having any sibling
Breast milk feeding, yes
78/861 (9.1)
720/916 (78.6)
(30.9)
(11.9) 161/196 (82.1)
538/837 (64.3)
117/179 (65.4)
Abbreviations: ETS, Environmental tobacco smoke; SD, Standard deviation. The student‟s t-test, Fisher‟s exact test, or Kruskal–Wallis test was used as appropriate.
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Table 2. Sensitization rate for common allergens among the four clinical phenotypes of BHR at baseline Sensitized
Non-BHR
Early-onset
allergens, n (%)
Late-onset BHR
transient BHR
Early-onset
P value
persistent BHR
153/941 (16.3)
54/201 (26.9)
26/86 (30.2)
37/75 (49.3)
< 0.001
Der f, n (%)
129/941 (13.7)
50/201 (24.9)
19/86 (22.1)
34/75 (45.3)
< 0.001
Cockroach, n
20/942 (2.1)
5/201 (2.5)
3/86 (3.5)
8/941 (0.9)
2/201 (1.0)
2/86 (2.3)
6/941 (0.6)
3/201 (1.5)
1/86 (1.2)
7/941 (0.7)
3/201 (1.5)
2/86 (2.3)
2/75 (2.7)
0.226
Mugwort, n (%)
9/941 (1.0)
2/201 (1.0)
1/86 (1.2)
0/75 (0.0)
0.855
Ragweed, n (%)
4/941 (0.4)
2/201 (1.0)
1/86 (1.2)
1/75 (1.3)
0.554
Dog, n (%)
8/942 (0.8)
6/201 (3.0)
1/86 (1.2)
1/75 (1.3)
0.100
Cat, n (%)
8/941 (0.9)
3/201 (1.5)
3/86 (3.5)
2/75 (2.7)
0.106
Alternaria, n
29/941 (3.1)
9/201 (4.5)
7/86 (8.1)
5/75 (6.7)
0.055
4/201 (2.0)
1/86 (1.2)
2/75 (2.7)
0.042
(%) Grasses, n (%) †
Trees mix I, n
§
Trees mix II, n
†
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tree mix I: alder, elm, hazel, poplar, willow. tree mix II: beech, birch, oak, plane tree.
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§
4/941 (0.4)
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(%)
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Aspergillus, n
M
(%)
(%)
Abbreviations: NA, not applicable.
5/75 (6.7)
0.104
1/75 (1.3)
0.609
1/75 (1.3)
0.613
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Table 3. Sensitization rate for common allergens among the four clinical phenotypes of BHR
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at follow-up. Sensitized
Non-BHR
allergens, n (%)
Early-onset
Late-onset
Early-onset
transient BHR
BHR
persistent BHR
263/941 (27.9)
70/200 (35.0)
46/87 (52.9)
43/74 (58.1)
< 0.001
Der f, n (%)
240/941 (25.5)
65/200 (32.5)
45/87 (51.7)
44/74 (59.5)
< 0.001
Cockroach, n
23/941 (2.4)
3/200 (1.5)
2/87 (2.3)
17/941 (1.8)
8/200 (4.0)
5/87 (5.7)
29/941 (3.1)
9/200 (4.5)
7/87 (8.0)
34/941 (3.6)
9/200 (4.5)
6/87 (6.9)
8/74 (10.8)
0.019
Mugwort, n (%)
23/941 (2.4)
6/200 (3.0)
7/87 (8.0)
1/74 (1.4)
0.021
Ragweed, n (%)
5/941 (0.5)
3/200 (1.5)
1/87 (1.1)
2/74 (2.7)
0.153
Dog, n (%)
25/941 (2.7)
11/200 (5.5)
6/87 (6.9)
4/74 (5.4)
0.045
Cat, n (%)
39/941 (4.1)
9/200 (4.5)
8/87 (9.2)
5/74 (6.8)
0.151
Alternaria, n
39/941 (4.1)
12/200 (6.0)
11/87 (12.6)
7/74 (9.5)
0.002
2/200 (1.0)
0/87 (0.0)
0/74 (0.0)
0.697
†
Trees mix I, n
(%) §
Trees mix II, n
5 6 7 8
0.871
3/74 (4.1)
0.044
7/74 (9.5)
0.009
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Alder, n (%)
14/573 (2.4)
5/81 (6.2)
4/72 (5.6)
4/42 (9.5)
0.030
Oak, n (%)
16/573 (2.8)
3/81 (3.7)
4/72 (5.6)
2/42 (4.8)
0.582
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(%)
7/941 (0.7)
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Aspergillus, n
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(%)
(%)
2/74 (2.7)
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Grasses, n (%)
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Der p, n (%)
(%)
3
P value
†
§
tree mix I: alder, elm, hazel, poplar, willow. tree mix II: beech, birch, oak, plane tree.
Abbreviations: NA, not applicable.
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Table 4. Comorbidities of allergic diseases at the baseline survey for each clinical phenotype of BHR Variables
Non-BHR
Early-onset
Late-onset
Early-onset
transient BHR
BHR
persistent
P value
BHR Wheeze, ever, n (%)
88/895 (9.8)
33/193 (17.1)
10/82 (12.2)
Wheeze, last 12 months, n
88/895 (9.8)
33/193 (17.1)
10/82 (12.2)
16/70 (22.9)
0.001
77/894 (8.6)
30/191 (15.7)
8/81 (9.9)
17/70 (24.3)
<0.001
31/895 (3.5)
14/193 (7.3)
6/82 (7.3)
10/70 (14.3)
<0.001
37/895 (4.1)
16/193 (8.3)
5/81 (6.2)
12/70 (17.1)
<0.001
Itchy eczema, ever, n (%)
314/881 (35.6)
75/194 (38.7)
31/80 (38.8)
37/71 (52.1)
0.048
Itchy eczema, last 12
196/881 (22.2)
50/194 (25.8)
18/80 (22.5)
23/71 (32.4)
0.212
270/880 (20.7)
69/193 (35.8)
22/80 (27.5)
32/71 (45.1)
0.041
111/877 (12.7)
29/186 (15.6)
14/79 (17.7)
12/71 (16.9)
0.381
158/880 (18.0)
45/193 (23.3)
14/80 (17.5)
19/71 (26.8)
0.126
AR symptoms, ever, n (%)
377/886 (42.6)
103/195 (52.8)
45/81 (55.6)
41/70 (58.6)
0.002
AR symptoms, last 12
290/328 (88.4)
70/82 (85.4)
33/35 (94.3)
30/33 (90.9)
0.545
AR diagnosis, ever, n (%)
194/885 (21.9)
56/195 (27.8)
25/81 (30.9)
23/70 (32.9)
0.023
AR treatment, last 12
164/886 (18.5)
47/194 (24.2)
23/81 (28.4)
18/70 (25.7)
0.044
179/886 (20.2)
49/195 (25.1)
22/81 (27.2)
18/70 (25.7)
0.204
12 months, n (%)
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Current asthma, n (%)
Diagnosis of AD, ever, n (%)
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Current AD, n (%)
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Treatment of AD, last 12
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months, n (%)
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n (%) Treatment of asthma, last
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16/70 (22.9)
months, n (%)
months, n (%) Current AR, n (%) 11
Abbreviations:
AD,
atopic
dermatitis;
AR,
allergic
rhinitis;
BHR,
bronchial
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12
hyperresponsiveness.
AC
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