Layperson-Led vs Professional-Led Behavioral Interventions for Weight Loss in Pediatric Obesity: A Systematic Review and Meta-analysis.

Importance: The appropriate approach for weight loss among children and adolescents with overweight and obesity remains unclear. Objective: To evaluate the difference in the treatment outcomes associated with behavioral weight loss interventions led by laypersons and professionals in comparison with unsupervised control arms among children and adolescents with overweight and obesity. Data Sources: For this systematic review and meta-analysis, the Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, the Cochrane Library, and Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases were searched from January 1, 1996, to June 1, 2019. Study Selection: Included in this study were randomized clinical trials (RCTs) of behavioral interventions lasting at least 12 weeks for children and adolescents (aged 5-18 years) with overweight and obesity. Exclusion criteria included non-RCT studies, interventions lasting less than 12 weeks, adult enrollment, participants with other medical diagnoses, pharmacological treatment use, and articles not written in English. Two of 6 reviewers independently screened all citations. Of 25 586 citations, after duplicate removal, 78 RCTs (5780 participants) met eligibility criteria. Data Extraction and Synthesis: A bayesian framework and Markov chain Monte Carlo simulation methods were used to combine direct and indirect associations. Random-effects and fixed-effect network meta-analysis models were used with the preferred model chosen by comparing the deviance information criteria. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Main Outcomes and Measures: The immediate and sustained changes in weight and body mass index (BMI) standardized mean difference (SMD) were primary outcomes planned before data collection began, whereas waist circumference and percent body fat were secondary outcomes. The hypothesis being tested was formulated before the data collection. Results: Of 25 586 citations retrieved, we included 78 RCTs (5780 participants), with a follow-up of 12 to 104 weeks. Compared with the control condition, random-effects models revealed that professional-led weight loss interventions were associated with reductions in weight (mean difference [MD], -1.60 kg [95% CI, -2.30 to -0.99 kg]; 68 trials; P < .001) and BMI (SMD, -0.30 [95% CI, -0.39 to -0.20]; 59 trials; P < .001) that were not sustained long term (weight MD, -1.02 kg [95% CI, -2.20 to 0.34 kg]; 21 trials; P = .06; BMI SMD, -0.12 [95% CI, -0.46 to 0.21]; 20 trials; P < .001). There was no association between layperson-led interventions and weight loss in the short-term (MD, -1.40 kg [95% CI, -3.00 to 0.26 kg]; 5 trials; P = .05) or long-term (MD, -0.98 kg [95% CI, -3.60 to 1.80 kg]; 1 trial; P = .23) compared with standard care. No difference was found in head-to-head trials (professional vs layperson MD, -0.25 kg [95% CI -1.90 to 1.30 kg]; 5 trials; P = .38). Conclusions and Relevance: This systematic review and meta-analysis found that professional-led weight loss interventions were associated with short-term but not sustained weight reduction among children and adolescents with overweight or obesity, and the evidence for layperson-led approaches was insufficient to draw firm conclusions.

Genetic determinants of acute asthma therapy response in children with moderate-to-severe asthma exacerbations.

BACKGROUND: We documented inter-individual variability in the response to acute asthma therapy in children, attributed in part to five clinical factors (oxygen saturation, asthma severity score, virus detection, fever, symptoms between exacerbations; DOORWAY study). The contribution of genetic determinants of failure of acute asthma management have not been elucidated. OBJECTIVE: We aim to determine single nucleotide polymorphisms (SNP) associated with emergency department (ED) management failure in children. METHODS: A prospective cohort of 591 Caucasian children aged 1-17 years with moderate-to-severe asthma managed with standardized protocol were included. We examined 53 SNPs previously associated with asthma development, phenotypes, or bronchodilator or corticosteroids response. Associations between SNPs and management failure (hospitalization, active asthma management ≥8 h in ED, or a return visit within 72 h for one of two previous criteria) were examined using logistic regression, adjusting for the five clinical predictors of management failure. RESULTS: Four-hundred ninety-one subjects had complete clinical data and usable DNA samples. While controlling for clinical determinants, rs295137 in SPATS2L (OR = 1.77, 95%CI: 1.17, 2.68) was significantly associated with increased odds of ED management failure. Two SNPs in IL33 were associated with decreased odds of ED management failure: rs7037276 (OR = 0.55, 95%CI: 0.33, 0.90), and rs1342326 (OR = 0.52, 95%CI: 0.32, 0.86). The addition of these three SNPs to the clinical predictors significantly improved the model's predictive performance (P < 0.0004). CONCLUSION: Three SNPs were significantly associated with ED management failure in addition to clinical predictors, contributing to inter-individual variability. None has been previously associated with treatment response to acute asthma management.

Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Systemic corticosteroids as the frontline treatment of respiratory distress syndrome (RDS) in preterm infants are associated with adverse effects on growth and neurodevelopmental outcome, but the pulmonary administration of steroids may help prevent the development of bronchopulmonary dysplasia (BPD) without these side effects. OBJECTIVES: To evaluate the efficacy and safety of pulmonary application of corticosteroids in preterm infants with RDS. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, the WHO's International Clinical Trials Registry and grey literature were searched with no restriction on date and language of publication from inception to May 2016. Using a random-effect model, we pooled data from randomised controlled trials (RCTs) comparing inhaled or endotracheal corticosteroids with the standard of care, placebo or no other intervention in preterm infants with RDS. RESULTS: We identified 873 potential citations and included 12 unique RCTs. Pulmonary corticosteroid therapy was associated with a significant reduction in the composite outcome of BPD or death (relative risk (RR) 0.85, 95% CI 0.76 to 0.96). Pulmonary application of corticosteroids significantly reduced the incidence of patent ductus arteriosus (PDA) (RR 0.82, 95% CI 0.74 to 0.92) and pneumonia (RR 0.57, 95% CI 0.35 to 0.92). There was no evidence of a significant difference regarding the risk of neurodevelopmental impairment or other side effects. CONCLUSIONS: Pulmonary administration of corticosteroids reduces the incidence of BPD or death, pneumonia, PDA without causing any major side effects in preterm infants with RDS.

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies.

BACKGROUND: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m2; 95% confidence interval [CI] -1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749.

Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma.

BACKGROUND: Asthma management guidelines recommend low-dose inhaled corticosteroids (ICS) as first-line therapy for adults and adolescents with persistent asthma. The addition of anti-leukotriene agents to ICS offers a therapeutic option in cases of suboptimal control with daily ICS. OBJECTIVES: To assess the efficacy and safety of anti-leukotriene agents added to ICS compared with the same dose, an increased dose or a tapering dose of ICS (in both arms) for adults and adolescents 12 years of age and older with persistent asthma. Also, to determine whether any characteristics of participants or treatments might affect the magnitude of response. SEARCH METHODS: We identified relevant studies from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, the Allied and Complementary Medicine Database (AMED), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the trial registries clinicaltrials.gov and ICTRP from inception to August 2016. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of adults and adolescents 12 years of age and older on a maintenance dose of ICS for whom investigators added anti-leukotrienes to the ICS and compared treatment with the same dose, an increased dose or a tapering dose of ICS for at least four weeks. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. The primary outcome was the number of participants with exacerbations requiring oral corticosteroids (except when both groups tapered the dose of ICS, in which case the primary outcome was the % reduction in ICS dose from baseline with maintained asthma control). Secondary outcomes included markers of exacerbation, lung function, asthma control, quality of life, withdrawals and adverse events. MAIN RESULTS: We included in the review 37 studies representing 6128 adult and adolescent participants (most with mild to moderate asthma). Investigators in these studies used three leukotriene receptor antagonists (LTRAs): montelukast (n = 24), zafirlukast (n = 11) and pranlukast (n = 2); studies lasted from four weeks to five years. Anti-leukotrienes and ICS versus same dose of ICSOf 16 eligible studies, 10 studies, representing 2364 adults and adolescents, contributed data. Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86; 815 participants; four studies; moderate quality); this is equivalent to a number needed to treat for additional beneficial outcome (NNTB) over six to 16 weeks of 22 (95% CI 16 to 75). Only one trial including 368 participants reported mortality and serious adverse events, but events were too infrequent for researchers to draw a conclusion. Four trials reported all adverse events, and the pooled result suggested little difference between groups (RR 1.06, 95% CI 0.92 to 1.22; 1024 participants; three studies; moderate quality). Investigators noted between-group differences favouring the addition of anti-leukotrienes for morning peak expiratory flow rate (PEFR), forced expiratory volume in one second (FEV1), asthma symptoms and night-time awakenings, but not for reduction in ß2-agonist use or evening PEFR. Anti-leukotrienes and ICS versus higher dose of ICSOf 15 eligible studies, eight studies, representing 2008 adults and adolescents, contributed data. Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39; 1779 participants; four studies; moderate quality) nor in all adverse events between groups (RR 0.96, 95% CI 0.89 to 1.03; 1899 participants; six studies; low quality). Three trials reported no deaths among 834 participants. Results showed no statistically significant differences in lung function tests including morning PEFR and FEV1 nor in asthma control measures including use of rescue ß2-agonists or asthma symptom scores. Anti-leukotrienes and ICS versus tapering dose of ICSSeven studies, representing 1150 adults and adolescents, evaluated the combination of anti-leukotrienes and tapering-dose of ICS compared with tapering-dose of ICS alone and contributed data. Investigators observed no statistically significant difference in % change from baseline ICS dose (mean difference (MD) -3.05, 95% CI -8.13 to 2.03; 930 participants; four studies; moderate quality), number of participants with exacerbations requiring oral corticosteroids (RR 0.46, 95% CI 0.20 to 1.04; 542 participants; five studies; low quality) or all adverse events (RR 0.95, 95% CI 0.83 to 1.08; 1100 participants; six studies; moderate quality). Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92; 621 participants; two studies; moderate quality), but deaths were too infrequent for researchers to draw any conclusions about mortality. Data showed no improvement in lung function nor in asthma control measures. AUTHORS' CONCLUSIONS: For adolescents and adults with persistent asthma, with suboptimal asthma control with daily use of ICS, the addition of anti-leukotrienes is beneficial for reducing moderate and severe asthma exacerbations and for improving lung function and asthma control compared with the same dose of ICS. We cannot be certain that the addition of anti-leukotrienes is superior, inferior or equivalent to a higher dose of ICS. Scarce available evidence does not support anti-leukotrienes as an ICS sparing agent, and use of LTRAs was not associated with increased risk of withdrawals or adverse effects, with the exception of an increase in serious adverse events when the ICS dose was tapered. Information was insufficient for assessment of mortality.

Behavior change interventions and policies influencing primary healthcare professionals' practice-an overview of reviews.

BACKGROUND: There is a plethora of interventions and policies aimed at changing practice habits of primary healthcare professionals, but it is unclear which are the most appropriate, sustainable, and effective. We aimed to evaluate the evidence on behavior change interventions and policies directed at healthcare professionals working in primary healthcare centers. METHODS: Study design: overview of reviews. DATA SOURCE: MEDLINE (Ovid), Embase (Ovid), The Cochrane Library (Wiley), CINAHL (EbscoHost), and grey literature (January 2005 to July 2015). STUDY SELECTION: two reviewers independently, and in duplicate, identified systematic reviews, overviews of reviews, scoping reviews, rapid reviews, and relevant health technology reports published in full-text in the English language. DATA EXTRACTION AND SYNTHESIS: two reviewers extracted data pertaining to the types of reviews, study designs, number of studies, demographics of the professionals enrolled, interventions, outcomes, and authors' conclusions for the included studies. We evaluated the methodological quality of the included studies using the AMSTAR scale. For the comparative evaluation, we classified interventions according to the behavior change wheel (Michie et al.). RESULTS: Of 2771 citations retrieved, we included 138 reviews representing 3502 individual studies. The majority of systematic reviews (91%) investigated behavior and practice changes among family physicians. Interactive and multifaceted continuous medical education programs, training with audit and feedback, and clinical decision support systems were found to be beneficial in improving knowledge, optimizing screening rate and prescriptions, enhancing patient outcomes, and reducing adverse events. Collaborative team-based policies involving primarily family physicians, nurses, and pharmacists were found to be most effective. Available evidence on environmental restructuring and modeling was found to be effective in improving collaboration and adherence to treatment guidelines. Limited evidence on nurse-led care approaches were found to be as effective as general practitioners in patient satisfaction in settings like asthma, cardiovascular, and diabetes clinics, although this needs further evaluation. Evidence does not support the use of financial incentives to family physicians, especially for long-term behavior change. CONCLUSIONS: Behavior change interventions including education, training, and enablement in the context of collaborative team-based approaches are effective to change practice of primary healthcare professionals. Environmental restructuring approaches including nurse-led care and modeling need further evaluation. Financial incentives to family physicians do not influence long-term practice change.

Factors associated with failure of emergency department management in children with acute moderate or severe asthma: a prospective, multicentre, cohort study.

BACKGROUND: The management of paediatric asthma exacerbations is based on trials in children of all ages. Recent studies from 2009 raised the possibility that preschoolers (younger than 6 years) with viral-induced wheezing and children exposed to tobacco smoke might be at an increased risk of treatment failure. The study objective was to identify factors associated with management failure in children presenting to the emergency department with moderate or severe asthma exacerbations. METHODS: We undertook a prospective, multicentre cohort study of children aged 1-17 years presenting to five emergency departments with moderate or severe asthma (defined as a Pediatric Respiratory Assessment Measure [PRAM] of 4 to 12). Children received oral corticosteroids and severity-specific inhaled bronchodilator therapy. The primary outcome was emergency department management failure (hospital admission, prolonged emergency department therapy [≥8 h], or relapse within 72 h of discharge from the emergency department with admission to hospital or prolonged emergency department stay). Viral cause was ascertained by PCR on nasopharyngeal specimens and environmental tobacco smoke exposure by salivary cotinine concentration. This study is registered at ClinicalTrials.gov (NCT02013076). FINDINGS: Between Feb 14, 2011, and Dec 20, 2013, we screened 1893 children and enrolled 1012 eligible children. Of those eligible children, 973 participants were included in the analysis. 165 (17%) of 965 children experienced management failure in the emergency department, which was significantly associated with viral detection (110 [19%] of 579 participants with virus detection vs 46 [13%] of 354 participants without viral detection, odds ratio [OR] 1·57; 95% CI 1·04-2·37), fever (24% vs 15%, 1·96; 1·32-2·92), baseline PRAM (OR 1·38 per 1-point increase; 1·22-1·56), oxygen saturation of less than 92% (50% vs 12%, 3·94; 1·97-7·89), and presence of symptoms between exacerbations (21% vs 16%, 1·73; 1·13-2·64). Age, salivary cotinine concentration, and oral corticosteroids dose were not significantly associated with management failure. Viral detection (67% vs 46%, p<0·0001) and fever (31% vs 16%, p<0·0001) occurred more frequently in preschoolers than in older children. Viral detection was also associated with reduced speed of recovery over the 10 days after discharge. INTERPRETATION: In children presenting with moderate or severe asthma, viral detection, but not age, was associated with failure of symptom management, independently from exacerbation severity (ie, baseline PRAM and oxygen saturation), fever, and symptom chronicity (viral detection). Although it did not reach statistical significance, the association between treatment management failure and exposure to tobacco smoke warrants further investigation. FUNDING: Canadian Institutes of Health Research.

Early Exposure to Nonnutritive Sweeteners and Long-term Metabolic Health: A Systematic Review.

CONTEXT: Nonnutritive sweetener (NNS) consumption is increasing among children, yet its long-term health impact is unclear, particularly when exposure occurs during early life. OBJECTIVE: To synthesize evidence from prospective studies evaluating the association of early-life NNS exposure and long-term metabolic health. DATA SOURCES: Medline, Embase, and Cochrane Library (inception to July 2015). STUDY SELECTION: We aimed to include randomized controlled trials (RCTs) evaluating NNS-based interventions and prospective cohort studies reporting NNS exposure among pregnant women, infants, or children (<12 years of age), with a minimum study duration of 6 months. DATA EXTRACTION: The primary outcome was BMI; secondary outcomes included growth velocity, overweight/obesity, adiposity, and adverse metabolic effects. Study quality and risk of bias were evaluated using validated assessment tools. RESULTS: We identified 6 eligible cohort studies and 2 RCTs (n = 15,641 children). Half of the cohorts reported increasing weight gain or fat mass accumulation with increasing NNS intake, and pooled data from 2 cohorts showed a significant correlation with BMI gain (weighted mean correlation 0.023, 95% confidence interval 0.006 to 0.041). RCTs reported contradictory effects on weight change in children receiving NNSs. No eligible studies evaluated prenatal or infant NNS exposure. LIMITATIONS: Meta-analysis was limited because of the small number of eligible studies and heterogeneity of populations and outcomes. CONCLUSIONS: There is limited and inconsistent evidence of the long-term metabolic effects of NNS exposure during gestation, infancy, and childhood. Further research is needed to inform recommendations for the use of NNSs in this sensitive population.

Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children.

BACKGROUND: Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are increasingly prescribed for children with asthma. OBJECTIVES: To assess the safety and efficacy of adding a LABA to an ICS in children and adolescents with asthma. To determine whether the benefit of LABA was influenced by baseline severity of airway obstruction, the dose of ICS to which it was added or with which it was compared, the type of LABA used, the number of devices used to deliver combination therapy and trial duration. SEARCH METHODS: We searched the Cochrane Airways Group Asthma Trials Register until January 2015. SELECTION CRITERIA: We included randomised controlled trials testing the combination of LABA and ICS versus the same, or an increased, dose of ICS for at least four weeks in children and adolescents with asthma. The main outcome was the rate of exacerbations requiring rescue oral steroids. Secondary outcomes included markers of exacerbation, pulmonary function, symptoms, quality of life, adverse events and withdrawals. DATA COLLECTION AND ANALYSIS: Two review authors assessed studies independently for methodological quality and extracted data. We obtained confirmation from trialists when possible. MAIN RESULTS: We included in this review a total of 33 trials representing 39 control-intervention comparisons and randomly assigning 6381 children. Most participants were inadequately controlled on their current ICS dose. We assessed the addition of LABA to ICS (1) versus the same dose of ICS, and (2) versus an increased dose of ICS.LABA added to ICS was compared with the same dose of ICS in 28 studies. Mean age of participants was 11 years, and males accounted for 59% of the study population. Mean forced expiratory volume in one second (FEV1) at baseline was ≥ 80% of predicted in 18 studies, 61% to 79% of predicted in six studies and unreported in the remaining studies. Participants were inadequately controlled before randomisation in all but four studies.There was no significant group difference in exacerbations requiring oral steroids (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.70 to 1.28, 12 studies, 1669 children; moderate-quality evidence) with addition of LABA to ICS compared with ICS alone. There was no statistically significant group difference in hospital admissions (RR 1.74, 95% CI 0.90 to 3.36, seven studies, 1292 children; moderate-quality evidence)nor in serious adverse events (RR 1.17, 95% CI 0.75 to 1.85, 17 studies, N = 4021; moderate-quality evidence). Withdrawals occurred significantly less frequently with the addition of LABA (23 studies, 471 children, RR 0.80, 95% CI 0.67 to 0.94; low-quality evidence). Compared with ICS alone, addition of LABA led to significantly greater improvement in FEV1 (nine studies, 1942 children, inverse variance (IV) 0.08 L, 95% CI 0.06 to 0.10; mean difference (MD) 2.99%, 95% CI 0.86 to 5.11, seven studies, 534 children; low-quality evidence), morning peak expiratory flow (PEF) (16 studies, 3934 children, IV 10.20 L/min, 95% CI 8.14 to 12.26), reduction in use of daytime rescue inhalations (MD -0.07 puffs/d, 95% CI -0.11 to -0.02, seven studies; 1798 children) and reduction in use of nighttime rescue inhalations (MD -0.08 puffs/d, 95% CI -0.13 to -0.03, three studies, 672 children). No significant group difference was noted in exercise-induced % fall in FEV1, symptom-free days, asthma symptom score, quality of life, use of reliever medication and adverse events.A total of 11 studies assessed the addition of LABA to ICS therapy versus an increased dose of ICS with random assignment of 1628 children. Mean age of participants was 10 years, and 64% were male. Baseline mean FEV1 was ≥ 80% of predicted. All trials enrolled participants who were inadequately controlled on a baseline inhaled steroid dose equivalent to 400 µg/d of beclomethasone equivalent or less.There was no significant group differences in risk of exacerbation requiring oral steroids with the combination of LABA and ICS versus a double dose of ICS (RR 1.69, 95% CI 0.85 to 3.32, three studies, 581 children; moderate-quality evidence) nor in risk of hospital admission (RR 1.90, 95% CI 0.65 to 5.54, four studies, 1008 children; moderate-quality evidence).No statistical significant group difference was noted in serious adverse events (RR 1.54, 95% CI 0.81 to 2.94, seven studies, N = 1343; moderate-quality evidence) and no statistically significant differences in overall risk of all-cause withdrawals (RR 0.96, 95% CI 0.67 to 1.37, eight studies, 1491 children; moderate-quality evidence). Compared with double the dose of ICS, use of LABA was associated with significantly greater improvement in morning PEF (MD 8.73 L/min, 95% CI 5.15 to 12.31, five studies, 1283 children; moderate-quality evidence), but data were insufficient to aggregate on other markers of asthma symptoms, rescue medication use and nighttime awakening. There was no group difference in risk of overall adverse effects, A significant group difference was observed in linear growth over 12 months, clearly indicating lower growth velocity in the higher ICS dose group (two studies: MD 1.21 cm/y, 95% CI 0.72 to 1.70). AUTHORS' CONCLUSIONS: In children with persistent asthma, the addition of LABA to ICS was not associated with a significant reduction in the rate of exacerbations requiring systemic steroids, but it was superior for improving lung function compared with the same or higher doses of ICS. No differences in adverse effects were apparent, with the exception of greater growth with the use of ICS and LABA compared with a higher ICS dose. The trend towards increased risk of hospital admission with LABA, irrespective of the dose of ICS, is a matter of concern and requires further monitoring.

Intermittent inhaled corticosteroid therapy versus placebo for persistent asthma in children and adults.

BACKGROUND: International guidelines advocate using daily inhaled corticosteroids (ICS) in the management of children and adults with persistent asthma. However, in real world clinical settings, these medicines are often used at irregular intervals by patients. Recent evidence suggests that the use of intermittent ICS, with treatment initiated at the time of early symptoms, may still have benefits for reducing the severity of an asthma exacerbation. OBJECTIVES: To compare the efficacy and safety of intermittent ICS versus placebo in the management of children and adults diagnosed with, or suspected to have, symptoms of mild persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), the ClinicalTrials.gov website and the World Health Organization (WHO) trials portal in March 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intermittent ICS versus placebo in children and adults with symptoms of persistent asthma. No co-interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the risk of asthma exacerbations requiring oral corticosteroids and the primary safety outcome was serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, and withdrawal rates. Quality of the evidence was assessed using the GRADE criteria. MAIN RESULTS: Six trials (representing 490 preschool children, 145 school-aged children and 240 adults) met the inclusion criteria. Study durations were 12 to 52 weeks. Results for preschool children were presented in a separate analysis as this represents a distinct clinical condition, not necessarily related to the development of long term asthma.There was a reduction in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids in older children (145 participants, odds ratio (OR) 0.57; 95% confidence interval (CI) 0.29 to 1.12, low quality evidence) and adults with asthma (240 participants, OR 0.10; 95% CI 0.01 to 1.95, low quality evidence). These analyses were each based on the findings of a single study. No group difference was observed in the risk of serious adverse health events (385 participants; OR 1.00; 95% CI 0.14 to 7.25, moderate quality evidence). Compared to the placebo group, there was an insufficient number of participants to make firm conclusions whether the intermittent ICS group displayed any reduction in the rate of hospitalisations, day time and night time symptoms scores, or adverse events. Lung function tests reported by a single study favoured the use of ICS. There was no significant group difference in growth rate of children, or overall withdrawals.In preschool children with frequent wheezing episodes, the use of intermittent ICS at the onset of early symptoms reduced the likelihood of requiring rescue oral corticosteroids by half (490 participants; OR: 0.48; 95% CI 0.31 to 0.73, moderate quality evidence with minimal heterogeneity). Intermittent therapy was associated with fewer serious adverse events (439 participants; OR 0.42; 95% CI 0.17 to 1.02, low quality evidence). There was no significant difference in hospitalisations or in a single study measuring parent perceived quality of life. However, intermittent therapy was associated with improvements in both day time and night time symptoms. There was no increase in the rates of withdrawals, and overall and treatment-specific adverse events. AUTHORS' CONCLUSIONS: In children and adults with mild persistent asthma, two studies have shown that the use of intermittent ICS at the time of exacerbation reduced the chances of needing oral corticosteroids by half. This result is statistically significant if we assume that the effect size is the same for each study population (fixed effects model), but is not statistically significant when using a random effects model. However, the paucity of published evidence limits our conclusions towards the 'as-needed' use of this medication. The small number of studies and participants were the major reasons for downgrading the overall quality of the findings. A corresponding result was found in preschool children with wheeze. In this age group, an improvement in day time and night time asthma symptoms score and parental perceived quality of life of children similarly favoured the ICS group. However, there was no statistical difference in hospitalisation rates in any group. This treatment was not associated with any significant increase in adverse events. There was no growth suppression noted with the use of intermittent ICS in either preschool or school-aged children. Considering the limited number of available studies, we emphasise the need for more randomised controlled studies in order to confirm these findings.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2 -agonist and generally compared low (50 to 100 µg) versus low to medium (200 µg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. PLAIN LANGUAGE SUMMARY: Does altering the dose of inhaled corticosteroids make a difference in growth among children with asthma? BACKGROUND: Asthma guidelines recommend inhaled corticosteroids (ICS) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms. Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma. However, parents and physicians remain concerned about the potential negative effect of ICS on growth. REVIEW QUESTION: Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma? WHAT EVIDENCE DID WE FIND?: We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2 -agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 µg) with low to medium (200 µg) doses of corticosteroids (converted in µg HFA-beclomethasone equivalent) over 12 to 52 weeks. RESULTS: We found a small but statistically significant group difference in growth over 12 months between these different doses clearly favouring the lower dose of ICS. The type of corticosteroid among newer molecules (ciclesonide, fluticasone, mometasone) did not seem to influence the impact on growth over one year. Differences in corticosteroid doses did not seem to affect the change in height, the gain in weight, the gain in bone mass index and the maturation of bones. QUALITY OF THE EVIDENCE: This review is based on a small number of trials that reported data and were conducted on children with mild to moderate asthma. Only 10 of 22 studies measured the few outcomes of interest for this review, and only four comparisons reported growth over 12 months. Our confidence in the quality of evidence is high for this outcome, however it is low to moderate for several other outcomes, depending on the number of trials reporting these outcomes. Moreover, a few outcomes were reported only by a single trial; as these findings have not been confirmed by other trials, we downgraded the evidence for these outcomes to low quality. An insufficient number of trials have compared the effect of a larger difference in dose, for example, between a high dose and a low dose of ICS and of other popular molecules such as budesonide and beclomethasone over a year or longer of treatment. CONCLUSIONS: We report an evidence-based ICS dose-dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents' and clinicians' concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma.

Addition of antileukotriene agents to inhaled corticosteroids in children with persistent asthma.

UNLABELLED: For the current issue of the Journal, we asked Drs Jimmy Chong and Bhupendrasinh Chauhan to comment on and put into context the Cochrane Review on the efficacy and safety of adding antileukotriene agents (LTRAs) to low-dose inhaled corticosteroids (ICS) in children with persistent asthma (1). BACKGROUND: In the treatment of children with mild persistent asthma, low-dose ICS are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an LTRA to existing ICS as one of three therapeutic options to intensify therapy (step 3). SEARCH STRATEGY: Trials were identified from the Cochrane Airways Group Specialised Register of Trials, which is derived from systematic searches of bibliographical databases, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, AMED and CINAHL, and a manual search of respiratory journals and meeting abstracts, as well as the web-site www.clinicaltrials.gov. The search was conducted until January 2013. SELECTION CRITERIA: Randomized controlled trials (RCTs) that involved children and adolescents one to 18 years of age, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS, and in whom LTRAs were added to ICS and compared with the same, an increased or a tapering dose of ICS for at least four weeks were considered for inclusion. DATA ANALYSIS: Sandard methods outlined by The Cochrane Collaboration were used. RESULTS: Five paediatric (parallel group or cross-over) trials met the inclusion criteria. Two (40%) trials were considered to be at a low risk for bias. Four published trials, representing 559 children (≥6 years of age) and adolescents with mild-to-moderate asthma, contributed data to the review. No trial enrolled preschool-age children. All trials used montelukast as the LTRA, administered for between four and 16 weeks. Three trials evaluated the combination of LTRAs and ICS compared with the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (n=268 participants; RR 0.80 [95% CI 0.34 to 1.91]). There was also no statistically significant difference in percent change in forced expiratory volume in 1 s (FEV1) in this trial, with a mean difference (MD) of 1.3 (95% CI -0.09 to 2.69); however, a significant group difference was observed in the morning and evening peak expiratory flow rates: n=218 participants; MD 9.70 L/min (95% CI 1.27 L/min to 18.13 L/min) and MD 10.70 L/min (95% CI 2.41 L/min to 18.99 L/min), respectively. One trial compared the combination of LTRAs and ICS with a higher dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over a 16-week period (n=182 participants; RR 0.82 [95% CI 0.54 to 1.25]), nor was there any significant difference in exacerbations requiring hospitalization. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding LTRAs as a means to taper the dose of ICS. CONCLUSIONS: The addition of LTRAs to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared with the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although LTRAs have been licensed for use in children for >10 years, the paucity of paediatric trials, the absence of data regarding preschool-age children and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of LTRAs as add-on therapy to ICS as a step 3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS. The full text of the Cochrane Review is available in The Cochrane Library (1).

Inhaled anticholinergics and short-acting beta(2)-agonists versus short-acting beta2-agonists alone for children with acute asthma in hospital.

BACKGROUND: Inhaled anticholinergics given in addition to ß2-agonists are effective in reducing hospital admissions in children presenting to the emergency department with a moderate to severe asthma exacerbation. It seems logical to assume a similar beneficial effect in children hospitalised for an acute asthma exacerbation. OBJECTIVES: To assess the efficacy and safety of anticholinergics added to ß2-agonists as inhaled or nebulised therapy in children hospitalised for an acute asthma exacerbation. To investigate the characteristics of patients or therapy, if any, that would influence the magnitude of response attributable to the addition of anticholinergics. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived through systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO and through handsearching of respiratory journals and meeting abstracts. The search is current to November 2013. SELECTION CRITERIA: Randomised trials comparing the combination of inhaled or nebulised anticholinergics and short-acting ß2-agonists versus short-acting ß2-agonists alone in children one to 18 years of age hospitalised for an acute asthma exacerbation were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the methodological quality of trials and extracted data; disagreement was resolved by consensus or with the input of a third review author, when needed. Primary outcomes were duration of hospital stay and serious adverse events. Secondary outcomes included admission and duration of stay in the intensive care unit (ICU), ventilation assistance, time to short-acting ß2-agonists spaced at four hours or longer, supplemental asthma therapy, duration of supplemental oxygen, change from baseline in asthma severity, relapse after discharge, adverse health effects and withdrawals. MAIN RESULTS: Seven randomised trials were included, four of which reported usable data on 472 children with asthma one to 18 years of age who were admitted to paediatric wards. No trials included patients admitted to the ICU. The anticholinergic used, ipratropium bromide 250 µg, was given every one to eight hours over a period from four hours to the entire length of the hospital stay. Two of four trials (50%) contributing data were deemed of high methodological quality. The addition of anticholinergics to ß2-agonists showed no evidence of effect on the duration of hospital admission (mean difference (MD) -0.28 hours, 95% confidence interval (CI) -5.07 to 4.52, 3 studies, 327 participants, moderate quality evidence) and no serious or non-serious adverse events were reported in any included trials. As a result of the similarity of trials, we could not explore the influence of age, admission site, intensity of anticholinergic treatment and co-interventions on primary outcomes. No statistically significant group difference was noted in other secondary outcomes, including the need for supplemental asthma therapy, time to short-acting ß2-agonists spaced at four hours or longer, asthma clinical scores, lung function and overall withdrawals for any reason. AUTHORS' CONCLUSIONS: In children hospitalised for an acute asthma exacerbation, no evidence of benefit for length of hospital stay and other markers of response to therapy was noted when nebulised anticholinergics were added to short-acting ß2-agonists. No adverse health effects were reported, yet the small number of trials combined with inadequate reporting prevent firm reassurance regarding the safety of anticholinergics. In the absence of trials conducted in ICUs, no conclusion can be drawn regarding children with impending respiratory failure. These findings support current national and international recommendations indicating that healthcare practitioners should refrain from using anticholinergics in children hospitalised for acute asthma.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 µg) versus low to medium (200 µg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma.

BACKGROUND: Asthma patients who continue to experience symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) and anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS. OBJECTIVES: To compare the safety and efficacy of adding LABA versus LTRA to the treatment regimen for children and adults with asthma who remain symptomatic in spite of regular treatment with ICS. We specifically wished to examine the relative impact of the two agents on asthma exacerbations, lung function, symptoms, quality of life, adverse health events and withdrawals. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register until December 2012. We consulted reference lists of all included studies and contacted pharmaceutical manufacturers to ask about other published or unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS along with a fixed dose of a LABA or an LTRA for a minimum of four weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design when necessary. MAIN RESULTS: We included 18 RCTs (7208 participants), of which 16 recruited adults and adolescents (6872) and two recruited children six to 17 years of age (336) with asthma and significant reversibility to bronchodilator at baseline. Fourteen (79%) trials were of high methodological quality.The risk of exacerbations requiring systemic corticosteroids (primary outcome of the review) was significantly lower with the combination of LABA + ICS compared with LTRA + ICS-from 13% to 11% (eight studies, 5923 adults and 334 children; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.76 to 0.99; high-quality evidence). The number needed to treat for an additional beneficial outcome (NNTB) with LABA compared with LTRA to prevent one additional exacerbation over four to 102 weeks was 62 (95% CI 34 to 794). The choice of LTRA, the dose of ICS and the participants' age group did not significantly influence the magnitude of effect. Although results were inconclusive, the effect appeared stronger in trials that used a single device rather than two devices to administer ICS and LABA and in trials of less than 12 weeks' duration.The addition of LABA to ICS was associated with a statistically greater improvement from baseline in lung function, as well as in symptoms, rescue medication use and quality of life, although the latter effects were modest. LTRA was superior in the prevention of exercise-induced bronchospasm. More participants were satisfied with the combination of LABA + ICS than LTRA + ICS (three studies, 1625 adults; RR 1.12, 95% CI 1.04 to 1.20; moderate-quality evidence). The overall risk of withdrawal was significantly lower with LABA + ICS than with LTRA + ICS (13 studies, 6652 adults and 308 children; RR 0.84, 95% CI 0.74 to 0.96; moderate-quality evidence). Although the risk of overall adverse events was equivalent between the two groups, the risk of serious adverse events (SAE) approached statistical significance in disfavour of LABA compared with LTRA (nine studies, 5658 adults and 630 children; RR 1.33, 95% CI 0.99 to 1.79; P value 0.06; moderate-quality evidence), with no apparent impact of participants' age group.The following adverse events were reported, but no significant differences were demonstrated between groups: headache (11 studies, N = 6538); cardiovascular events (five studies, N = 5163), osteopenia and osteoporosis (two studies, N = 2963), adverse events (10 studies, N = 5977 adults and 300 children). A significant difference in the risk of oral moniliasis was noted, but this represents a low occurrence rate. AUTHORS' CONCLUSIONS: In adults with asthma that is inadequately controlled by predominantly low-dose ICS with significant bronchodilator reversibility, the addition of LABA to ICS is modestly superior to the addition of LTRA in reducing oral corticosteroid-treated exacerbations, with an absolute reduction of two percentage points. Differences favouring LABA over LTRA as adjunct therapy were observed in lung function and, to a lesser extend, in rescue medication use, symptoms and quality of life. The lower overall withdrawal rate and the higher proportion of participants satisfied with their therapy indirectly favour the combination of LABA + ICS over LTRA + ICS. Evidence showed a slightly increased risk of SAE with LABA compared with LTRA, with an absolute increase of one percentage point. Our findings modestly support the use of a single inhaler for the delivery of both LABA and low- or medium-dose ICS. Because of the paucity of paediatric trials, we are unable to draw firm conclusions about the best adjunct therapy in children.

Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma.

BACKGROUND: In the treatment of children with mild persistent asthma, low-dose inhaled corticosteroids (ICS) are recommended as the preferred monotherapy (referred to as step 2 of therapy). In children with inadequate asthma control on low doses of ICS (step 2), asthma management guidelines recommend adding an anti-leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy (step 3). OBJECTIVES: To compare the efficacy and safety of the combination of anti-leukotriene agents and ICS to the use of the same, an increased, or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS. In addition, we wished to determine the characteristics of people or treatments, if any, that influenced the magnitude of response attributable to the addition of anti-leukotrienes. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of Trials (CAGR), which were derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, AMED, and CINAHL; and the handsearching of respiratory journals and meeting abstracts, as well as the www.clinicaltrials.gov website. The search was conducted until January 2013. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) conducted in children and adolescents, aged one to 18 years, with asthma, who remained symptomatic despite the use of a stable maintenance dose of ICS and in whom anti-leukotrienes were added to the ICS if they were compared to the same, an increased, or a tapering dose of ICS for at least four weeks. DATA COLLECTION AND ANALYSIS: We used standard methods expected by The Cochrane Collaboration. MAIN RESULTS: Five paediatric (parallel group or cross-over) trials met the inclusion criteria. We considered two (40%) trials to be at a low risk of bias. Four published trials, representing 559 children (aged ≥ six years) and adolescents with mild to moderate asthma, contributed data to the review. No trial enrolled preschoolers. All trials used montelukast as the anti-leukotriene agent administered for between four and 16 weeks. Three trials evaluated the combination of anti-leukotrienes and ICS compared to the same dose of ICS alone (step 3 versus step 2). No statistically significant group difference was observed in the only trial reporting participants with exacerbations requiring oral corticosteroids over four weeks (N = 268 participants; risk ratio (RR) 0.80, 95% confidence interval (CI) 0.34 to 1.91). There was also no statistically significant difference in percentage change in FEV1 (forced expiratory volume in 1 second) with mean difference (MD) 1.3 (95% CI -0.09 to 2.69) in this trial, but a significant group difference was observed in the morning (AM) and evening (PM) peak expiratory flow rates (PEFR): N = 218 participants; MD 9.70 L/min (95% CI 1.27 to 18.13) and MD 10.70 (95% CI 2.41 to 18.99), respectively. One trial compared the combination of anti-leukotrienes and ICS to a higher-dose of ICS (step 3 versus step 3). No significant group difference was observed in this trial for participants with exacerbations requiring rescue oral corticosteroids over 16 weeks (N = 182 participants; RR 0.82, 95% CI 0.54 to 1.25), nor was there any significant difference in exacerbations requiring hospitalisation. There was no statistically significant group difference in withdrawals overall or because of any cause with either protocol. No trial explored the impact of adding anti-leukotrienes as a means to taper the dose of ICS. AUTHORS' CONCLUSIONS: The addition of anti-leukotrienes to ICS is not associated with a statistically significant reduction in the need for rescue oral corticosteroids or hospital admission compared to the same or an increased dose of ICS in children and adolescents with mild to moderate asthma. Although anti-leukotrienes have been licensed for use in children for over 10 years, the paucity of paediatric trials, the absence of data on preschoolers, and the variability in the reporting of relevant clinical outcomes considerably limit firm conclusions. At present, there is no firm evidence to support the efficacy and safety of anti-leukotrienes as add-on therapy to ICS as a step-3 option in the therapeutic arsenal for children with uncontrolled asthma symptoms on low-dose ICS.

Intermittent versus daily inhaled corticosteroids for persistent asthma in children and adults.

BACKGROUND: Daily inhaled corticosteroids (ICS) are the recommended mainstay of treatment in children and adults with persistent asthma. However, often, ICS are used intermittently by patients or recommended by physicians to be used only at the onset of exacerbations. OBJECTIVES: The aim of this review was to compare the efficacy and safety of intermittent versus daily ICS in the management of children and adults with persistent asthma and preschool-aged children suspected of persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov web site up to October 2012. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared intermittent ICS versus daily ICS in children and adults with persistent asthma. No co-interventions were permitted other than rescue relievers and oral corticosteroids used during exacerbations. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, methodological quality and extracted data. The primary efficacy outcome was the number of patients with one or more exacerbations requiring oral corticosteroids and the primary safety outcome was the number of patients with serious adverse health events. Secondary outcomes included exacerbations, lung function tests, asthma control, adverse effects, withdrawal rates and inflammatory markers. Equivalence was assumed if the risk ratio (RR) estimate and its 95% confidence interval (CI) were between 0.9 and 1.1. Quality of the evidence was assessed using GRADE. MAIN RESULTS: Six trials (including one trial testing two relevant protocols) met the inclusion criteria for a total of seven group comparisons. The four paediatric trials (two involving preschool children and two school-aged children) and two adult parallel-group trials, lasting 12 to 52 weeks, were of high methodological quality. A total of 1211 patients with confirmed, or suspected, persistent asthma contributed to the meta-analyses. There was no statistically significant group difference in the risk of patients experiencing one or more exacerbations requiring oral corticosteroids (1204 patients; RR 1.07; 95% CI 0.87 to 1.32; the large confidence interval translates into a risk of exacerbations in the intermittent ICS group varying between 17% and 25%, assuming a 19% risk with daily ICS). Age, severity of airway obstruction, step-up protocol used during exacerbations and trial duration did not significantly influence the primary efficacy outcome. No group difference was observed in the risk of patients with serious adverse health events (1055 patients; RR 0.82; 95% CI 0.33 to 2.03). Compared to the daily ICS group, the intermittent ICS group displayed a smaller improvement in change from baseline peak expiratory flow rate (PEFR) by 2.56% (95% CI -4.49% to -0.63%), fewer symptom-free days (standardised mean difference (SMD) -0.15 (95% CI -0.28 to -0.03), fewer asthma control days -9% (95% CI -14% to -4%), more use of rescue ß2-agonists by 0.12 puffs/day (95% CI 0 to 0.23) and a greater increase from baseline in exhaled nitric oxide of 16.80 parts per billion (95% CI 11.95 to 21.64). There was no significant group difference in forced expiratory volume in one second (FEV1), quality of life, airway hyper-reactivity, adverse effects, hospitalisations, emergency department visits or withdrawals. In paediatric trials, intermittent ICS (budesonide and beclomethasone) were associated with greater growth by 0.41 cm change from baseline (532 children; 95% CI 0.13 to 0.69) compared to daily treatment. AUTHORS' CONCLUSIONS: In children and adults with persistent asthma and in preschool children suspected of persistent asthma, there was low quality evidence that intermittent and daily ICS strategies were similarly effective in the use of rescue oral corticosteroids and the rate of severe adverse health events. The strength of the evidence means that we cannot currently assume equivalence between the two options.. Daily ICS was superior to intermittent ICS in several indicators of lung function, airway inflammation, asthma control and reliever use. Both treatments appeared safe, but a modest growth suppression was associated with daily, compared to intermittent, inhaled budesonide and beclomethasone. Clinicians should carefully weigh the potential benefits and harm of each treatment option, taking into account the unknown long-term (> one year) impact of intermittent therapy on lung growth and lung function decline.