ORIGINAL ARTICLE
Combined use of fractional exhaled nitric oxide and bronchodilator response in predicting future loss of asthma control among children with atopic asthma JE-KYUNG KIM,1 JAE-YUB JUNG,1 HEON KIM,2 SANG-YONG EOM2 AND YOUN-SOO HAHN1 1
Department of Pediatrics, Chungbuk National University, and 2Department of Preventive Medicine, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Republic of Korea
ABSTRACT Background and objective: Recognition of patients at risk of asthma exacerbation is important for future asthma care and improved outcome. The aim of the present study was to see whether measurements of bronchodilator response (BDR) and fractional exhaled nitric oxide (FeNO) in combination provide prognostic information superior to either measurement alone in children with atopic asthma. Methods: A total of 201 atopic children aged 8–16 years with intermittent or mild persistent asthma were included. Pulmonary function tests including BDR and FeNO were serially monitored 10 times or more over 2 years when subjects were not receiving controller medications. After completion of monitoring, 1-year observation for a loss of asthma control was performed. Results: During the monitoring period, positive BDRs (≥12% in forced expiratory volume in 1 s (FEV1) from pre-bronchodilator value) and FeNO higher than 35 parts per billion (ppb) were observed at least once in 59% and 77% of participants. When analysed as continuous variables, both BDR (hazard ratio (HR): 1.21; 95% CI: 1.04–1.41; P = 0.014) and FeNO (HR: 1.27; 95% CI: 1.09–1.49; P = 0.003) were associated with increased risks for a control loss. Compared with patients showing either positive BDRs (HR: 3.19; 95% CI: 1.05–9.64) or FeNO higher than 35 ppb (HR: 4.70; 95% CI: 1.68–13.11), patients with both findings (HR: 7.08; 95% CI: 2.57–19.49) had greater risks for a control loss. Conclusion: These data support that combined use of BDR and FeNO measurements can modify predictive risk obtained from either measurement alone. Key words: asthma, atopy, bronchodilator response, child, fractional exhaled nitric oxide, loss of asthma control. Abbreviations: , ACQ5, Asthma Control Questionnaire 5; ATS/ ERS, American Thoracic Society/European Respiratory Society;
Correspondence: Youn-Soo Hahn, Department of Pediatrics, College of Medicine, Chungbuk National University, 410 Seongbong-ro, Hungduk-gu, Cheongju 361-763, Republic of Korea. Email:
[email protected] Received 23 March 2016; invited to revise 1 June, 12 July and 8 August 2016; revised 26 June, 20 July and 12 August 2016; accepted 19 August 2016 (Associate Editor: Giorgio Piacentini). © 2016 Asian Pacific Society of Respirology
SUMMARY AT A GLANCE High bronchodilator response (BDR) as well as high fractional exhaled nitric oxide (FeNO) are associated with increased risk of asthma control losses among children with atopic asthma. Combined use of BDR and FeNO measurements could improve the prediction capacity for upcoming asthma control losses. AUC, area under the curve; bd, twice daily; BDR, bronchodilator response; BMI, body mass index; FEF25–75, forced expiratory flow between 25% and 75% of vital capacity; FeNO, fractional exhaled NO; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; ICC, intraclass correlation; ICS, inhaled corticosteroid; Ig, immunoglobulin; L-%FEF25–75, lowest value of percent predicted FEF25–75; L-%FEV1, lowest value of percent predicted FEV1; L-%FVC, lowest value of percent predicted FVC; L-FEV1/FVC, lowest value of FEV1/FVC; lnPC20, natural log-transformed PC20; M-BDR, maximal value of BDR; MFeNO, maximal value of FeNO; NO, nitric oxide; PC20, concentration of methacholine causing a 20% fall in FEV1; ppb, parts per billion; ROC, receiver-operating characteristic.
INTRODUCTION Childhood asthma is a highly prevalent chronic disease and its exacerbation is one of the most distressing events.1,2 Recognition of patients at high risk for asthma exacerbations is thus important for future asthma care and outcome. Current asthma treatment guidelines have increasingly focused on how to best assess asthma control because poor asthma control can lead to severe asthma exacerbations.3 Fractional exhaled nitric oxide (FeNO) has been suggested as an effective risk marker of deterioration in asthma control.4 In addition, there are several studies reporting the usefulness of FeNO measurements in prediction of upcoming asthma impairment among asthmatic individuals.5–7 Because of fluctuations and inconsistency of FeNO which are related to multiple confounding factors,8,9 single FeNO measurement may not be predictive of future asthma exacerbations. Therefore, repeated FeNO measurements for a certain period of time may be needed to obtain more clarified information about the ongoing status of asthma. Respirology (2017) 22, 466–472 doi: 10.1111/resp.12934
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Combined use of FeNO and BDR in asthma
Because there is a substantial within-subject variability of bronchodilator responses (BDRs),10,11 repetitive measurements over time are sometimes required to make decisions on whether patients have significant BDRs. Clinical and prognostic significance of a positive BDR among asthmatic patients remains elusive because previous studies examining relations between BDRs and other asthma outcomes have shown mixed results.12–15 In this study, we investigated whether combination of FeNO and BDR measurements improves the prediction capacity of upcoming asthma control losses in children with atopic asthma.
METHODS Subjects Asthmatic patients aged 8–16 years were recruited from the outpatient clinic of the Chungbuk National University Hospital, Cheongju, Republic of Korea. To qualify, subjects were required to have atopy demonstrated by the ImmunoCAP system (Immunodiagnostics; Thermo Fisher Scientific, Uppsala, Sweden) and diagnoses of asthma based on the documentation of airway hyperresponsiveness (concentration of methacholine causing a 20% fall in forced expiratory volume in the 1 s (FEV1) (PC20) ≤ 8 mg/mL) and/or reversible airflow obstruction (a 12% or greater change in FEV1 in response to inhaled short-acting β2-agonist). All enrolled patients were classified as having intermittent or mild persistent asthma based on the guidelines from the National Asthma Education and Prevention Program.16 The study was approved by the Ethics Committee of Chungbuk National University Hospital Institutional Review Board and all parents of children signed a written informed consent.
to the hospital and a loss of control was assessed at each clinic visit. After confirming that asthma control was maintained for more than 1 month without use of controller medications, each period was commenced. According to the previous report,17 patients were classified as having controlled asthma if their Asthma Control Questionnaire 5 (ACQ5) scores were
