www.nature.com/scientificreports OPEN Efect of antibiotic use for acute bronchiolitis on new-onset asthma in children Received: 4 October 2017 I.-Lun Chen1,2, Hsin-Chun Huang1, Yu-Han Chang3, Hsin-Yi Huang3, Wei-Ju Yeh3, Ting-Yi Wu3, Accepted: 26 March 2018 Jau-Ling Suen 2, San-Nan Yang4 & Chih-Hsing Hung2,5,6,7,8 Published: xx xx xxxx Early-life use of antibiotics is associated with asthma. We examined the efect of antibiotic use for early-life bronchiolitis on the development of new-onset asthma in children from Taiwan between 2005 and 2010. Data were from the National Health Insurance Research Database 2010, and diseases were coded using the International Classifcation of Disease (ICD). We classifed the patients, all of whom had bronchiolitis, as having asthma or not having asthma. Asthma was diagnosed using ICD criteria and by use of an inhaled bronchodilator and/or corticosteroid twice in one year. We identifed age at asthma onset, sex, residential area, history of atopy and NSAID use, age at frst use of antibiotics, and the specifc antibiotic, and adjusted for these factors using conditional logistic regression analysis. Among all individuals, there was a relationship between risk of new-onset asthma with use of a high dose of an antibiotic (adjusted odds ratio [aOR] = 3.33, 95% confdence interval [CI] = 2.67–4.15). Among the diferent antibiotics, macrolides (aOR = 2.87, 95% CI = 1.99–4.16), and azithromycin specifcally (aOR = 3.45, 95% CI = 1.62–7.36), had the greatest efect of development of asthma. Environmental and genetic factors play important roles in the development of asthma. In particular, the “hygiene hypothesis” proposes that growing up in a hygienic environment, with reduced exposure to microbes, promotes T-helper type 2 (T2) immunity1. Te association of early-life use of antibiotics with wheezing symptoms and allergic rhinoconjunctivitis in childhood, and the lack of adverse efects of antibiotics on atopic diseases in child- hood among infants who live in rural environments, are consistent with this hypothesis2,3. Among babies younger than 1 year-old, acute bronchiolitis (a lower respiratory tract infection) is the leading cause of hospitalization due to recurrent wheezing episodes, and a history of bronchiolitis during infancy is associated with an increased risk for development of asthma4. Infants hospitalized with bronchiolitis due to res- piratory syncytial virus (RSV) infection have a 2 to 3-fold increased risk of developing asthma later in childhood5. Another study also demonstrated that rhinovirus-induced wheezing within the frst 3 years of life was associated with a nearly 10-fold increased risk for development of asthma by age six6. Although most cases of acute bronchiolitis are due to viral infections, antimicrobial drugs may be used if there is suspected co-infection by bacteria or for their anti-infammatory efects. In fact, a high incidence of bacterial co-infection was reported in children with severe bronchiolitis who required mechanical ventilation7. Bacterial PCR of blood samples showed that 10% of patients with acute bronchiolitis may have bacteremia, and the major species are Haemophilus infuenza and Streptococcus pneumonia8. However, use of antibiotics early in life and a history of bronchiolitis increase the risk for asthma in young adolescents9. Other studies reported that polymor- phisms of Toll-like receptor 4 might modify the efect of environmental factors, such as use of antibiotics, on the 1Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Kaohsiung City, Taiwan. 2Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. 3Teaching and Research Center of Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung City, Taiwan. 4Department of Pediatrics, E-DA Hospital and School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan. 5Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. 6Department of Pediatrics, Faculty of Pediatrics, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan. 7Department of Pediatrics, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung City, Taiwan. 8Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Correspondence and requests for materials should be addressed to S.-N.Y. (email: [email protected]) or C.-H.H. (email: [email protected]) SCIENTIFIC REPORTS | (2018) 8:6090 | DOI:10.1038/s41598-018-24348-5 1 www.nature.com/scientificreports/ Non-asthma group Asthma group (n = 2082) (n = 2082) N (%) N (%) p value Age, mean ± SD 3.32 ± 1.25 3.34 ± 1.26 0.497 Gender Female 921 (44.2) 907 (43.6) 0.662 Male 1161 (55.8) 1175 (56.4) Resident urbanization Urban 463 (22.2) 451 (21.7) 0.807 Suburban 806 (38.7) 818 (39.3) Rural 813 (39.0) 813 (39.0) Comorbidities Allergic rhinitis 644 (30.9) 668 (32.1) 0.423 Atopic dermatitis 466 (22.4) 456 (21.9) 0.709 Chronic rhinitis 309 (14.8) 322 (15.5) 0.574 Acute sinusitis 1615 (77.6) 1628 (78.2) 0.627 GERD 31 (1.5) 23 (1.1) 0.273 Medication NSAIDs 482 (23.2) 471 (22.6) 0.685 Table 1. Te characteristics of non-asthma and asthma group (N = 4,164). development of asthma10,11. Tus, reducing the use of antibiotics and prevention of bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects. Tere is strong evidence of an association between acute bronchiolitis and asthma, but it is unclear whether this is a causal relationship. Although antibiotic use in early life increases the risk of asthma, the efect of antibiotic use by children for treatment of early-life bronchiolitis on the development of new-onset asthma is unknown. Te aim of this study, which used the Taiwan National Health Insurance Research Database (NHIRD) 2010 database, was to assess the relationship of early-life antibiotic use for bronchiolitis with new-onset asthma in children. Methods Data source. Tis study examined claims data from the NHIRD, which includes the medical records of 99% of the 23.74 million residents of Taiwan, and 97% of Taiwanese hospitals and clinics who have contracts with the National Health Research Institute in Taiwan. Te NHIRD contains comprehensive healthcare information, including demographic data of insured individuals, dates of clinical visits, diagnostic codes, and prescription details. All data in this study were from the NHIRD 2010, and all diseases were classifed using the International Classifcation of Disease, Ninth Revision, Clinical Modifcation (ICD-9-CM). Patients with records indicat- ing a diagnosis of bronchiolitis (ICD-9:466.19) during the frst 2 years of life from 2000 to 2010 were included. New-onset asthma was diagnosed using the criteria of ICD-9:493 and receipt of selective beta-2 agonists and/or inhaled corticosteroid treatments twice within one year from age 2 to 18 years-old. Tis study was approved by the Institutional Review Board of Kaohsiung Medical University (KMUHIRB-E (I)-20150168). All methods were performed in accordance with the relevant guidelines and regulations. Use of antibiotics. Te use of antibiotics was obtained from the outpatient prescription database, which listed the name of the drug and had data on dosage, date, and duration of prescription. To investigate the efect of antibiotic dosage, the cumulative defned daily dose (DDD) was calculated. Antibiotic use was defned as the prescription of at least one antibiotic (anatomical therapeutic chemical [ATC] code J01*) in the 5 years before onset of asthma. We analyzed data on 3 individual common classes of antibiotics—penicillins (ATC code J01C*), cephalosporins (ATC code J01D*), and macrolides (ATC code J01F*). Other types of antibiotics (quinolones, sulphonamides, glycopeptides, lincosamides) were analyzed separately. Potential confounders. Te potential confounders of asthma included urban residence, allergic rhinitis (ICD9-CM: 477.8, 477.9), atopic dermatitis (ICD9-CM: 691.8), chronic rhinitis (ICD9-CM:472.0), acute sinus- itis (ICD9-CM:461), gastroesophageal refux disease (GERD) (ICD9-CM:530.81), and use of a nonsteroidal anti-infammatory drug (NSAID) in the 120 days before the onset of asthma. Statistical analysis. Pearson’s chi-square test or Fisher’s exact test and the independent t test were used to evaluate the signifcance of diferences of categorical and continuous variables in patients with and without asthma. Conditional logistic regression analysis was used to calculate the association between asthma and anti- biotic use. As recommended by the World Health Organization (WHO), cumulative DDD was used to quantify the cumulative dose of antibiotics, and the categories were “low dose”, “moderate dose”, and “high dose”. Several co-variables, including age, sex, residential area, history of atopy, and use of NSAIDs, were included in the sta- tistical model. Te efect of antibiotic class was also analyzed by adjusting for co-variables and type of antibiotic, except for penicillins, cephalosporins, and macrolides. Odds ratios (ORs), adjusted ORs (aORs) and 95% conf- dence intervals (CIs) were calculated to show the risk for development of asthma. We further used false discovery SCIENTIFIC REPORTS | (2018) 8:6090 | DOI:10.1038/s41598-018-24348-5 2 www.nature.com/scientificreports/ Non-asthma group Asthma group (n = 2082) (n = 2082) Unadjusted Model Adjusted Model Antibiotic use N (%) N (%) OR (95% CI) p value OR (95% CI) p value J01 antibiotic* No 419 (20.1) 233 (11.2) 1.00 1.00 Yes