Early Biomarker for Treatment Study Group, Innovative Asthma Association, Japan
Received date: April 01, 2013; Accepted date: May 15, 2014; Published date: May 20, 2014
Citation: Shirai T, Kawayama T, Nagase H, Inoue H, Sato S, et al. (2014) Exhaled Nitric Oxide Measurement may Predict Asthma Exacerbation after Stepping down Formoterol/Budesonide Combination Therapy in Adult Asthma. J Allergy Ther 5:173. doi: 10.4172/2155-6121.1000173
Copyright: © 2014 Shirai T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Objective: The Global Initiative for Asthma (GINA) guidelines state that when asthma control is maintained for at least 3 months, treatment can be stepped down; however, prediction tools have not been established for the reappearance of symptoms and increased risk of exacerbation on stepping down treatment. This study was designed to assess whether FeNO measurement predicts asthma exacerbation after stepping down from fixed dose formoterol/budesonide combination (FBC)9/320 μg bid to 4.5/160 μg bid (UMIN000005406).
Methods: Subjects included 37 patients receiving a fixed-dose FBC 9/320 μg bid for at least 3 months, and achieving controlled asthma (GINA) in conjunction with an Asthma Control Questionnaire (5-item version (ACQ5) score ≤ 0.75). Based on the FeNO value at stepping down, patients were classified into 25 patients with FeNO<37 ppb and 12 with FeNO ≥ 37 ppb. The primary endpoint was the occurrence of asthma exacerbation within 8 weeks and from 8 weeks until 12 months. Secondary endpoints, including ACQ5, FeNO, and pulmonary function tests, were measured at baseline and until 8 weeks.
Results: There was no difference in the incidence of exacerbation between patients with FeNO ≥ 37 ppb and those with FeNO<37 ppb within 8 weeks; however, in a long-term follow up until 12 months, the incidence was significantly higher in patients with FeNO ≥ 37 ppb than in those with FeNO<37 ppb (odds ratio 11.33, 95% confidence interval 1.45 to 88.52).There was no statistically significant differencein changes in ACQ5, pulmonary functions, and FeNO between the 2 groups by 2-way repeated measures analysis of variance.
Conclusions: Higher FeNO levels may predict asthma exacerbation not within a short period of time, but in a long-term follow-up after stepping down FBC therapy in adult asthma.
Asthma; Asthma control questionnaire; Exacerbation; Exhaled nitric oxide; Fixed-dose; Formoterol/budesonide combination; Step-down therapy
ACQ5: Asthma Control Questionnaire: 5-item version; ACT: Asthma Control Test; ANOVA: Analysis of Variance; FBC: Formoterol/Budesonide Combination; FEF50%: Forced Expiratory Flow at 50% of FVC; FeNO: Fractional Exhaled Nitric Oxide; GINA: Global Initiative for Asthma; ICS: Inhaled Corticosteroid LABA: Long-Acting β2-Agonist; Min% Max PEF: Lowest PEF Expressed as a Percentage of the Highest PEF; PEF: Peak Expiratory Flow; ROC: Receiver-Operator Characteristic; SABA: Short-Acting β2-Agonist; SFC: Salmeterol/Fluticasone Combination
The current asthma guidelines emphasize achieving current control and reducing future risk [1,2]. The Global Initiative for Asthma (GINA) guidelines state that when asthma control is maintained for at least 3 months, treatment can be stepped down ; however, there is little information on the optimal timing, sequence, and magnitude of treatment reductions in asthma, and the approach will differ from patient to patient depending on the medications and the doses to achieve control. Prediction tools for the reappearance of symptoms and increased risk of exacerbation would be useful for stepping down treatment.
Measurement of fractional exhaled nitric oxide (FeNO) is a quantitative, noninvasive, simple, and safe method of evaluating eosinophilic airway inflammation, the hallmark of asthma . Common reasons for measuring FeNO include a guide to changes in doses of anti-inflammatory medications: stepping down dosing, stepping up dosing, or discontinuation of anti-inflammatory medications . Previous studies indicated that as a predictor of asthma control, FeNO is no better than more conventional tests and that the predictive values of a single measurement of FeNO for loss of asthma control are insufficiently sensitive and specific [3-5]; however, these studies were concerned with adjusting the inhaled corticosteroid (ICS) dose in not only controlled but uncontrolled patients while very few have examined the usefulness of FeNO measurement as a predictor of asthma exacerbation in patients with well-controlled asthma receiving an ICS in combination with a long-acting β2-agonist (LABA). Gelb et al. reported that combined baseline FeNO ≥ 28 ppb and FEV1 ≤ 76% of predicted were reliable predictors of exacerbation in patients who were clinically stable for 6 weeks and receiving salmeterol/fluticasone combination (SFC)100/500 μg per day . Hojo et al. found that FeNO ≤ 28 ppb plus an Asthma Control Test (ACT) score ≥ 22 for more than 3 months was a safe criterion for stepping down formoterol/budesonide combination (FBC) 18/640 μg per day to 9/320 μg per day without an increased incidence of exacerbation . Thus, we hypothesized that FeNO measurement would predict asthma exacerbation after stepping down FBC therapy in patients with well-controlled asthma. In this prospective, multicenter, open-label, uncontrolled observational study, we assessed the effect of stepping down treatment regimens, from FBC delivered via Turbuhaler 4.5/160 μg2 inhalations bid to 1 inhalation bid, on the occurrence of asthma exacerbation, asthma control level, FeNO, and pulmonary functions.
Patients with asthma who attended outpatient clinics at Kinki University Hospital, Keio University Hospital, Fukushima Medical University Hospital, Kagoshima University Medical and Dental Hospital, Teikyo University Hospital, Kurume University Hospital, and Shizuoka General Hospital for routine check-ups between August 2011 and May 2012were enrolled in this study. All patients satisfied the definition of asthma as defined by GINA . Atopy was defined by positive specific IgE antibodies to at least one common inhalant allergen (CAP system; Pharmacia, Uppsala, Sweden). Inclusion criteria were as follows: (1) age over18 years; (2) ability to perform an adequate forced expiratory maneuver; (3) asthma duration more than 6 months; (4) receiving fixed-dose FBC 4.5/160 μg2 inhalations bid for at least 3 months; (5) achievement of controlled asthma as defined by GINA (daytime symptoms, none or less than twice per week; limitation of activities, none; nocturnal symptoms/awakening, none; need for reliever/rescue treatment, none or less than twice per week; and lung function, normal)  for at least 3 months; and (6) an Asthma Control Questionnaire, 5-item version (ACQ5) score ≤ 0.75. Patients were excluded from the study if they (1) were current smokers or had quit smoking within 1 month prior to the study; (2) had a smoking history more than 10 pack-years; (3) had chronic obstructive pulmonary disease, bronchiectasis, lung cancer, collagen vascular disease, pulmonary hypertension, old pulmonary tuberculosis, diffuse panbronchiolitis, or interstitial pneumonia; or (4) had a history of hospitalization within 1 year, or an emergency department visit or systemic corticosteroid treatment within 3 months due to asthma symptoms. Peak expiratory flow (PEF) monitoring was performed using a Mini wright peak flow meter (Clement Clarke Int. Ltd, Harlow, UK).
This was a prospective, multicenter, open-label, uncontrolled observational study. At visit 1, after 4 weeks of a run-in period, patients completed the ACQ5 and patients with a score ≤ 0.75 were eligible for this study. FBC 4.5/160 μg2 inhalations bid were stepped down to 1 inhalation bid and they attended the hospitals at weeks 4and 8 of the treatment period, as shown in Figure 1. The inhaler technique of each patient was checked by the involved doctors, nurses, or pharmacists not only during the run-in period but after stepping down the regimens. This study was conducted in accordance with the principles of the Declaration of Helsinki, this protocol was approved by each local ethics committee (UMIN000005406) and informed consent was obtained from all patients prior to the study.
The primary endpoint was the occurrence of asthma exacerbation. Secondary endpoints, including ACQ5, FeNO, and pulmonary function tests, were measured in that order at weeks 0, 4, and 8.
Asthma exacerbation: Asthma exacerbation was defined as hospitalization, emergency department visit, systemic corticosteroid treatment, or >12 puffs of short-acting β2-agonist (SABA) use for 3 days due to asthma symptoms according to the recommendations with modifications .
ACQ5: The ACQ5 (Japanese version) consists of 5 items assessing nocturnal waking, morning symptoms, activity limitation, shortness of breath, and wheeze during the previous 7 days, excluding the frequency of SABA use and FEV1% predicted, each scored on a scale of 0-6, where 0 represents good control and 6 represents poor control . The overall score of the ACQ5 is the mean of the five responses.The cut-point for well-controlled asthma is ≤ 0.75, and a value ≥ 1.50 confirms not wellcontrolled asthma . A 0.5 change in each score was considered a clinically meaningful difference .
FeNO: FeNO was measured by an online method using a handheld NO analyzer (NIOX MINO; Aerocrine AB, Solna, Sweden) according to the American Thoracic Society/European Respiratory Society recommendations . Subjects emptied their lungs, inhaled deeply through the filter to total lung capacity, and then exhaled at a flow rate of 50 mL/s (assisted by visual and auditory cues) for 10 seconds. Repeated and reproducible exhalations were performed to obtain at least 3 NO plateau values that agreed within 10% of each other. The average of 3plateau values was recorded.
A previous study reported 36.8 ppb as the upper limit of FeNO for healthy Japanese adults . According to the cut-off levels of 37 ppb at stepping down, patients were classified into 2 groups: high FeNO and low FeNO groups (≥ 37 ppb versus <37 ppb).
Pulmonary functions: FVC, FEV1, forced expiratory flow at 50% of FVC (FEF50%), and FEF75% were expressed as a percentage of predicted values according to the formula of the Japanese Respiratory Society  using an electrical spirometer, which was calibrated once a week, at each institution. The mean diurnal PEF variability and the lowest PEF expressed as a percentage of the highest PEF (Min% Max PEF) values  during the 1-week period prior to each visit were calculated. Patients were requested not to use SABA for at least 6 h prior to the measurement.
From 8 weeks until 12 months after stepping down, patients attended outpatient clinics at each institute for routine check-ups monthly, bimonthly, or trimonthly. The involved doctors were requested to maintain the reduced dose of FBC 4.5/160 μg 1 inhalation bidas long as possible. Any measurements depended on each involved doctor. The occurrence of asthma exacerbation was assessed by medical records after 12 months.
All data are expressed as the medians with interquartile ranges. Comparisons between groups were made using the Kruskal-Wallis test or Wilcoxon signed-rank test. The chi-square or Fisher’s exact test was used to test for significance in group differences. Comparisons between groups and between pre- and post-stepping down were performed by 2-way repeated measures analysis of variance (ANOVA). A receiveroperator characteristic (ROC) curve was constructed to assess which level of FeNO would predict asthma exacerbation. StatView Version 5.0 (SAS Institute, Cary, NC) and R version 2.11.1 (The R Foundation for Statistical Computing, Vienna, Austria, 2010) were used for statistical calculations. A p value of <0.05 was considered significant, and all tests were 2-sided.G*Power 126.96.36.199 (http://www.gpower.hhu.de/) was used for power calculations.
Thirty-seven patients receiving a fixed-dose FBC 9/320 μg bid and achieving controlled asthma (GINA) for at least 3 months and an ACQ5 score ≤ 0.75 were enrolled. Based on the FeNO value at stepping down, patients were classified into 2 groups; 25 patients with FeNO<37 ppb and 12 with FeNO ≥ 37 ppb (Figure 2). The characteristics of the patients are shown in Table 1. Patients with FeNO ≥ 37 ppb had a significantly higher rate of coexisting allergic rhinitis and higher %FVC values than those with FeNO<37 ppb. Allergic rhinitis was defined from interviews, medical records, or subjects own reporting. Within 8 weeks after stepping down to FBC 4.5/160 μg bid, one of the patients with FeNO<37 ppb developed asthma exacerbation, but none in those with FeNO ≥ 37 ppb (Figure 2).
|All patients (n = 37)||Patients with FeNO<37 ppb (n = 25)||Patients with FeNO ≥37 ppb (n = 12)||p-Value|
|Body mass index (kg/m2)||23.0(19.4-25.4)||23.4(19.4-26.1)||21.9(19.7-24.6)||0.6037|
|Duration of asthma, years||5.0(1.0-14.0)||5.0(2.0-16.0)||4.5(1.0-10.0)||0.2032|
|Coexisting allergic rhinitis||16||8||8*||0.0463|
|ACQ5, overall score||0.0(0.0-0.2)||0.0(0.0-0.2)||0.0(0.0-0.1)||0.5040|
|%FVC (% predicted)||106.2(88.6-113.5)||97.9(88.0-109.6)||115.8(104.6-134.2)||0.0071|
|%FEV1 (% predicted)||89.4(80.6-108.2)||88.2(80.6-105.1)||106.2(79.1-112.0)||0.2561|
|PEF variability, %||3.3(2.0-4.8)||3.3(2.0-5.7)||2.7(1.8-4.6)||0.6063|
|Min%Max PEF, %||90.2(87.7-93.0)||90.3(87.1-93.0)||90.0(87.8-94.8)||0.8539|
Table 1: Characteristics of the study subjects at baseline.
The changes in ACQ5, pulmonary functions, and FeNO until 8 weeks after stepping down are shown in Table 2. Greater than 0.5 score of changes in ACQ5was observed in one patient with FeNO<37 ppb and 2 with FeNO ≥ 37 ppb, respectively; however, there was no statistically significant change in ACQ5 and pulmonary functions in each group or any difference between the 2 groups by 2-way repeated measures ANOVA. FeNO in the patients with FeNO<37 ppb increased significantly but not in those with FeNO ≥ 37 ppb; however, there was no significance between the 2 groups by 2-way repeated measures ANOVA.
|Patients with FeNO<37 ppb (n = 25)||Patients with FeNO ≥ 37 ppb(n = 12)||ANOVA|
|ACQ5, overall score||0.0(0.0-0.2)||0.0(0.0-0.2)||0.2341||0.0(0.0-0.1)||0.0(0.0-0.0)||1.0000||0.7678|
|%FEV1 (% predicted)||88.2(80.6-105.1)||85.9(76.9-104.8)||0.0593||106.2(79.1-112.0)||101.9(72.0-111.0)||0.3329||0.7697|
|PEF variability, %||3.3(2.0-5.7)||3.0(2.0-4.7)||0.1440||2.7(1.8-4.6)||2.9(1.4-5.9)||0.2026||0.8770|
|Min%Max PEF, %||90.3(87.1-93.0)||91.0(86.1-93.0)||0.9405||90.0(87.8-94.8)||91.5(86.1-95.6)||0.4413||0.2957|
Table 2: Changes in ACQ5, pulmonary functions, and FeNOuntil 8 weeks after stepping down.
In a long-term follow up until 12 months after stepping down, one patient with FeNO<37 ppb and 4 with FeNO ≥ 37 ppb developed asthma exacerbation (Figure 2). Therapy was stepped up again without exacerbation in 4 patients with FeNO<37 ppb and 2 with FeNO ≥ 37 ppb by the involved doctors. The incidence of exacerbation was significantly higher in patients with FeNO ≥ 37 ppb than in those with FeNO<37 ppb (odds ratio 11.33, 95% confidence interval 1.45 to 88.52 (Table 3).
|FeNO at baseline (visit 1)|
|<37 ppb||≥37 ppb|
|Asthma exacerbation||Did not occur||17||6|
Table 3: Association between FeNO level at baseline and asthma exacerbation from 8 weeks until 12 months after stepping down.
The ROC curve is shown in Figure 3 and the area under the curve was 0.728.The best cut point for predicting exacerbation was 27 ppb (sensitivity, 0.833; and specificity, 0.609) and the second best was 36 ppb (sensitivity, 0.667; and specificity, 0.739).A re-analysis revealed that using the cut off value of 27 ppb, one patient with FeNO<27 ppb and 4 with FeNO ≥ 27 ppb developed asthma exacerbation whereas 11 with FeNO<27 ppb and 12 with FeNO ≥ 27 ppb did not, which was not statistically significant.
We assessed whether FeNO measurement predicts asthma exacerbation after stepping down from fixed dose FBC 9/320 μg bid to 4.5/160 μg bid. It was demonstrated that the incidence of exacerbation from 8 weeks until 12 months after stepping down was significantly higher in patients with FeNO ≥ 37 ppb than in those with FeNO<37 ppb but that there was no difference in the incidence within 8 weeks between the 2 groups. These findings suggest that FeNO measurement at stepping down therapy may be useful for the long-term follow up of adult asthma as a predictor of asthma exacerbation.
Previous studies suggest that when asthma is controlled with ICS/ LABA combinations, the preferred approach to step-down therapy is to reduce the ICS dose by approximately 50% while continuing LABA, rather than discontinuing LABA alone . Godard et al.  reported that in patients achieving asthma control with SFC 250 μg bid, stepping down treatment with SFC 100 μg bid was at least as effective on lung function and symptoms as continuing SFC 250, whereas fluticasone 250 μg bid was not. Since single inhaler maintenance and reliever therapy of FBC was not approved in Japan at the beginning of the present study, we investigated fixed-dose FBC step-down therapy.
Several reports have assessed the effect of stepping down treatment with ICS/LABA combinations, including FBC and SFC, on asthma control outcomes; however, very few have examined the usefulness of FeNO measurement in patients with well-controlled asthma. Recently, Hojo et al.  reported a study on step-down FBC therapy following the achievement of complete asthma control in terms of not only clinical symptoms but also eosinophilic airway inflammation. After receiving FBC 9/320 μg bid for an average of 3 months, treatment was stepped down to 4.5/160 μg bidif FeNO ≤ 28 ppb plus ACT score ≥ 22 was met as a criterion. They found that the number of SABA use and moderate to severe exacerbation were comparable before and 48 weeks after stepping down in 51 patients. In the present study, we found that FeNO<37 ppb was a predictor of relatively safe step-down FBC therapy in a long-term follow-up of 37 patients achieving controlled asthma (GINA) for at least 3 months and an ACQ5 score ≤ 0.75.There are several differences in the study design between Hojo et al. and the present study, including a slight shorter duration of asthma control prior to stepping down, more strict FeNO (≤ 28 ppb) as a criterion, and comparing the incidence of exacerbation before and after stepping down in their study; however, these two studies show that complete control of asthma, not only clinical symptoms but also eosinophilic airway inflammation, is essential for successful step-down treatment. Also, we clarified that the future risks associated with step-down treatment may be related to the control of underlying inflammation activity, as reflected in biomarker levels.
We classified patients into high and low FeNO groups according to the cut-off of 37 ppb at baseline, which was higher than25 ppb, the level of less likelihood of eosinophilic inflammation recommended by the clinical practice guidelines . This was because 16 of 37 patients (43%) had allergic rhinitis, a factor associated with higher FeNO; however, the mean value was 22.2 ppb in the low FeNO group while the mean baseline value of 55.5 ppb in the high FeNO group corresponded to the level of eosinophilic inflammation indicated by the guidelines (3). Considering this and the results of ROC analysis, the cut-off was appropriate in the present study.
The occurrence of exacerbation just after stepping down means the failure of stepping down itself and the need to step up again. If there is no exacerbation in this period, stepping down therapy is successful in any way. The next problem is whether asthma control will be maintained in the presence of factors that precipitate exacerbation, including seasons, weather, temperature, and infections. That’s the reason why we assessed within 8 weeks and from 8 weeks until 12 months separately.
FeNO measurement predicted asthma exacerbation not within 8 weeks but from 8 weeks until 12 months after step-down FBC therapy in the present study. A possible explanation may be that the effect of underlying eosinophilic airway inflammation on future exacerbation takes a certain period of time. Previous studies [7,15,16] and the present study showed that FeNO increased gradually after step-down treatment. Future studies will clarify whether adjustment of therapy based on FeNO measurement can prevent or when to measure FeNO to prevent asthma exacerbation.
The involved doctors were requested to maintain the reduced dose of FBC 4.5/160 μg inhalation bid as long as possible; however, in some patients therapy was stepped up to respond to the patients’ request. Actually, exacerbation did not occur but the patients preferred the initial dose before stepping down due to increased symptoms. It is true that this may bias the exacerbation results, but we excluded these patients from the analysis.
Regular FENO measurements rather than a single baseline would have clinical importance in predicting exacerbations; however, FeNO measuring devices are very expensive and not widely and frequently used in clinical practice. We believe that a single FeNO measurement, at least partly, gives us useful information on exacerbation.
The major limitation of the present study is a small sample size. Due to several circumstances, we could not collect more patients. The statistical power of the present study was 57.1%. Further studies with more patients are needed to clarify the usefulness of FeNO measurements in stepping down therapy.
In conclusion, higher FeNO predicts asthma exacerbation from 8 weeks until 12 months, but not within 8 weeks, after stepping down from fixed-dose FBC 9/320 μg bid to 4.5/160 μg bid. FeNO<37 ppb may be a predictor of relatively safe step-down therapy of adult patients achieving well-controlled asthma.
We thank Tomoyoshi Tsuchiya, MD, PhD (Shizuoka City Shimizu Hospital, Department of Respiratory Medicine) for his assistance with statistical analysis.