It remains controversial whether inhaled corticosteroid (ICS) should be used in patients with intermittent asthma. The present study aimed to assess the effect of ICS compared with placebo or other therapies in patients with intermittent asthma. Medline, Embase and CNKI databases were searched up to June 2016 and a meta-analysis was conducted. The findings demonstrated that in adult patients, when compared with placebo, ICS increased forced expiratory volume in 1 sec FEV1 [standardized mean difference (SMD), 0.51; 95% confidence interval (CI), 0.22–0.80] and alleviated airway hyper-responsiveness, which was indicated as log transformed PC20FEV1 (concentrations of methacholine when there was a fall in FEV1 ≥20%; SMD, 0.87; 95% CI, 0.60 to 1.14). ICS also reduced fractional exhaled nitric oxide (FeNO) levels [weighted mean difference (WMD), −12.57 parts per billion (ppb; a unit of NO concentration in exhaled air); 95% CI −15.88 to −9.25 ppb]. However, symptom scores did not change after ICS treatment (SMD, −0.26; 95% CI, −0.52 to 0). When compared with leukotriene receptor antagonists (LTRA), ICS had no advantage in increasing FEV1 (WMD, 0.04 l; 95% CI, −0.06 to 0.13 l), reducing sputum eosinophil percentage (WMD, −6%; 95% CI, −12.38 to 0.38%) or symptom scores (SMD, 0.44; 95% CI, −0.02 to 0.9). However, in child patients, ICS significantly (P<0.05) increased the possibility of symptom control when compared with placebo [relative risk (RR), 8; 95% CI, 1.04 to 61.52] or LTRA (RR, 2.67; 95% CI, 0.39 to 18.42). In conclusion, ICS improves lung function and alleviates airway hyper-responsiveness and airway inflammation but cannot influence symptom scores, and has no advantage over LTRA in terms of lung function improvement and airway inflammation control in adult patients with mild intermittent asthma. However, in children, the benefit of ICS in symptom control is more significant than with LTRA.
Asthma is a common, chronic heterogeneous respiratory disease affecting 1–18% of the population worldwide; in China it has a prevalence of 1.24% (
Although 50–75% of asthma patients are categorized as having mild asthma, few studies have focused on these subtypes, particularly mild intermittent asthma (
Hence the present meta-analysis aimed to analyze the effects of ICS on lung function, airway hyper-responsiveness (AHR), symptom control, airway inflammation and adverse effects in patients with mild intermittent asthma.
Our inclusion criteria for considering studies for this review were as follows: i) Randomized controlled trials (RCT); ii) studies assessing patients with intermittent asthma that may be defined as using SABA only, few symptoms (daytime symptoms ≤2 times/week and nocturnal symptoms ≤2 times/month), forced expiratory volume in 1 sec (FEV1) predicted ≥80%, and peak expiratory flow (PEF) variability ≤20%. For studies only describing some of these criteria and not implying other types of asthma, three independent researchers discussed and came to an agreement whether this study should be included; iii) ICS as the intervention compared with placebo or other therapies or ICS in combination with other therapies vs. other therapies alone; and iv) outcomes of studies reflecting lung function, AHR, airway inflammation, symptom control or adverse effects of the drugs in patients with intermittent asthma.
We excluded studies that recruited mixed groups of participants (patients with mild intermittent and persistent asthma) and those that did not report the outcomes separately.
MEDLINE (
China National Knowledge Internet (CKNI) database was also searched from inception to June 2016 using Chinese terms matched to the English terms outlined. Abstracts of citations resulting from this search were imported into a bibliographic database and hand-searched by two reviewers for duplicate publications, which were removed. Citations were initially excluded if it was clear that the study: i) Was not concerned with the treatment of chronic mild asthma in humans; ii) was not an RCT or iii) did not include a treatment arm with ICS.
Where uncertainty existed, the full text version of the publication was retrieved, and more detailed checks were conducted against our eligibility criteria. A third researcher evaluated the decision of inclusion or exclusion in discussion with the two reviewers. We also manually searched through the systematic reviews for any other articles that may be potentially suitable.
We used preformatted tables to record study design and participant characteristics, description of mild intermittent asthma, pharmacological agent (dose, device and frequency), and duration of follow-up. Two reviewers independently extracted data on relevant outcomes, including FEV1, forced vital capacity (FEV1/FVC), the concentration of methacholine when there was a fall in FEV1 ≥20% (PC20 FEV1), fractional exhaled nitric oxide (FeNO), number or percentage of sputum eosinophil and drug-related adverse effects. If an intention-to-treat analysis was not used by the researchers, and it was not shown in the results how many participants were in each group at the time of the final evaluation of that outcome, the number of patients in each group was calculated by subtracting the number of patients who discontinued or were lost to follow-up from those randomized to each group. Any discrepancies were resolved through the involvement of a third reviewer after rechecking the source papers.
Two reviewers independently assessed the methodological quality of the included studies. The risk of bias was evaluated using the Jadad scale of 0–5 (
A pooled treatment effect across trials was calculated using RevMan 5.1.6 (Cochrane, UK). For continuous outcomes, a weighted mean difference (WMD) or standardized mean difference (SMD) was calculated, as appropriate. For dichotomous outcomes, a relative risk (RR) was calculated. Pooled treatments effects were expressed with their 95% confidence intervals (95% CI). Heterogeneity of effect size across pooled studies was calculated. P<0.05 was considered to indicate a statistically significant difference.
Statistical heterogeneity was assessed using the I2 statistic with I2>50% indicating a substantial level of heterogeneity. In accordance with the recommendations of the Cochrane Handbook, we derived any standard deviations from 95% CIs or P-values (
Sensitivity analyses were performed on the basis of methodological quality. Results were re-analyzed using studies of only the highest quality (Jadad scores 3–5). Subgroup analyses based on ICS treatment duration and patient age (children or adults) were conducted.
In total, 838 potentially relevant articles were screened and 16 studies were included in this systemic review. The process of study selection is shown in
Validity assessment of the studies is shown in
A significant improvement in FEV1 was noted after 3–6 months of ICS treatment vs. placebo (3 studies; SMD, 0.45; 95% CI, 0.20 to 0.71; I2=0%;
When compared with leukotriene receptor antagonists (LTRA), more than 2 months ICS treatment had no advantage on FEV1 improvement (
A decrease of PEF variability was observed after 1 month of treatment with ICS compared with placebo (
Apparent change of FEV1/FVC could be seen after 6 months of treatment, while 1 year of treatment made no further difference (6 months, 1 study; WMD, 2.7%; 95% CI, 0.99 to 4.41% vs. 1 year, 1 study; WMD, −0.2%; 95% CI, −2.86 to 2.46%;
With treatment of ICS for 1 month, 2–6 months or 1 year, the AHR (indicated as log transformed PC20FEV1) was attenuated compared with placebo (
Notably, 1 month of ICS treatment reduced the sputum eosinophil percentage compared with placebo, whereas 1-year treatment could not (
Only one study compared the influence of ICS on sputum eosinophil percentage with LTRA, and showed that ICS decreased sputum eosinophil percentage with no statistical significance (
ICS treatment within 1 month reduced FeNO levels compared with placebo (
When the duration of ICS treatment was no more than 1 month, the effect of ICS on symptom control (indicated as symptom score change) was not significant compared with placebo (
There was only one study (
Some studies also assessed the safety of ICS in addition to its effectiveness. However, there was an insufficient number of related. Only one study assessed the effect of ICS on the hypothamo-pituitary-adrenocortical axis, in which Rüdiger
The present systemic review attempted to assess the effects of ICS compared with placebo or LTRA on lung function, AHR, airway inflammation, symptom control and its adverse effects in patients with mild intermittent asthma. The findings demonstrated that, compared with a placebo, ICS improved lung function and reduced AHR and airway inflammation in adult patients. However, symptom control was unchanged, and ICS had no advantage over LTRA for improving lung function and attenuating airway inflammation. In children with mild intermittent asthma, ICS had a positive effect on symptom control and was superior to LTRA in terms of symptom control.
Previous findings have revealed that ICS treatment results in improved lung function, diminished AHR, fewer symptoms of asthma and fewer episodes of uncontrolled asthma compared with as needed SABA alone (
The present results showed that a longer duration of ICS treatment induces a superior improvement in lung function and the alleviation of AHR; however, the effect of attenuated airway inflammation reduces as the treatment duration increases. A previous study focused on patients with mild persistent asthma, lung function and observed an improvement during the first year (
In our study, both sputum eosinophil percentages and FeNO levels were used as markers for airway inflammation, but the FeNO change was more obvious. In the majority of asthmatic patients, the correlation between sputum eosinophil and FeNO is well established, except in patients with severe asthma (
Side effects of ICS are always a concern. Short-term ICS use is believed to be safe (
There are a number of limitations to the present systemic review. Firstly, the treatment duration of all the studies included may not sufficient. This limitation prevents us from identifying more positive and negative effects of ICS on patients with mild intermittent and confuses the evaluation of the balance of ICS benefits and risks. Secondly, the number of included studies is too small, thus publication bias may exist, and the conclusion from the review may not be able to applicable to a larger population. Thirdly, some of the included studies were not high quality trials, which may result in an increased risk of bias.
In conclusion, the present systemic review demonstrates that ICS may improve lung function, alleviate airway inflammation and AHR, but cannot ameliorate symptom control in adult patients with mild intermittent asthma, and has no advantage over LTRA on these effects. On the contrary, children with mild intermittent asthma treated with ICS seemingly have a better control of asthma symptoms vs. placebo or LTRA treatment. Our findings indicate that ICS may be an effective and safe therapy for patients with mild intermittent showing signs of progression or exacerbation, and LTRA should be an alternate choice for adult patients to improve lung function and reduce airway inflammation. As for child patients, ICS seems to be the superior choice to control symptoms, but should be used with caution, as the evidence remains insufficient.
Flow diagram of study selection. ICS, inhaled corticosteroid; RCT, randomized controlled trial.
ICS improves FEV1 but has no advantage over LTRA. (A) Effect of ICS vs. placebo on FEV1 change. (B) Effect of ICS vs. LTRA on FEV1 change. ICS, inhaled corticosteroid; FEV1, forced expiratory volume in 1 sec; SD, standard deviation; SMD, standardized mean difference; MD, mean difference; CI, confidence interval; LTRA, leukotriene receptor antagonists.
ICS improves PEF variability change but not FEV1/FVC. (A) Effect of ICS vs. placebo on PEF variability change. (B) Effect of ICS vs. placebo on FEV1/FVC change. ICS, inhaled corticosteroid; PEF, peak expiratory flow; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; SD, standard deviation; MD, mean difference; CI, confidence interval.
ICS treatment attenuates airway hyper-responsiveness, when compared with placebo treatment. ICS, inhaled corticosteroid; SD, standard deviation; SMD, standardized mean difference; CI, confidence interval.
Airway inflammation reduces with ICS treatment. (A) Effect of ICS vs. placebo on sputum eosinophil change. (B) Effect of ICS vs. placebo on FeNO change. ICS, inhaled corticosteroid; SD, standard deviation; MD, mean difference; CI, confidence interval; FeNO, fractional exhaled nitric oxide.
Symptom scores do not change with ICS treatment, but rescue inhaler use reduces. (A) Effect of ICS vs. placebo on symptom score change. (B) Effect of ICS on frequency of rescue inhaler use change. ICS, inhaled corticosteroid; SD, standard deviation; SMD, standardized mean difference; MD, mean difference; CI, confidence interval.
Characteristics of the included studies.
Author/(Refs.) year | Location | Inclusion criteria | Intervention | Treatment duration | Male patients (%) | Mean age (years) | Mean FEV1% predicted | Non.smoker patients (%) |
---|---|---|---|---|---|---|---|---|
Jatakanon |
Imperial College School of Medicine at National Heart and Lung Institute, UK | i) Non-smoking stable allergic asthmatic patients who required only short-acting β-agonist; ii) history of intermittent wheezing and chest tightness | i) BUD: 100 µg daily (n=8); ii) BUD: 400 µ daily (n=7); iii) BUD: 1,600 µ (n=10); iv) placebo (n=6). Delivery method: Turbohaler DPI. Parallel and crossover design. | 4 weeks | 74.2 | 29.9 | 93.4 | 100.0 |
Boulet |
Multicenter Canada | i) Mild asthma; ii) use of a short-acting µ2-agonist alone (<3 times/week) | i) FP: 3-month course of 250 µg/day followed by 9-month maintenance treatment of 100 µg/day (n=24); ii) placebo: Matched inhalers with FP to preserve the blinding (n=33). Delivery method: Diskus MDI (metered.dose inhaler). Parallel design. | 12 months | 36.8 | 26.6 | 98.0 | 80.7 |
Bousquet |
Multiple centers, Europe | Mild intermittent asthma according to GINA | i) 1,600 µg BDP daily by nebulizer (n=10); ii) 3,200 µ BDP daily by nebulizer (n=10); iii) 800 µ BDP daily by MDI (n=10); iv) placebo (n=10). Parallel design. | 3 weeks | NR | 26.3 | NR | NR |
Ponce, |
Children Hospital Eva Samano de Lopez Mateos, Mexico | Mild intermittent asthma according to GINA | i) Salbutamol as required and BUD: 200 µg 1 pf twice daily 400 µg/day) for children aged 6.14 years, 200 µg 1 pf once daily (200 µg/day) for children aged 1.5 years (n=9); ii) salbutamol as required n=18); iii) salbutamol as required and ML: 5 mg daily for children aged 6.14 years, 4 mg daily for children aged 1.5 years (n=6); iv) salbutamol as required and ML and BUD n=17). Delivery method: Inhalation. Parallel design. | 3 months | 50.0 | 7.2 | NR | NR |
Dahlén |
Karolinska University Hospital, Sweden | Non-smoking subjects with intermittent allergic asthma (GINA) treated only with a short.acting β2.agonist p.r.n | i) Formoterol: 4.5 µg 2 pfs once daily (n=15); ii) BUD/formoterol: 160 µg/4.5 µg 2 pfs once daily (n=15); iii) placebo: 2 pfs daily (n=15). Delivery method. Turbuhaler DPI. Crossover design. | 7 days | 53.3 | 30.5 | 105.2 | 100.0 |
Ehrs |
Unit of Lung and Allergy Research, Sweden | i) Diagnosis of asthma; ii) regarding themselves as free of symptoms | i) FP: 250 µg 1 pf twice daily (500 µg/day; n=36); ii) placebo: 1 pf twice daily (n=34). Delivery device: Accuhaler DPI. Parallel design. | 3 months | 30.0 | 38.5 | 89.9 | 47.1 |
Gyllfors |
Karolinska University Hospital, Sweden | Mild atopic asthma treated only with a short-acting β2-agonist as required ≤2 times/week | i) FP: 500 µg 1 pf twice daily (1,000 µg/day; n=13); ii) placebo: 1 pf twice daily (n=13). Delivery method: Diskus DPI. Crossover design. | 2 weeks | 23.1 | 31.0 | 101 | 100.0 |
Haahtela |
Multiple centers, Europe | Mild intermittent asthma according to GINA 2005 guidelines | i) BUD/formoterol: 160/4.5 µg as required (n=44); ii) formoterol: 4.5 µg as required (n=43). Delivery method: Turbuhaler DPI. Parallel design. | 6 months | 30.4 | 37.0 | 100.9 | 83.7 |
Reddel |
Woolock Institute of Medical Research and University of Sydney, Australia | i) An established history of asthma; ii) FEV1 >90% predicted; iii) symptoms ≤2 times/week; iv) sambutamol use ≤2 times/week | i) FP: 125 µg 1 pf twice daily (250 µg/day; n=23); ii) placebo: 1 pf twice daily (n=21). Delivery method: MDI. Parallel design. | 11 months | 36.4 | 39.3 | 99.2 | 75 |
Rüdiger |
University Hospital Basel, Switzerland | Patients with symptom-free asthma | i) BUD, 400 µg single dose (n=8); ii) control: Placebo (n=8). Delivery method: Inhalation. Crossover design. | Single dose | Not reported | 32.0 | NR | NR |
Mendes |
University of Miami School of Medicine, | Mild intermittent asthma as defined by GINA 2002 USA | i) FP + ML: FP 220 µg 1 pf twice daily (440 µg daily) + 10.mg ML tablet p.o. once daily (n=12); ii) FP + placebo: FP 220 µg 1 pf twice daily (440 µg daily) + placebo tablet p.o. once daily (n=12); iii) placebo + ML: Placebo 1 pf twice daily + ML 10 mg p.o. once daily (n=12); iv) placebo + placebo: Placebo 1 pf twice daily + placebo tablet p.o. once daily (n=12). Crossover design. | 2 weeks | 16.7 | 39.8 | 95.4 | 100.0 |
Pizzichini |
St. Joseph's Hospital, Canada | Mild asthma with little or no symptoms, treatment only with inhaled β2-agonist when needed | i) BDP: 500 µg once (n=8); ii) salmoterol: 100 µg once (n=8); iii) placebo: 0 µg once (n=8). Delivery method: Nebuhaler. Crossover design. | Single dose | 37.5 | 30.6 | 90.8 | 75 |
Lim |
Imperial College School of Science and Medicine at the National Heart and Lung Institute, UK | Mild stable asthma treated with only inhaled β2-adrenergic agonist aerosol albuterol for intermittent relief of wheezing | i) BUD: 800 µg b.i.d. (n=14); ii) placebo: Matched with BUD b.i.d. (n=14). Delivery method: Turbohaler DPI. Crossover design. | 4 weeks | 42.9 | 28.6 | 95.6 | 100.0 |
Stanković |
Clinic for Lung Diseases and Tuberculosis, Serbia | Mild intermittent asthma according to GINA 2006 guideline | i) BDP: 250 µg/day and short.acting β2 agonists (Ventolin) as required as rescue medication (n=45); ii) control: Only short-acting β2 agonists (Ventolin) as required as rescue medication daily (n=40). Delivery method: Inhalation. Parallel design. | 6 months | 37.6 | 34.8 | NR | 78.8 |
Tamaoki |
Multiple centers, Japan | Mild intermittent asthma fulfilling ATS criteria and GINA 2006 | i) BDP: 100 µg 1 pf twice daily (200 µg/day) via MDI using a spacing chamber (n=38); ii) pranlukast: 225 mg b.i.d. p.o. (n=36). Parallel design. | 2 months | 27.0 | 37.0 | 84.8 | NR |
Wongtim |
Chest and Allergy Clinic, Chulalongkorn Hospital, Thailand | i) Mild asthma with exacerbation of cough and wheezing ≤1–2 times/week; ii) nocturnal attack ≤1–2 times/month | i) BUD: 200 µg/pf, 2 pfs each time, twice daily (800 µg daily; n=10); ii) placebo: 0 µg 2 pfs twice daily (0 µg daily; n=10). Delivery method: Turbuhaler DPI. Parallel design. | 2 months | 50.0 | 33.0 | NR | NR |
Pf, puff of inhaler; BUD, budesonide; DPI, dry power inhaler; MDI, metered-dose inhaler; ATS, American Thoracic Society; GINA, Global Initiative for Asthma; FEV1, forced expiratory volume in 1 sec; FP, fluticasone propionate; BDP, beclometasone dipropionate; ML, montelukast; p.r.n., when necessary; p.o., orally; b.i.d., twice daily.
Study validity and outcomes.
Author/(Refs.), year | Randomization | Allocation concealment | Blinding of participants and personnel | Number of patients discontinued or lossed to follow-up, N (%) | Outcomes | JADAD score |
---|---|---|---|---|---|---|
Jatakanon |
Yes; method not stated | Method not stated | Adequate | 1 (3.2) | Lung function; airway responsiveness; sputum measurement | 4 |
Boulet |
Yes; method not stated | Adequate | Adequate | 12 (17.4) at 3 months post.treatment; 25 (36.2) at 6 months post-treatment; 31 (44.9) at 9 months post-treatment; 38 (55.1) at 12 months post-treatment | Methacholine airway responsiveness; induced sputum; respiratory symptoms; peak expiratory flows; asthma exacerbations | 4 |
Bousquet |
Yes; method not stated | Method not stated | Adequate | None | Airway responsiveness; lung function; adverse events | 4 |
Ponce |
Yes; method not stated | Method not stated | Not blind | Not stated | Number of children with disappearing symptoms or symptoms that decreased by ≥70% | 1 |
Dahlén |
Yes; method not stated | Method not stated | Adequate | Not stated | Airway responsiveness to methacholine; FeNO; sputum measurements; lung function; asthma symptoms | 3 |
Ehrs |
Yes; method not stated | Method not stated | Yes; method not stated | None | FEV1 (% predicted) and FVC; FEV1 (% predicted) after inhalation of the bronchodilators; PD20FEV1; FEV1 decrease after dry air hyperpnoea; exhaled NO; AQLQ scores | 3 |
Gyllfors |
Yes; method not stated | Method not stated | Yes; method not stated | 1 (7.1) | FeNO; urinary-LTE4; airway responsiveness | 3 |
Haahtela |
Yes; using a computer program to generate random sequences | Method not stated | Adequate | 6 (6.5) | FeNO; FEV1; number of inhalations of study medication; asthma symptom | 5 |
Reddel |
Yes; randomization was by computer-generated sequences | Randomization code remained concealed until analysis | Adequate | 12 (27.3) | Morning PEF; morning FEV1; symptom score; β2-agonist use; waking due to asthma; symptom-free days; reliever-free days; FVC; asthma-related quality of life; FeNO; airway responsiveness; total fluticasone dose | 5 |
Rüdiger |
Yes; method not stated | Method not stated | Adequate | 3 (37.5) | Serum level of ACTH and cortisol 60 min after drug inhalation | 4 |
Mendes |
Yes; method not stated | Method not stated | Adequate | Not stated | FEV1; FVC; FEV1/FVC; MEF50; airway blood flow | 3 |
Pizzichini |
Yes; method not stated | Method not stated | Adequate | Not stated | FEV1; methochacholine responsiveness; airway inflammation markers | 3 |
Lim |
Yes; method not stated | Method not stated | Adequate | Not stated | Lung function; PC20; eNO; airway inflammation | 3 |
Stanković |
Yes; method not stated | Method not stated | Not blind | 11 (11.5) | FEV1/FVC; FVC; PEF; diurnal PEF variability; bronchoprovocative test | 2 |
Tamaoki |
Yes; method not stated | Method not stated | Not blind | 11 (12.9) | Asthma symptoms; pulmonary function; use of relief medication; sputum analysis | 2 |
Wongtim |
Yes; method not stated | Method not stated | Adequate | None | Lung function; airway responsiveness; symptom score | 4 |
FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 sec; FVC, forced vital capacity; PEF, peak expiratory flow; eNO, exhaled nitric oxide; PC20, FEV1≥20%; MEF50, maximal expiratory flow at 50%; ACTH, adrenocorticotropic hormone; AQLQ, Asthma Quality of Life Questionnaire; LTE4, leukotriene E4.