Abstract
Background. The use of FENO in association with current guidelines in the treatment of asthma has not been studied thoroughly. This study aimed to evaluate the beneficial role of FENO in combination with GINA (Global Initiative for Asthma) guidelines for titration of inhaled corticosteroids (ICS) in asthmatic children. Methods. It was a prospective and descriptive study. Uncontrolled asthmatic children were randomized to two groups: group 1 (followed GINA guidelines) or group 2 (followed GINA guidelines + FENO modification for ICS titration). The two groups were followed-up for 12 months. Results. The mean age of the patients in the study was 10 ± 4 years for group 1 (n = 116) and 11 ± 5 years for group 2 (n = 108). There were 87.9% patients in group 1 and 82.4% in group 2 that had a familial allergic history. There were 58.6% of moderate asthma and 41.4% of severe asthma in group 1, versus 56.4% and 43.6% in group 2, respectively. The percentage of moderate and severe asthma was also significantly modified after 6th and 12th month versus at inclusion (43.1% and 35.3% versus 58.6%, P < 0.01 and P < 0.005; 23.2% and 12.9% versus 41.4%, P < 0.005 and P < 0.001, respectively). The total daily dose of ICS in group 2 at 12th months was significantly lower than that in group 1 (3515 ± 1175 versus 4785 ± 1235 mcg; P < 0.005). The daily cost of ICS treatment in group 2 was also lower than that of group 1 (18 ± 4 versus 27 ± 3 USD; P < 0.05). Conclusion. The use of FENO in combination with GINA guidelines for ICS titration is useful in reducing the daily ICS dose and treatment cost.
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1. Introduction
The measurement of fractional concentration of exhaled nitric oxide (FENO) has been used for more than 20 years in the diagnosis and treatment of asthma [1]. Currently, FENO is considered to be a relevant biomarker of asthma and it can be measured routinely by using portable devices. The use of FENO in asthma management has been recommended by many academic societies [2–5]. A high level of FENO reflects the airway inflammation in asthmatic patients and correlates closely with the response to inhaled corticosteroid (ICS) treatment [6, 7]. Moreover, FENO is not only used as biomarker of inflammatory process in asthma, but it has also been used to predict the frequency of asthma symptoms, as well as the level of asthma control. A dramatic increase of FENO in comparison with baseline amounts in asthmatic patients with free-symptoms might suggest asthma exacerbation or loss of asthma control [8].
In patients with asthma, previous studies showed that the higher level of FENO, the higher dose of ICS were needed to reduce FENO and to establish asthma control [6, 9]. Therefore, the measurement of FENO may be used for assessing therapy response and for optimizing ICS treatment. This concept has been based on the strong correlation between the FENO level and the effect of ICS therapy as demonstrated by previous studies [7, 10, 11]. Changes in FENO values between two visits might reflect the efficacy of asthma control. In addition, FENO measurement has been considered now as a non-invasive and high-performance tool to monitor the adherence of ICS therapy. Moreover, as recommended by the ATS (American Thoracic Society), FENO predicts the likelihood of response to ICS more consistently than spirometry, bronchodilator response, peak flow variation, or airway bronchial challenge testing to methacholine [4]. Recently, FENO measurement has been recommended by GINA (Global Initiative for Asthma) in monitoring patients with asthma [12]. In children with asthma, a high level of FENO is also a reliable marker for airway inflammation mediated by eosinophils and suggests a robust response to ICS [13].
However, the use of FENO as an additional tool in association with international guidelines in the management of patients with asthma has not been well demonstrated; the present study was aimed to evaluate the beneficial role of FENO measurement in association with GINA guidelines for the titration of ICS dose in the control of asthma in children.
2. Patients and methods
2.1. Patients
Asthmatic children ≥6 years-old who presented at different clinical department of health centers with uncontrolled asthma and had high level of FENO, were included in the present study. The parents or guardians signed the Institutional Review Board of Lam Dong Medical College (IRB-LMC-23.02.16)-approved consent on the patients' behalf. All study patients were randomly assigned to 2 groups: GINA guideline-defined treatment for step-up or step-down (group 1) or GINA guideline-defined treatment plus FENO value (group 2) for titration of ICS doses.
2.1.1. Inclusion criteria
All children with uncontrolled asthma, who were between the ages of 6–17 years and under discontinued asthma treatment in the previous months or who had untreated asthma were included. They were able to perform spirometry, FENO measurement, skin prick test (SPT), and blood analysis (blood eosinophil count and total IgE quantifying). The diagnosis of asthma was based on the criteria recommended by GINA for children over five years [12].
2.1.2. Exclusion criteria
Asthmatic children having one of the following features were excluded: other significant chronic or acute non-respiratory diseases, acute respiratory infections, severe asthma exacerbations needing systemic corticosteroid therapy (oral or injection) at inclusion, or who were unable to do a laboratory test. Asthmatic children with non reproducible FEV1 and FENO measurements were also excluded in the present study.
2.2. Methods
2.2.1. Study design
It was a prospective and descriptive study. All children with uncontrolled asthma were included and treated at inclusion as recommended by GINA [12]. They were randomized into two groups: group 1 (followed GINA guidelines for step-up or step-down ICS doses) or group 2 (followed GINA guidelines + FENO modification for step-up or step-down ICS doses). All study subjects were followed-up for 12 months. Asthmatic children who met inclusion criteria were classified into four different levels of asthma severity for management following the method of Hoang et al 2017 (intermittent asthma: short-acting beta agonist [SABA] as needed; mild asthma: low dose ICS + SABA as needed; moderate asthma: moderate to high dose ICS + SABA as needed; severe asthma: moderate to high dose ICS + long-acting beta agonist [LABA] + SABA as needed) [14].
ICS response and asthma control were evaluated by physicians as recommended by GINA: controlled, partially controlled, or uncontrolled asthma. An asthma control test (ACT) was used as a self-assessment by study subjects (>12 years old) or their parents (<12 years old). Group 1 served as the control-group where ICS adjustments were based on criteria established by the GINA for the control of asthma [12] (asthma symptoms, night-time waking, bronchodilator use, and risk of asthma exacerbation). For group 2, ICS adjustments were based on GINA criteria as described previously, associated with FENO values (>20 ppb). The cutoff-point of FENO < 20 ppb had been used to target the treatment; above which an increase in the dose of ICS was prescribed. In this group (group 2), the modification of FENO more than 10 ppb was used to determine a significant increase or reduction of FENO for step-up or step-down ICS (fluticasone) as recommend [4].
2.2.2. Laboratory techniques
2.2.2.1. Skin prick test (SPT)
Skin prick test (Stallergenes; London, UK): nine respiratory allergens including Dermatophagoides Pteronyssius (Dp), Dermatophagoides Farinae (Df), Blomia tropicalis (Blo), dog hairs, cat hairs, cockroaches, Phoenix dactylisera, Alternaria spp, and mixed pollens (Dactylus glomerata, Phleum pratense, Lolium perenne) were performed for all study subjects. SPT was considered positive when the wheal size exceeded the negative control by 3 mm. The negative control was 0.9% saline solution and the positive control was 1 mg ml−1 of histamine.
2.2.2.2. Total IgE measuring and blood eosinophil count (BEC)
Blood samples of all study subjects were collected through venipuncture and used for measuring the total IgE and for counting eosinophils. The increases of total IgE and eosinophil in peripheral blood were defined by a local biology lab (increased IgE: >214 KU/L; hypereosinophilia: >6%). BEC in peripheral blood was analyzed by automatic machines (XT-4000i-SYSMEX; Kope, Japan); IgE concentration in peripheral blood was quantified by a chemical luminescence technique (COBASC 501; Hitachi, Japan).
2.2.2.3. Lung function testing (LFT)
All study subjects underwent lung function testing with blue spiro or Body Box (Medisoft; Sorinnes, Belgium). The reversibility of airway obstruction was measured by FEV1 (forced expiratory volume in one second) after 15 min using 200 μg of salbutamol. The reversibility test was defined as positive when there was an increase of FEV1 ≥ 12% and >200 ml.
2.2.2.4. Fractional exhaled nitric oxide (FENO) measurement
FENO was measured with constant aspiratory flow using the Hypair FeNO+ Device (Medisoft; Sorinnes, Belgium), which is an electrochemical based analyzer. Technical measurement of FENO to assure expiratory flow of 50 ml s−1 and its level were conducted according to manufacturer's instructions and as recommended by the American Thoracic Society/ERS (European Respiratory Society) guidelines for children (<20 ppb: normal; 20–35 ppb: increased; >35 ppb: highly increased) [2–4, 15]. The use of a nose clip to avoid the risk of contamination from NO produced in the nasal and sinus cavities was respected as recommended previously [5].
2.2.3. Statistical analysis
SPSS 22.0 software (IBM Corporation, Armonk; NY, USA) had been used to analyze data. Categorical variables were presented as a mean ± standard deviation (SD). Normal distribution was evaluated by using a Skewness-Kurtosis test. A chi-square test was used to compare the ratio; the comparison of percentage was measured by Z-test. The pair-comparison of mean using Mann–Whitney U test. The comparison was stated as statistically significant when the p value was <0.05.
3. Results
3.1. Clinical and functional characteristic of asthmatic patients in study groups
From January 2016 to June 2018, 256 asthmatic children over five years of age were included in the present study. They were randomized in group 1 or group 2 as described above (128 patients in each group). At the end of study, there were only 116 patients in group 1 and 108 patients in group 2 who had completed the follow-up of 12 months.
The mean age was 10 ± 4 years in group 1 (n = 116), and 11 ± 5 years in group 2 (n = 108) with a predominance of males in both groups (62% and 63.8%, respectively; table 1). There were 87.9% patients in group 1 and 82.4% in group 2 who had a familial allergic history and 100% of them had personal allergic history with at least one allergic manifestation. There were no significant differences of both groups for the mean age of asthma onset and acute asthma exacerbations in the last 12 months (3.5 ± 1.4 versus 3.1 ± 2.3 years and 2.6 ± 1.3 versus 2.3 ± 1.5, respectively; P > 0.05 and P > 0.05; table 1). There was no significant difference between two groups for asthma severity: 58.6% and 41.4% of patients in group 1 had moderate and severe asthma versus 56.4% and 43.6% in group 2 (table 1). They were under discontinued or unregularly treated (52.5% versus 51.9% and 47.5% versus 48.1%; respectively) and their asthma was triggered almost entirely by allergens (99.1% in group 1 and 99.0 % and group 2; respectively; table 1). There was not any significant difference between two groups for lung function testing (FVC: forced vital capacity, FEV1: forced expiratory in one second, PEF: peak expiratory flow, and FEF 25%–75%: forced expiratory flow at 25% and 75% of FVC), blood eosinophil count (BEC), total IgE, and FENO level (table 1).
Table 1. Characteristics of asthmatic patients of group 1 and group 2 at inclusion.
| Characteristic parameters | Group 1 (n = 116) | Group 2 (n = 108) | P |
|---|---|---|---|
| Anthropometry | |||
| Age, years (min–max) | 10 ± 4 (6–16) | 11 ± 5 (6–16) | NS |
| Sex, male (female), % | 62.0 (38.0) | 63.8 (36.2) | NS |
| BMI, kg m−2 | 17.5 ± 2.3 | 17.1 ± 3.4 | NS |
| Atopy | |||
| Familiar allergic history, % | 87.9 | 82.4 | NS |
| Personal allergic history, % | 100 | 100 | NS |
| Eczema | 68.1 | 67.5 | NS |
| Conjunctivitis | 65.5 | 65.7 | NS |
| Allergic rhinitis | 75.8 | 75.9 | NS |
| Drug allergy | 33.6 | 30.5 | NS |
| Food allergy | 50.8 | 51.8 | NS |
| Asthma onset | 3.5 ± 1.4 | 3.1 ± 2.3 | NS |
| Asthma exacerbation | 2.6 ± 1.3 | 2.3 ± 1.5 | NS |
| Asthma severity | |||
| Moderate (stage 3), % | 58.6 | 56.4 | NS |
| Severe (stage 4), % | 41.4 | 43.6 | NS |
| Asthma treatment | |||
| Never treated, % | 0.0 | 0.0 | NS |
| Discontinuous treated, % | 52.5 | 51.9 | NS |
| Unregularly treated, % | 47.5 | 48.1 | NS |
| Asthma trigger | |||
| Allergens, % | 99.1 | 99.0 | NS |
| SPT*, % | |||
| Blomia | 79.3 | 79.6 | NS |
| D. farinae | 84.4 | 82.4 | NS |
| D. pteronyssinus | 85.3 | 83.3 | NS |
| Cockroach | 45.6 | 47.2 | NS |
| Dog hair | 44.8 | 49.0 | NS |
| Cat hair | 50.8 | 48.1 | NS |
| LFT (after BD) | |||
| FVC, % predicted | 91 ± 12 | 92 ± 13 | NS |
| FEV1, % predicted | 72 ± 11 | 71 ± 12 | NS |
| FEV1/FVC, % | 81 ± 6 | 83 ± 5 | NS |
| PEF, % predicted | 69 ± 11 | 68 ± 12 | NS |
| FEF 25–75, % predicted | 68 ± 8 | 67 ± 9 | NS |
| Bronchodilator reversibility, % | 93.1 | 93.5 | NS |
| Biological testing | |||
| BEC, % (G/L) | 8.2 ± 2.4 (678 ± 176) | 8.3 ± 2.7 (693 ± 189) | NS |
| IgE, UI ml−1 | 1897 ± 993 | 1925 ± 866 | NS |
| Exhaled NO | |||
| FENO, ppb | 45 ± 11 | 46 ± 9 | NS |
BMI: body mass index; SPT: skin prick test; LFT: lung function testing; BD: bronchodilator; FVC: forced vital capacity; FEV1: forced expiratory in one second; PEF: peak expiratory flow; FEF 25%–75%: forced expiratory flow at 25% and 75% of FVC; BEC: blood eosinophil count; NO: nitric oxide; FENO: fractional exhaled NO; ppb: part per billion; NS: non-significant.
3.2. Improvement of clinical and functional characteristics of asthmatic patients after treatment
The results showed that in group 1, the severity of asthma improved after 3 months, 6 months and 12 months of treatment with a significant increase in mild asthma percentage (16.3%, 33.7%, and 51.8% versus 0.0% at inclusion with P < 0.001, P < 0.01, and P < 0.01; table 2(A)). The percentages of moderate and severe asthma were also significantly reduced after the 6th and 12th month in compared to at inclusion (43.1% and 35.3% versus 58.6% with P < 0.01 and P < 0.005; 23.2% and 12.9% versus 41.4% with P < 0.005 and P < 0.001; respectively; table 2(A)). In this group, ACT cores were significantly increased after 3rd, 6th, and 12th month after treatment (P < 0.05, P < 0.005, and P < 0.005; respectively; table 2(A)) and the number of asthma exacerbation during the 3rd, 6th, and 12th month was significantly lower than that in previous year (at inclusion) (table 2(A)). In group 1, the percentage of asthmatic children who received low, moderate or high doses of ICS was similar to the percentage of asthma severity. The use of LABA (long acting beta 2 agonist) and SABA (short acting beta 2 agonist) was also significantly reduced at the 6th and 12th month in comparrison with that at the 3rd month (table 2(A)). The lung function parameters were significantly improved after treatment and associated with the reduction of FENO level in asthmatic children of group 1 (table 2(A)).
Table 2. (A) Evolution of clinical and functional characteristics of asthmatic patients treated by following GINA guidelines (Group 1; n = 116). (B) Evolution of clinical and functional characteristics of asthmatic patients treated by following GINA guidelines + FENO (Group 2; n = 108).
| Characteristic parameters | At inclusion | 3rd month | 6th month | 12th month | P values |
|---|---|---|---|---|---|
| Asthma severity | |||||
| Mild, % (n) | 0.0 (0/116) | 16.3 (19/116) | 33.7 (39/116) | 51.8 (60/116) | <0.001*; 0.0012**; 0.0026***; <0.0001#; <0.0001## |
| Moderate, % (n) | 58.6 (68/116) | 51.0 (59/116) | 43.1 (50/116) | 35.3 (41/116) | NS*; NS**; NS***; 0.0090 #; 0.0001## |
| Severe, % (n) | 41.4 (48/116) | 32.7 (38/116) | 23.2 (27/116) | 12.9 (15/116) | NS*; NS**; 0.0203***; 0.0016#; <0.001## |
| ACT | 13 ± 4 | 16 ± 3 | 18 ± 4 | 22 ± 3 | 0.0241*; NS**; 0.0246***; 0.0023#; 0.0012## |
| Asthma exacerbation | 2.6 ± 1.3 | ¥1.7 ± 0.7 | ¥1.5 ± 0.6 | ¥1.4 ± 0.5 | 0.0362*; NS**; NS***; 0.0314#; 0.0247## |
| Asthma treatment | |||||
| ICS, % (n) | 100 (116/116) | 100 (116/116) | 100 (116/116) | 100 (116/116) | NS |
| Low, % | 0.0 | 16.3 | 33.7 | 51.8 | <0.001*; 0.0012**; 0.0026***; <0.0001#; <0.0001## |
| Medium, % | 58.6 | 51.0 | 43.1 | 35.3 | NS*; NS**; NS***; 0.0090 #; 0.0001## |
| High, % | 41.4 | 32.7 | 23.2 | 12.9 | NS*; NS**; 0.0203***; 0.0016#; <0.001## |
| LABA, % | 100 (116/116) | 83.7 (97/116) | 66.3 (77/116) | 48.2 (56/116) | <0.0001*; 0.0012**; 0.0026***; <0.0001#; <0.0001## |
| SABA as needed (weekly) | 100 (116/116) | 61.2 (71/116) | 39.6 (46/116) | 6.8 (8/116) | <0.0001*; 0.0005**; <0.0001***; <0.0001#; <0.0001## |
| LFT (after BD) | |||||
| FVC, % predicted | 92 ± 13 | 93 ± 13 | 95 ± 11 | 98 ± 9 | NS*; NS**; 0.0451***; 0.0250#; 0.0013## |
| FEV1, % predicted | 71 ± 12 | 81 ± 11 | 84 ± 13 | 89 ± 11 | 0.0132*; NS**; 0.0214***; 0.0013#; 0.0002## |
| FEV1/FVC, % | 83 ± 5 | 82 ± 5 | 80 ± 7 | 81 ± 5 | NS*; NS**; NS***; 0.0213#; 0.0432## |
| PEF, % predicted | 68 ± 12 | 74 ± 9 | 79 ± 8 | 86 ± 7 | 0.0022*; 0.0451**; 0.0033***; 0.0001#; <0.0001## |
| Exhaled NO | |||||
| FENO, ppb | 45 ± 11 | 32 ± 7 | 26 ± 8 | 15 ± 7 | 0.0001*; 0.0015**; 0.0001***; <0.0001#; <0.0001## |
| Characteristic parameters | At inclusion | 3rd month | 6th month | 12th month | P values |
| Asthma severity | |||||
| Mild, % (n) | 0.0 (0/108) | 21.2 (23/108) | 37.1 (40/108) | 68.5 (74/108) | <0.0001*; 0.0054**; <0.0001***; <0.0001#; <0.0001## |
| Moderate, % (n) | 56.4 (61/108) | 46.4 (50/108) | 37.9 (41/108) | 24.1 (26/108) | NS*; NS**; 0.0136***; 0.0032#; <0.0001## |
| Severe, % (n) | 43.6 (47/108) | 32.4 (35/108) | 25.0 (27/108) | 7.4 (8/108) | 0.0462*; NS**; 0.0002***; 0.0020#; <0.0001## |
| ACT | 12 ± 5 | 16 ± 4 | 18 ± 5 | 23 ± 3 | 0.0134*; NS**; 0.0127***; 0.0017#; 0.0015## |
| Asthma exacerbation | 2.3 ± 1.5 | ¥1.4 ± 0.9 | ¥1.2 ± 0.6 | ¥0.8 ± 0.4 | 0.0313*; NS**; NS***; 0.0215#; 0.0054## |
| Asthma treatment | |||||
| ICS, % (n) | 100 (108/108) | 100 (108/108) | 100 (108/108) | 100 (108/108) | |
| Low, % | 0.0 | 21.2 | 37.1 | 68.5 | <0.0001*; 0.0054**; <0.0001***; <0.0001#; <0.0001## |
| Medium, % | 56.4 | 46.4 | 37.9 | 24.1 | NS*; NS**; 0.0136***; 0.0032#; <0.0001## |
| High, % | 43.6 | 32.4 | 25.0 | 7.4 | 0.0462*; NS**; 0.0002***; 0.0020#; <0.0001## |
| LABA, % | 100 (108/108) | 78.8 (85/108) | 62.0 (67/108) | 31.5 (34/108) | <0.0001*; 0.0036**; <0.0001***; <0.0001#; <0.0001## |
| SABA as needed (weekly) | 100 (108/108) | 62.9 (68/108) | 42.5 (46/108) | 8.3 (9/108) | <0.0001*; 0.0013**; <0.0001***; <0.0001#; <0.0001## |
| LFT (after BD) | |||||
| FVC, % predicted (Liter) | 91 ± 12 | 93 ± 12 | 96 ± 13 | 97 ± 10 | 0.0173*; 0.0421**; NS***; 0.0016#; 0.0012## |
| FEV1, % predicted (Liter) | 72 ± 11 | 82 ± 10 | 84 ± 13 | 88 ± 12 | 0.0012*; NS**; 0.0247***; 0.0003#; 0.0001## |
| FEV1/FVC, % | 81 ± 6 | 81 ± 6 | 82 ± 7 | 83 ± 6 | NS* ; NS** ; NS*** ; NS# ; NS## |
| PEF, % predicted | 69 ± 11 | 75 ± 8 | 78 ± 9 | 85 ± 8 | 0.0053*; 0.0489**; 0.0047***; 0.0002#; <0.0001## |
| Exhaled NO | |||||
| FENO, ppb | 46 ± 9 | 29 ± 11 | 22 ± 9 | 16 ± 4 | <0.0001*; 0.0017**; 0.0015***; <0.0001#; <0.0001## |
ACT: asthma control test; ICS: inhaled corticosteroid; LFT: lung function testing; BD: bronchodilator; FVC: forced vital capacity; FEV1: forced expiratory in one second; PEF: peak expiratory flow; NO: nitric oxide; FENO: fractional exhaled NO; ppb: part per billion; NS: non-significant; ¥: in previous months after inclusion. *: 3th month versus inclusion; **: 6th month versus 3th month; ***: 12th month versus 6th month; #: 6th month versus inclusion; ##: 12th month versus inclusion.ACT: asthma control test; ICS: inhaled corticosteroid; LFT: lung function testing; BD: bronchodilator; FVC: forced vital capacity; FEV1: forced expiratory in one second; PEF: peak expiratory flow; NO: nitric oxide; FENO: fractional exhaled NO; ppb: part per billion; NS: non-significant; ¥: in previous months after inclusion. *: 3th month versus inclusion; **: 6th month versus 3th month; ***: 12th month versus 6th month; #: 6th month versus inclusion; ##: 12th month versus inclusion.
The results of group 2 showed that the percentage of mild asthma was increased after 3, 6, and12 months of treatment (21.2%, 37.1%, and 68.5% with P < 0.0001, P < 0.01, and P < 0.0001; table 2(B)). The percentages of moderate and severe asthma in this group were also significantly reduced after the 6th and 12th month in comparison with those at inclusion (P < 0.005 and P < 0.0001; P < 0.005 and P < 0.005; respectively; table 2(B)). ACT cores were significantly increased after 3rd, 6th, and 12th month after treatment (16 ± 4, 18 ± 5, and 23 ± 3 versus 12 ± 5; P < 0.05, P < 0.005, and P < 0.005; respectively; table 2(B)). In this group, the number of asthma exacerbations during the 3rd, 6th, and 12th month was also significantly lower than that in the previous year (table 2(B)). The same occurred with group 1, the percentage of asthmatic children in group 2 who received low, moderate or high dose of ICS was compatible with asthma severity (table 2(B)). The use of LABA and SABA in this group was also significantly reduced at 6th and 12th month (table 2(B)). FVC, FEV1, and PEF were significantly increased after treatment at 6th and 12th month in compared to that at inclusion (table 2(B)). FENO level was also significantly decreased at the 6th and 12th month in comparison with at inclusion (22 ± 9 and 16 ± 4 versus 46 ± 9; P < 0.0001 and P < 0.0001, respectively; table 2(B)).
3.3. Comparison of clinical and functional characteristics of study subjects after treatment
The results of present study showed that after 6 months of treatment, the percentage of mild, moderate and severe asthma was not significant difference between group 1 and group 2 (33.7%, 43.1%, and 23.2% versus 37.1%, 37.9%, and 25.0%; P > 0.05, P > 0.05, and P > 0.05; respectively; table 3). ACT scores were also not significantly different between two groups at 6 months (18 ± 4 versus 18 ± 5; P > 0.05). There was nothing significantly different between two groups concerning the number of asthma exacerbations (table 3). The percentage of patients treated with mild, moderate and high dose of ICS was similar between the two groups (table 3). At 6 months, lung function parameters were not significant differences between two groups. The level of FENO in group 2 was significantly lower than that in group 1 (22 ± 9 versus 26 ± 8 ppb; table 3).
Table 3. Comparison of clinical and functional characteristics of study subjects after 6th and 12th month of treatment.
| 6th month | P values | 12th month | ||||
|---|---|---|---|---|---|---|
| Characteristic parameters | Group 1 (n = 116) | Group 2 (n = 108) | Group 1 (n = 116) | Group 2 (n = 108) | P values | |
| Asthma severity | ||||||
| Mild, % | 33.7 (39/116) | 37.1 (40/108) | NS | 51.8 (60/116) | 68.5 (74/108) | 0.0052 |
| Moderate, % | 43.1 (50/116) | 37.9 (41/108) | NS | 35.3 (41/116) | 24.1 (26/108) | 0.0328 |
| Severe, % | 23.2 (27/116) | 25.0 (27/108) | NS | 12.9 (15/116) | 7.4 (8/108) | NS |
| ACT | 18 ± 4 | 18 ± 5 | NS | 22 ± 3 | 23 ± 3 | NS |
| Asthma exacerbation¥ | 1.5 ± 0.6 | 1.2 ± 0.6 | NS | 1.4 ± 0.5 | 0.8 ± 0.4 | 0.0267 |
| Asthma treatment | ||||||
| ICS, % | 100 (116/116) | 100 (108/108) | NS | 100 (116) | 100 (108/108) | NS |
| Low, % | 33.7 | 37.1 | NS | 51.8 | 68.5 | 0.0052 |
| Medium, % | 43.1 | 37.9 | NS | 35.3 | 24.1 | 0.0328 |
| High, % | 23.2 | 25.0 | NS | 12.9 | 7.4 | NS |
| LABA, % | 66.3 (77/116) | 62.0 (67/108) | NS | 48.2 (56/116) | 31.5 (34/108) | 0.0052 |
| SABA as needed (weekly) | 39.6 (46/116) | 42.5 (46/108) | NS | 6.8 (8/116) | 8.3 (9/108) | NS |
| LFT (after BD) | ||||||
| FVC, % predicted (Liter) | 95 ± 11 | 96 ± 13 | NS | 98 ± 9 | 97 ± 10 | NS |
| FEV1, % predicted (Liter) | 84 ± 13 | 84 ± 15 | NS | 89 ± 11 | 88 ± 12 | NS |
| FEV1/FVC, % | 80 ± 7 | 82 ± 7 | NS | 81 ± 5 | 83 ± 6 | NS |
| PEF, % predicted | 79 ± 8 | 78 ± 9 | NS | 86 ± 7 | 85 ± 8 | NS |
| Exhaled NO | ||||||
| FENO, ppb | 26 ± 8 | 22 ± 9 | 0.0162 | 15 ± 7 | 16 ± 4 | NS |
ACT: asthma control test; ICS: inhaled corticosteroid; LABA: long acting beta 2 agonist; SABA: short acting beta 2 agonist; LFT: lung function testing; BD: bronchodilator; FVC: forced vital capacity; FEV1: forced expiratory in one second; PEF: peak expiratory flow; NO: nitric oxide; FENO: fractional exhaled NO; ppb: part per billion; ¥: in previous months after inclusion. NS: non-significant.
At 12 months, the percentage of mild asthma in group 2 was significantly higher than that in group 1 (68.5% versus 51.8%; P < 0.01; table 3 and figure 1) whereas the percentage of moderate and severe asthma in group 2 was higher than it was in group 1 (35.3% and 24.1% versus 12.9% and 7.4%; P < 0.05 and P > 0.05; respectively; table 3 and figure 1). ACT scores were also not different between two groups (table 3 and figure 1). At 12 months, the number of asthma exacerbations in group 2 was significantly lower than those in group 1 (P < 0.05). The percentage of asthmatic children treated with high doses of ICS was not significantly different between the two groups at 12 months (12.9% and 7.4%; P > 0.05; table 3 and figure 1). The percentage of LABA used was lower in group 2 compared with group 1 (31.5% versus 48.2%; P < 0.01). Lung function parameters and FENO level were not significantly different between the two groups at 12 months (table 3).
Figure 1. Comparison of clinical and functional characteristics of study subjects after treatment. ACT: asthma control test; ICS: inhaled corticosteroid; LABA: long acting beta 2 agonist; SABA: short acting beta 2 agonist; FEV1: forced expiratory in one second; NS: non-significant.
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Standard image High-resolution image3.4. Comparison of delta (Δ) difference at 12th month versus at inclusion and cost of ICS treatment
The difference in modification (Δ) of clinical and functional parameters at 12 months, compared to those at inclusion, showed that Δ mild asthma in group 2 was significantly higher than in group 1 (+68.5 versus + 51.8%; P < 0.01; table 4 and figure 2). There was no significant difference between the two groups for Δ moderate and severe asthma (P > 0.05; table 4). Δ ACT was not different between group 1 and group 2 after 12 months (+9 ± 2 versus +11 ± 3; P > 0.05). Although the reduction of asthma exacerbation (Δ number of asthma exacerbation) in group 2 was higher than group 1, there was no significant difference (table 4). There were significant differences between the two groups for Δ FEV1 and Δ PEF (+13 ± 8 and +17 ± 4 versus +16 ± 7 and +15 + 5; P > 0.05 and P > 0.05; respectively; table 4 and figure 2). Δ FENO was similar between the two groups (−30 ± 4 versus −31 ± 3; P > 0.05).
Table 4. Comparison of delta (Δ) difference and cost of ICS treatment at 12 months versus at inclusion.
| Characteristic parameters | Group 1 (N = 116) | Group 2 (N = 108) | P values |
|---|---|---|---|
| Asthma severity | |||
| Δ Mild, % | +51.8 | +68.5 | 0.0052 |
| Δ Moderate, % | −23.3 | −32.3 | NS |
| Δ Severe, % | −28.5 | −36.2 | NS |
| Asthma control | |||
| Δ ACT | +9 ± 2 | +11 ± 3 | NS |
| Δ Asthma exacerbation | −1.3 ± 0.7 | −1.5 ± 0.6 | NS |
| LFT (after BD) | |||
| Δ FEV1, % | +13 ± 8 | +16 ± 7 | NS |
| Δ PEF, % | +17 ± 4 | +15 ± 5 | NS |
| Exhaled NO | |||
| Δ FENO, ppb | −30 ± 4 | −31 ± 3 | NS |
| ICS treatment for all patients at 12th month | |||
| Total daily ICS dose+, mcg | +4785 ± 1235 | +3515 ± 1175 | 0.0012 |
| Total daily ICS cost, USD | 27 ± 3 | 18 ± 4 | 0.0135 |
| Total monthly ICS cost, USD | 823 ± 94 | 537 ± 86 | 0.0002 |
ACT: asthma control test; ICS: inhaled corticosteroid; LFT: lung function testing; BD: bronchodilator; FEV1: forced expiratory in one second; PEF: peak expiratory flow; NO: nitric oxide; FENO: fractional exhaled NO; ppb: part per billion; NS: non-significant. 0.05 USD/1 spray with 125 mcg of fluticasone proportionate); 0.125 USD/1 spray with 250 mcg of fluticasone propionate +25 mcg of salmeterol; +: mean daily dose during last monthly for all patients in each group.
Figure 2. Comparison of delta (Δ) difference at 12th month versus at inclusion. ACT: asthma control test; FEV1: forced expiratory in one second; PEF: peak expiratory flow; NO: nitric oxide; FENO: fractional exhaled NO; NS: non-significant.
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The result showed that mean total daily dose of ICS in group 2 in the last month (12th month) was significantly lower than that in group 1 (3515 ± 1175 versus 4785 ± 1235 mcg; P < 0.005; table 4). The total monthly ICS cost in group 2 was lower than that in group 1 (537 ± 86 versus 823 ± 94 USD; P < 0.0005; table 4). With the local price of ICS alone and ICS combined with LABA (0.05 USD/spray of 125 mcg fluticasone propionate and 0.125 USD/spray of 250 mcg of fluticasone propionate +25 mcg of salmeterol), the result showed that the daily cost of ICS treatment for asthmatic patients in group 2 was lower than that in group 1 (18 ± 4 versus 27 ± 3; P < 0.05; table 4).
4. Discussion
The main results of the present study showed that: (1) the asthma severity, asthma control, and lung function parameters were improved after treatment in both study groups (group 1: GINA-guided treatment; group 2: GINA + FENO-guided treatment); (2) the number of asthmatic children with mild asthma, the use of low dose ICS, and the percentage of LABA withdrawal were significantly higher in group 2 at 12 months; (3) the daily cost of ICS for all patients in group 2 was lower than in group 1 for patients with the same level of clinical and functional parameter improvement.
In the present study, all asthmatic children had the characteristics of allergic asthma with familial and personal allergic history (table 1). It is a relevant characteristic of allergic asthma in children with early onset of asthma. These patients also had other biological characteristics of allergic asthma revealed by positive SPT, high BEC, increased total IgE, and high FENO level. Patients with allergic asthma are usually potential candidates for ICS treatment and have a good treatment response [16–18]. In the present study, all patients had their asthma during preschool age. However, at the inclusion, these patients were unregularly or discontinuously treated although having the medical history of emergency care for asthma exacerbation (>2 times in the last twelve months).
In this study, all diagnosed asthmatic children were treated following GINA guidelines (group 1) or GINA [12] + modification of FENO for step-up or step-down (group 2) as recommended by ATS/ERS [15]. The results showed that the asthma severity, asthma control, and lung function parameters were improved in both study groups after the 3rd, 6th and 12th months (tables 2(A), (B)). Especially, at 12 months, the number of asthmatic children with mild asthma, the use of low dose ICS, and the percentage of LABA withdrawal were significantly higher in group 2 (tables 2(A), (B) and tables 3, 4; figures 1, 2). The number of asthma exacerbation of asthmatic patients in group 2 was significant lower than in group 1 (table 3). Currently, the treatment of asthma in children has been defined very well by the international recommendations [19–24]; however, the use of FENO in combination with clinical symptoms for management asthma in children has not been well demonstrated. In addition, FENO measurement is recommended only for children over 6 years old due to the low tenchical performance of FENO measurement in younger children [15, 25, 26]. In the present study, FENO was measured with multiflow electrocheminescence device which assured the accurate values of FENO.
Currently, there are some limitations in the use of clinical symptoms for step-up or step-down asthma treatment after the asthma is well-controlled. In GINA guidelines, the control of asthma has been evaluated based on daily and nocturnal symptoms in previous months; when well-controlled symptoms have been maintained for at least 3 months, the ICS dose must be carefully titrated to the minimum dose and used regularly. This guide will help asthmatic patients to maintain a good symptom control, to minimize the risk of acute asthma exacerbation, and to reduce the potential for side-effects [12, 20]. Therefore, the use of FENO may be helpful as a relevant biomarker to guide physicians to knowing exactly when asthma treatment could be stepped down and eventually for ICS dose reduction [6, 27, 28].
Although the safety of ICS use with moderate and high dose has been demonstrated in children with asthma, the systemic effect of high dose ICS in long term treatment is always an awareness for the children's parents [29, 30]. Previous studies showed that the use of sputum eosinophil were also an accurate tool for titration of ICS dose in asthmatic patients [31–33]. Unfortunately, this method is time consuming and requires material equipment; it is also difficult to realize in children. Moreover, there are only a few centres worldwide that have routine access to induced sputum eosinophils for the management of asthma. Fortunately, the use of FENO in asthma, developed nearly three decades ago, is an alternative method for diagnosis and follow-up of allergic asthma because there is a strong correlation between the FENO level and airway eosinophils as demonstrated previously [34–36].
In their study on the use of FENO in adults with asthma, Syk et al [37] suggested FENO might be used to guide ICS treatment within primary care significantly by reducing the exacerbation rate and improving the control of asthma without increasing ICS use. The recent systematic review on FENO for the management of asthma in adults [38] also showed a statistically significant reduction in exacerbations of any severity but not for severe exacerbations. However, the use of FENO in adults with asthma is still controversial. In one randomized controlled trial (BASALT: Best Adjustment Strategy for Asthma in the Long Term) in adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, Calhoun et al [39] stated the use of FENO adjustment of ICS was not superior to physician assessment-based adjustment of ICS in time to treatment failure. This statement is similar to the conclusion of a study done by Shaw et al who also demonstrated the treatment of asthma based on the measurement of FENO did not result in a large reduction in asthma exacerbations or in the total amount of ICS therapy [40]. Another randomized controlled trial studied adding FENO to guideline-based asthma treatment in adolescents and young adults and demonstrated the addition of FENO as a control indicator, resulted in a higher dose of ICS without a clinically important improvement in symptomatic asthma control [41]. In children with asthma, our previous study showed the measurement of FENO levels was a useful and feasible tool to predict clinical, biological, and asthma control children [13].
In the present study, the use of FENO level in combination with asthma symptoms for titration ICS dose showed the advantage in reducing the number of asthmatic children treated with high or moderate doses of ICS after well controlled asthma had been achieved (table 3). The measurement of FENO nowadays may be developed in all health care centers with the use of portable devices for asthma management. In addition, the results of present study also showed that the monthly and daily cost of ICS treatment in asthmatic patients using GINA + FENO measurement was lower, compared to GINA alone (table 4). Therefore, the cost of ICS treatment will be more significant if the use of GINA + FENO could be done for a large number of patients with asthma. Hence, the use of FENO measurement as an additional biomarker of treatment response in the management of asthma may be useful in regarding cost—effect for the health care system. However, the present study has some limitations concerning a small number of study patients and a lack of cumulative ICS doses and FENO measurement costs during study period; thus, further studies in the field of cost—effect of FENO measurement in asthma management are necessary in the future.
5. Conclusion
FENO is usually increased in asthmatic patients, especially for children with the early onset of asthma. FENO is a relevant biomarker for asthma management. The use of FENO in combination with GINA guidelines in the titration of inhaled corticosteroids for asthma control is more advantageous in reducing the daily ICS dose and treatment cost.
Acknowledgments
All the authors declare no conflict of interests.