Data in support for the measurement of serum 25-hydroxyvitamin D (25OHD) by tandem mass spectrometry.

This article provides data and a method related to a research paper entitled "Assessing vitamin D nutritional status: is capillary blood adequate?" (Jensen et al., 2016) [1]. Circulating 25OHD, the accepted biomarker of the vitamin D nutritional status, is routinely measured by automated immunoassays, that although may be performed in hospital central laboratories, often suffer from a lack of specificity with regards to the different vitamin D metabolites, "Measurement of circulating 25-hydroxyvitamin D: a historical review" (Le Goff et al., 2015) [2]. Mass spectrometry offers this specificity. This article describes the performance of an in-house tandem mass spectrometry method for the individual measurement of 25OHD3, 25OHD2 and 3-épi-25OHD3.

Assessing vitamin D nutritional status: Is capillary blood adequate?

BACKGROUND: Venous blood is the usual sample for measuring various biomarkers, including 25-hydroxyvitamin D (25OHD). However, it can prove challenging in infants and young children. Hence the finger-prick capillary collection is an alternative, being a relatively simple procedure perceived to be less invasive. We elected to validate the use of capillary blood sampling for 25OHD quantification by liquid chromatography tandem-mass spectrometry (LC/MS-MS). METHODS: Venous and capillary blood samples were simultaneously collected from 15 preschool-aged children with asthma 10days after receiving 100,000IU of vitamin-D3 or placebo and 20 apparently healthy adult volunteers. 25OHD was measured by an in-house LC/MS-MS method. RESULTS: The venous 25OHD values varied between 23 and 255nmol/l. The venous and capillary blood total 25OHD concentrations highly correlated (r(2)=0.9963). The mean difference (bias) of capillary blood 25OHD compared to venous blood was 2.0 (95% CI: -7.5, 11.5) nmol/l. CONCLUSION: Our study demonstrates excellent agreement with no evidence of a clinically important bias between venous and capillary serum 25OHD concentrations measured by LC/MS-MS over a wide range of values. Under those conditions, capillary blood is therefore adequate for the measurement of 25OHD.

Determinants Of Oral corticosteroid Responsiveness in Wheezing Asthmatic Youth (DOORWAY): protocol for a prospective multicentre cohort study of children with acute moderate-to-severe asthma exacerbations.

INTRODUCTION: Oral corticosteroids are the cornerstone of acute asthma management in the emergency department. Recent evidence has raised doubts about the efficacy of this treatment in preschool-aged children with viral-induced wheezing and in smoking adults. The aims of the study were to: (1) document the magnitude of response to oral corticosteroids in children presenting to the emergency department with moderate or severe asthma; (2) quantify potential determinants of response to corticosteroids and (3) explore the role of gene polymorphisms associated with the responsiveness to corticosteroids. METHODS AND ANALYSIS: The design is a prospective cohort study of 1008 children aged 1-17 years meeting a strict definition of asthma and presenting with a clinical score of ≥4 on the validated Pediatric Respiratory Assessment Measure. All children will receive standardised severity-specific treatment with prednisone/prednisolone and cointerventions (salbutamol with/without ipratropium bromide). Determinants, namely viral aetiology, environmental tobacco smoke and single nucleotide polymorphism, will be objectively documented. The primary efficacy endpoint is the failure of emergency department (ED) management within 72 h of the ED visit. Secondary endpoints include other measures of asthma severity and time to recovery within 7 days of the index visit. The study has 80% power for detecting a risk difference of 7.5% associated with each determinant from a baseline risk of 21%, at an α of 0.05. ETHICS AND DISSEMINATION: Ethical approval has been obtained from all participating institutions. An impaired response to systemic steroids in certain subgroups will challenge the current standard of practice and call for the immediate search for better approaches. A potential host-environment interaction will broaden our understanding of corticosteroid responsiveness in children. Documentation of similar effectiveness of corticosteroids across determinants will provide the needed reassurance regarding current treatment recommendations. RESULTS: Results will be disseminated at international conferences and manuscripts targeted at emergency physicians, paediatricians, geneticists and respirologists. TRIAL REGISTRATION NUMBER: This study is registered at Clinicaltrials.gov (NCT02013076).

Asthma action plans are highly variable and do not conform to best visual design practices.

BACKGROUND: Asthma action plans improve asthma outcomes and are recommended in guidelines. However, delivery by physicians and usage by patients remain low. This may be because of variability in existing plans and a failure to consider visual design and usability factors in plan development. OBJECTIVE: To characterize the variability in both the content and the format of existing plans, and the extent to which their format conforms to evidence-based visual design recommendations. METHODS: We collected plans from the internet, Canadian experts and associations, guidelines, and published trials. We inductively developed analytic criteria for format and content analyses. RESULTS: We collected 69 unique English or French-language adult outpatient plans from around the world. We found large variability in format, and plans fulfilled a mean of only 3.5 out of 8 evidence-based visual design recommendations. Content was also variable, including different descriptions of the baseline clinical state and descriptions and instructions at each "action point" (point recommending a change in treatment). CONCLUSION: Existing plans vary widely in content and format. Accordingly, studies evaluating the effectiveness of action plans may not be directly comparable. Also, visual design may affect usability, uptake, and effectiveness. Our results suggest that this has not been adequately addressed in most plans, and design evidence and experts should be included in future development.

Canadian Thoracic Society Asthma Management Continuum--2010 Consensus Summary for children six years of age and over, and adults.

BACKGROUND/OBJECTIVE: To integrate new evidence into the Canadian Asthma Management Continuum diagram, encompassing both pediatric and adult asthma. METHODS: The Canadian Thoracic Society Asthma Committee members, comprised of experts in pediatric and adult respirology, allergy and immunology, emergency medicine, general pediatrics, family medicine, pharmacoepidemiology and evidence-based medicine, updated the continuum diagram, based primarily on the 2008 Global Initiative for Asthma guidelines, and performed a focused review of literature pertaining to key aspects of asthma diagnosis and management in children six years of age and over, and adults. RESULTS: In patients six years of age and over, management of asthma begins with establishing an accurate diagnosis, typically by supplementing medical history with objective measures of lung function. All patients and caregivers should receive self-management education, including a written action plan. Inhaled corticosteroids (ICS) remain the first-line controller therapy for all ages. When asthma is not controlled with a low dose of ICS, the literature supports the addition of long-acting beta2-agonists in adults, while the preferred approach in children is to increase the dose of ICS. Leukotriene receptor antagonists are acceptable as second-line monotherapy and as an alternative add-on therapy in both age groups. Antiimmunoglobulin E therapy may be of benefit in adults, and in children 12 years of age and over with difficult to control allergic asthma, despite high-dose ICS and at least one other controller. CONCLUSIONS: The foundation of asthma management is establishing an accurate diagnosis based on objective measures (eg, spirometry) in individuals six years of age and over. Emphasis is placed on the similarities and differences between pediatric and adult asthma management approaches to achieve asthma control.

WITHDRAWN: Cow's milk protein avoidance and development of childhood wheeze in children with a family history of atopy.

BACKGROUND: In infants with a family history of atopy, food allergen avoidance has been advocated as means of preventing the development of atopic disease, when breast-feeding is not possible or supplemental feeding is needed. Most infant formulas are based on cow's milk protein. Alternative choices include soya based and hydrolysed cows milk formulas. OBJECTIVES: To estimate the effect of dietary avoidance of cow's milk protein on the development of asthma or wheeze in children. SEARCH STRATEGY: We searched the Cochrane database for eligible trials until February 2002. We obtained the full text papers of all abstracts identified as RCTs and two reviewers independently reviewed them. SELECTION CRITERIA: We included randomised controlled trials involving children with a family history of atopy in at least one first degree relative, if feeding with cow's milk based standard formula was compared to dietary avoidance of cow's milk protein, using soya or other hypoallergenic formula during the initial four months of life or longer. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently. A priori defined subgroups were the types of hypoallergenic artificial feed and dietary restrictions on mother and/or child's diet. MAIN RESULTS: Six trials used hydrolysed formula for at least four months, in addition to dietary restrictions and in some cases dust-mite reduction measures. The risk of infants experiencing asthma or wheeze during the first year of life was reduced compared to standard cow's milk based formula (Relative Risk 0.40, 95% Confidence Intervals 0.19 to 0.85). Feeding soya-based formula as opposed to standard cow's milk formula did not reduce the risk of having asthma or wheeze at any age. AUTHORS' CONCLUSIONS: Breast-milk should remain the feed of choice for all babies. In infants with at least one first degree relative with atopy, hydrolysed formula for a minimum of four months combined with dietary restrictions and environment measures may reduce the risk of developing asthma or wheeze in the first year of life. There is insufficient evidence to suggest that soya-based milk formula has any benefit.

Corticosteroids for preventing relapse following acute exacerbations of asthma.

BACKGROUND: Acute asthma is responsible for many emergency department (ED) visits annually. Between 12 to 16% will relapse to require additional interventions within two weeks of ED discharge. Treatment of acute asthma is based on rapid reversal of bronchospasm and reducing airway inflammation. OBJECTIVES: To determine the benefit of corticosteroids (oral, intramuscular, or intravenous) for the treatment of asthmatic patients discharged from an acute care setting (i.e. usually the emergency department) after assessment and treatment of an acute asthmatic exacerbation. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register and reference lists of articles. In addition, authors of all included studies were contacted to locate unpublished studies. The most recent search was run in October 2006. SELECTION CRITERIA: Randomized controlled trials comparing two types of corticosteroids (oral, intra-muscular, or inhaled) with placebo for outpatient treatment of asthmatic exacerbations in adults or children. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. MAIN RESULTS: Six trials involving 374 people were included. One study used intramuscular corticosteroids, five studies used oral corticosteroids. The review was split into two reviews and although the latest search yielded no additional placebo controlled trials an additional IM study was included. Significantly fewer patients in the corticosteroid group relapsed to receive additional care in the first week (Relative risk (RR) 0.38; 95% confidence interval (CI) 0.2 to 0.74). This favourable effect was maintained over the first 21 days (RR 0.47; 95% CI 0.25 to 0.89) and there were fewer subsequent hospitalizations (RR 0.35; 95% CI 0.13 to 0.95). Patients receiving corticosteroids had less need for beta(2)-agonists (mean difference (MD) -3.3 activations/day; 95% CI -5.6 to -1.0). Changes in pulmonary function tests (SMD 0.045; 95% CI -0.47 to 0.56) and side effects (SMD 0.03; 95% CI -0.38 to 0.44) in the first 7 to 10 days, while rarely reported, showed no significant differences between the treatment groups. Statistically significant heterogeneity was identified for the side effect results; all other outcomes were homogeneous. From these results, as few as ten patients need to be treated to prevent relapse to additional care after an exacerbation of asthma. AUTHORS' CONCLUSIONS: A short course of corticosteroids following assessment for an asthma exacerbation significantly reduces the number of relapses to additional care, hospitalizations and use of short-acting beta(2)-agonist without an apparent increase in side effects. Intramuscular and oral corticosteroids are both effective.

Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma.

BACKGROUND: Patients who continue to experience asthma symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Leukotriene receptor antagonists (LTRA) and long-acting beta(2)-agonists (LABA) agents may both be considered as add-on therapy to inhaled corticosteroids (ICS). OBJECTIVES: We compared the efficacy and safety profile of adding either daily LABA or LTRA in asthmatic patients who remained symptomatic on ICS. SEARCH STRATEGY: The Cochrane Airways Group Specialised Register was searched for randomised controlled trials up to and including March 2006. Reference lists of all included studies and reviews were screened to identify potentially relevant citations. Inquiries regarding other published or unpublished studies supported by the authors of the included studies or pharmaceutical companies who manufacture these agents were made. Conference proceedings of major respiratory meetings were also searched. SELECTION CRITERIA: Only randomised controlled trials conducted in adults or children with recurrent asthma where a LABA (for example, salmeterol or formoterol) or LTRA (for example, montelukast, pranlukast, zafirlukast) was added to ICS for a minimum of 28 days were considered for inclusion. Inhaled short-acting beta(2)-agonists and short courses of oral steroids were permitted as rescue medications. Other daily asthma treatments were permitted, providing the dose remained constant during the intervention period. Two reviewers independently reviewed the literature searches. DATA COLLECTION AND ANALYSIS: Data extraction and trial quality assessment were conducted independently by two reviewers. Whenever possible, primary study authors were requested to confirm methodology and data extraction and to provide additional information and clarification when needed. Where necessary, expansion of graphic reproductions and estimation from other data presented in the paper was performed. MAIN RESULTS: Fifteen randomised controlled trials met the inclusion criteria; eleven trials including 6,030 participants provided data in sufficient detail to permit aggregation. All eleven trials pertained to adults with moderate airway obstruction (% predicted FEV(1) 66-76%) at baseline. Montelukast (n=9) or Zafirlukast (n=2) was compared to Salmeterol (n=9) or Formoterol (n=2) as add-on therapy to 400-565 mcg of beclomethasone or equivalent. Risk of exacerbations requiring systemic corticosteroids was significantly lower with LABA+ICS when compared to LTRA+ICS (RR= 0.83, 95% Confidence Interval (95%CI): 0.71, 0.97): the number needed to treat with LABA compared to LTRA, to prevent one exacerbation over 48 weeks, was 38 (95% CI: 23 to 247). The following outcomes also improved significantly with the addition of LABA compared to LTRA to inhaled steroids (Weighted Mean Difference; 95%CI): morning PEFR (16 L/min; 13 to 18), evening PEFR (12 L/min; 9 to 15), FEV(1) (80 mL; 60 to 100), rescue-free days (9%; 5% to 13%), symptom-free days (6%; 2 to 11), rescue beta(2)-agonists (-0.5 puffs/day; -0.2 to -1), quality of life (0.1; 0.05 to 0.2), symptom score (Standard Mean Difference -0.2; -0.1 to -0.3), night awakenings (-0.1/week; -0.06 to -0.2) and patient satisfaction (RR 1.12; 1.07 to 1.16). Risk of withdrawals due to any reason was significantly lower with LABA+ICS compared to LTRA+ICS (Risk Ratio 0.83, 95% CI 0.73 to 0.95). Withdrawals due to adverse events or due to poor asthma control, hospitalisation, osteopenia, serious adverse events, overall adverse events, headache or cardiovascular events were not significantly different between the two study groups. AUTHORS' CONCLUSIONS: In asthmatic adults inadequately controlled on low doses of inhaled steroids, the addition of LABA is superior to LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and the use of rescue beta(2)-agonists.

Written action plans for asthma in children.

BACKGROUND: While all asthma consensus statements recommend the use of written action plan (WAP) as a central part of asthma management, a recent systematic review of randomised trials highlighted the paucity of trials where the only difference between groups was the provision or not of a written action plan. OBJECTIVES: The objectives of this review were firstly to evaluate the independent effect of providing versus not providing a written action plan in children and adolescents with asthma, and secondly to compare the effect of different written action plans. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register (November 2004), which is derived from searches of CENTRAL, MEDLINE, EMBASE, CINAHL, as well as handsearched respiratory journals, and meeting abstracts. We also searched bibliographies of included studies and identified review articles. SELECTION CRITERIA: Randomised controlled trials were included if they compared a written action plan with no written action plan, or different written action plans with each other. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials, assessed trial quality and extracted the data. Study authors were contacted for additional information. MAIN RESULTS: Four trials (three RCTs and one quasi-RCT) involving 355 children were included. Children using symptom-based WAPs had lower risk of exacerbations which required an acute care visit (N = 5; RR 0.73; 95% CI 0.55 to 0.99). The number needed to treat to prevent one acute care visit was 9 (95% CI 5 to 138). Symptom monitoring was preferred over peak flow monitoring by children (N = 2; RR 1.21; 95% CI 1.00 to 1.46), but parents showed no preference (N = 2; RR 0.96; 95% CI 0.18 to 2.11). Children assigned to peak flow-based action plans reduced by 1/2 day the number of symptomatic days per week (N = 2; mean difference: 0.45 days/week; 95% CI 0.04 to 0.26). There were no significant group differences in the rate of exacerbation requiring oral steroids or admission, school absenteeism, lung function, symptom score, quality of life, and withdrawals. AUTHORS' CONCLUSIONS: The evidence suggests that symptom-based WAP are superior to peak flow WAP for preventing acute care visits although there is insufficient data to firmly conclude whether the observed superiority is conferred by greater adherence to the monitoring strategy, earlier identification of onset of deteriorations, higher threshold for presentation to acute care settings, or the specific treatment recommendations.

Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) and sodium cromoglycate (SCG) have become established as effective controller medications for children and adults with asthma, but their relative efficacy is not clear. OBJECTIVES: To compare the relative effectiveness and adverse effects of ICS and SCG among children and adults with chronic asthma. SEARCH STRATEGY: Systematic search of the Cochrane Airways Group's special register of controlled trials (to Feb. 2004), hand searches of the reference lists of included trials and relevant review papers, and written requests for identification of additional trials from pharmaceutical manufacturers. SELECTION CRITERIA: Randomized controlled trials comparing the effect of ICS with SCG in children and adults with chronic asthma. DATA COLLECTION AND ANALYSIS: All studies were assessed independently for eligibility by three review authors. Disagreements were settled by consensus. Trial authors were contacted to supply missing data or to verify methods. Eligible studies were abstracted and fixed- and random-effects models were implemented to pool studies. Separate analyses were conducted for paediatric and adult studies. Subgroup analyses and meta-regression models were fit to explore heterogeneity of lung function outcomes by type of RCT, category of ICS or SCG dosage, asthma severity of participants, and study quality on outcomes. MAIN RESULTS: Of 67 identified studies, 17 trials involving 1279 children and eight trials involving 321 adults with asthma were eligible. Thirteen (76%) of the paediatric studies and six (75%) of the adult studies were judged to be high quality. Among children, ICS were associated with a higher final mean forced expiratory volume in 1 second [FEV1] (weighted mean difference [WMD] 0.07 litres, 95% confidence interval [CI] 0.02 to 0.11) and higher mean final peak expiratory flow rate [PEF] (WMD 17.3 litres/minute, 95% CI 11.3 to 23.3) than SCG. In addition, ICS were associated with fewer exacerbations (WMD -1.18 exacerbations per year, 95% CI -2.15 to - 0.21), lower asthma symptom scores, and less rescue bronchodilator use than SCG. There were no group differences in the proportion of children with adverse effects. Among adults, ICS were similarly associated with a higher mean final FEV1 (WMD 0.21 litres, 95% CI 0.13 to 0.28) and a higher final endpoint PEF (WMD 28.2 litres/minute, 95% CI 18.7 to 37.6) than SCG. ICS were also associated with fewer exacerbations (WMD -3.30 exacerbations per year, 95% CI -5.62 to -0.98), lower asthma symptom scores among cross-over trials but not parallel trials, and less rescue bronchodilator use than SCG. There were no differences in the proportion of adults with adverse effects. In subgroup analyses involving lung function measures, paediatric and adult studies judged to be of high quality had results consistent with the overall results. Lung function measures in children were higher in studies with medium BDP-equivalent steroid dosages than low BDP-equivalent dosages, while adult studies could not be compared by steroid dosage since they all incorporated similar dosages. There were no significant differences in lung function by the asthma severity of participants for adult or child studies. AUTHORS' CONCLUSIONS: ICS were superior to SCG on measures of lung function and asthma control for both adults and children with chronic asthma. There were few studies reporting on quality of life and health care utilization, which limited our ability to adequately evaluate the relative effects of these medications on a broader range of outcomes. Although there were no differences in adverse effects between ICS and SCG, most trials were short and may not have been of sufficient duration to identify long-term effects. Our results support recent consensus statements in the U.S. and elsewhere that favour the use of ICS over SCG for control of persistent asthma.

Oral xanthines as maintenance treatment for asthma in children.

BACKGROUND: Xanthines have been used in the treatment of asthma as a bronchodilator, though they may also have anti-inflammatory effects. The current role of xanthines in the long-term treatment of childhood asthma needs to be reassessed. OBJECTIVES: To determine the efficacy of xanthines (e.g. theophylline) in the maintenance treatment of paediatric asthma. SEARCH STRATEGY: A search of the Cochrane Airways Group Specialised Register was undertaken with predefined search terms. Searches are current to May 2005. SELECTION CRITERIA: Randomised controlled trials,lasting at least four weeks comparing a xanthine with placebo, regular short-acting beta-agonist (SABA), inhaled corticosteroids (ICS), cromoglycate (SCG), ketotifen (KET) or leukotriene antagonist, in children with diagnosed with chronic asthma between 18 months and 18 years old. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected each study for inclusion in the review and extracted data. Primary outcome was percentage of symptom-free days. MAIN RESULTS: Thirty-four studies (2734 participants) of adequate quality were included. Xanthine versus placebo (17 studies): The proportion of symptom free days was larger with xanthine compared with placebo (7.97% [95% CI 3.41, 12.53]). Rescue medication usage was lower with xanthine, with no significant difference in symptom scores or hospitalisations. FEV1 , and PEF were better with xanthine. Xanthine was associated with non - specific side-effects. Data from behavioural scores were inconclusive. Xanthine versus ICS (four studies) : Exacerbations were less frequent with ICS, but no significant difference on lung function was observed. Individual studies reported significant improvements in symptom measures in favour of steroids, and one study reported a difference in growth rate in favour of xanthine. No difference was observed for study withdrawal or tremor. Xanthine was associated with more frequent headache and nausea. Xanthine versus regular SABA (10 studies): No significant difference in symptoms, rescue medication usage and spirometry. Individual studies reported improvement in PEF with beta-agonist. Beta-agonist treatment led to fewer hospitalisations and headaches. Xanthine was associated with less tremor. Xanthine versus SCG (six studies ): No significant difference in symptoms, exacerbations and rescue medication. Sodium cromoglycate was associated with fewer gastro-intestinal side-effects than xanthine. Xanthine versus KET (one study): No statistical tests of significance between xanthine and ketotifen were reported. Xanthine + ICS versus placebo + same dose ICS (three studies) : Results were conflicting due to clinical/methodological differences, and could not be aggregated. AUTHORS' CONCLUSIONS: Xanthines as first-line preventer alleviate symptoms and reduce requirement for rescue medication in children with mild to moderate asthma. When compared with ICS they were less effective in preventing exacerbations. Xanthines had similar efficacy as single preventative agent compared with regular SABA and SCG. Evidence on AEs (adverse effects) was equivocal: there was evidence for increased AEs overall, but no evidence that any specific AE (including effects on behaviour and attention) occurred more frequently than with placebo. There is insufficient evidence from available studies to make firm conclusions about the effectiveness of xanthines as add-on preventative treatment to ICS, and there are no published paediatric studies comparing xanthines with alternatives in this role. Our data suggest that xanthines are only suitable as first-line preventative asthma therapy in children when ICS are not available. They may have a role as add-on therapy in more severe asthma not controlled by ICS, but further studies are needed to examine this, and to define the risk-benefit ratio compared with other agents.

Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma.

BACKGROUND: Long-acting inhaled beta2-adrenergic agonists are recommended as 'add-on' medication to inhaled corticosteroids in the maintenance therapy of asthmatic adults and children aged two years and above. OBJECTIVES: To quantify in asthmatic patients the safety and efficacy of the addition of long-acting beta2-agonists to inhaled corticosteroids on the incidence of asthma exacerbations, pulmonary function and other measures of asthma control. SEARCH STRATEGY: We identified randomised controlled trials (RCTs) through electronic database searches (the Cochrane Airways Group Specialised Register, MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers, until April 2004. SELECTION CRITERIA: RCTs were included that compared the addition of inhaled long-acting beta2-agonists to corticosteroids with inhaled corticosteroids alone for asthma therapy in children aged two years and above and in adults. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by two review authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of asthma exacerbations requiring systemic corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptom scores, adverse events and withdrawal rates. MAIN RESULTS: Of 594 identified citations, 49 trials met the inclusion criteria: 27 full-text publications, one unpublished full-text report and 21 abstracts. Twenty-three citations (21 abstracts and two full-text publications) provided data in insufficient detail, 26 trials contributed to this systematic review. All but three trials were of high methodological quality. Most interventions (N = 26) were of four-month duration or less. Eight trials focused on children and 18 on adults, with participants generally symptomatic with moderate airway obstruction despite their current inhaled steroid regimen. If a trial had more than one intervention or control group, additional control to intervention comparisons were considered separately. Formoterol (N = 17) or salmeterol (N = 14) were most frequently added to low-dose inhaled corticosteroids (200 to 400 microg/day of beclomethasone (BDP) or equivalent). The addition of a daily long-acting beta2-agonist (LABA) reduced the risk of exacerbations requiring systemic steroids by 19% (relative risk (RR) 0.81, 95% CI 0.73 to 0.90). The number needed to treat for one extra patient to be free from exacerbation for one year was 18 (95% CI 13 to 33). The addition of LABA significantly improved FEV1 (weighted mean difference (WMD) 170 mL, 95% CI 110 to 240) using a random-effects model, increased the proportion of symptom-free days (WMD 17%, 95% CI 12 to 22, N = 6 trials) and rescue-free days (WMD 19%, 95% CI 12 to 26, N = 2 trials). The group treated with LABA plus inhaled corticosteroid showed a reduction in the use of rescue short-acting beta2-agonists (WMD -0.7 puffs/day, 95% CI -1.2 to -0.2), experienced less withdrawals due to poor asthma control (RR 0.5, 95% CI 0.4 to 0.7) and less withdrawals due to any reason (RR 0.9, 95% CI 0.8 to 0.98), using a random-effects model. There was no group difference in risk of overall adverse effects (RR 0.98, 95% CI 0.92 to 1.05), withdrawals due to adverse health events (RR 1.29, 95% CI 0.96 to 1.75) or specific adverse health events. AUTHORS' CONCLUSIONS: In patients who are symptomatic on low to high doses of inhaled corticosteroids, the addition of a long-acting beta2-agonist reduces the rate of exacerbations requiring systemic steroids, improves lung function, symptoms and use of rescue short-acting beta2-agonists. The similar number of serious adverse events and withdrawal rates in both groups provides some indirect evidence of the safety of long-acting beta2-agonists as add-on therapy to inhaled corticosteroids.

Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma.

BACKGROUND: In asthmatic patients inadequately controlled on inhaled corticosteroids and/or those with moderate persistent asthma, two main options are recommended: the combination of a long-acting inhaled beta2 agonist (LABA) with inhaled corticosteroids (ICS) or use of a higher dose of inhaled corticosteroids. OBJECTIVES: To determine, in asthmatic patients, the effect of the combination of long-acting beta2 agonists and inhaled corticosteroids compared to a higher dose of inhaled corticosteroids on the incidence of asthma exacerbations, on pulmonary function and on other measures of asthma control and to look for characteristics associated with greater benefit for either treatment option. SEARCH STRATEGY: We identified randomized controlled trials (RCTs) through electronic database searches (MEDLINE, EMBASE and CINAHL), bibliographies of RCTs and correspondence with manufacturers until April 2004. SELECTION CRITERIA: RCTs were included that compared the combination of inhaled LABA and ICS to a higher dose of inhaled corticosteroids, in children aged 2 years and older, and in adults with asthma. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by two authors for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of patients experiencing one or more asthma exacerbations requiring oral corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptoms, use of rescue beta2 agonists, adverse events and withdrawal rates. The meta-analysis was done with RevMan Analyses and the meta-regression, with Stata. MAIN RESULTS: Of 593 citations identified, 30 (three pediatric; 27 adult) trials were analysed recruiting 9509 participants, including one study providing two control-intervention comparisons. Only one trial included corticosteroid-naive patients. Participants were symptomatic, generally (N=20 trials) presenting with moderate (FEV1 60-79% of predicted) rather than mild airway obstruction. Trials tested the combination of salmeterol (N=22) or formoterol (N=8) with a median of 400 mcg of beclomethasone or equivalent (BDP-eq) compared to a median of 800 to 1000 mcg/day of BDP-eq. Trial duration was 24 weeks or less in all but four trials. There was no significant group difference in the rate of patients with exacerbations requiring systemic corticosteroids [N=15, RR=0.88 (95% CI: 0.77, 1.02)]. The combination of LABA and ICS resulted in greater improvement from baseline in FEV1 [N=7, WMD=0.10 L (95% CI: 0.07, 0.12)], in symptom-free days [N=8 , WMD=11.90% (95% CI:7.37, 16.44), random effects model], and in the daytime use of rescue beta2 agonists than a higher dose of ICS [N=4, WMD= -0.99 puffs/day (95% CI: -1.41, -0.58), random effects model]. There was no significant group difference in the rate of overall adverse events [N=15, RR=0.93 (95% CI: 0.84, 1.03), random effects model], or specific side effects, with the exception of a three-fold increase rate of tremor in the LABA group [N= 10, RR=2.96 (95%CI: 1.60, 5.45)]. The rate of withdrawals due to poor asthma control favoured the combination of LABA and ICS [N=20, RR=0.69 (95%CI: 0.52, 0.93)]. AUTHORS' CONCLUSIONS: In adult asthmatics, there was no significant difference between the combination of LABA and ICS and a higher dose of ICS for the prevention of exacerbations requiring systemic corticosteroids. Overall, the combination therapy led to greater improvement in lung function, symptoms and use of rescue beta2 agonists, (although most of the results are from trials of up to 24 weeks duration). There were less withdrawals due to poor asthma control in this group than when using a higher dose of inhaled corticosteroids. Apart from an increased rate of tremor, the two options appear safe although adverse effects associated with long-term ICS treatment were seldom monitored.

Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults.

BACKGROUND: Consensus statements recommend the addition of long-acting inhaled beta2-agonists only in asthmatic patients who are inadequately controlled on inhaled corticosteroids. OBJECTIVES: To compare the efficacy of initiating anti-inflammatory therapy using the combination of inhaled corticosteroids and long-acting beta2-agonists (ICS+LABA) as compared to inhaled corticosteroids alone (ICS alone) in steroid-naive children and adults with persistent asthma. SEARCH STRATEGY: We identified randomised controlled trials (RCTs) through electronic database searches (Cochrane Airways Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL) until April 2004, bibliographies of identified RCTs and correspondence with manufacturers. SELECTION CRITERIA: RCTs comparing the combination of inhaled corticosteroids and long-acting beta2-agonists (ICS + LABA) to inhaled corticosteroids (ICS) alone in steroid-naive children and adults with asthma. DATA COLLECTION AND ANALYSIS: Studies were assessed independently by each reviewer for methodological quality and data extraction. Confirmation was obtained from the trialists when possible. The primary endpoint was rate of asthma exacerbations requiring systemic corticosteroids. Secondary endpoints included pulmonary function tests (PFTs), symptoms, use of other measures of asthma control, adverse events, and withdrawal rates. MAIN RESULTS: Eighteen trials met the inclusion criteria; nine (totaling 1061 adults) contributed sufficient data to be analysed. Baseline forced expiratory volume in one minute (FEV1) was less than 80% predicted value in four trials and equal to or greater than 80% in five trials. The long-acting beta2-agonists (LABA) formoterol (N=2) or salmeterol (N=7) were added to a dose of at least 800 microg/day of beclomethasone dipropionate (BDP) equivalent of inhaled corticosteroids (ICS) in three trials and to at least 400 microg/day in the six remaining trials. Treatment with ICS plus LABA was not associated with a lower risk of exacerbations requiring oral corticosteroids than ICS alone (relative risk (RR) 1.2; 95% confidence interval (CI) 0.8 to 1.9). FEV1 improved significantly with LABA (weighted mean difference (WMD) 210 ml; 95% CI 120 to 300), as did symptom-free days (WMD 10.74%; 95% CI 1.86 to 19.62), but the change in use of rescue fast-acting beta2-agonists was not significantly different between the groups (WMD -0.4 puff/day, 95% CI -0.9 to 0.1). There was no significant group difference in adverse events (RR 1.1; 95% CI 0.8 to 1.5), withdrawals (RR 0.9; 95% CI 0.6 to 1.2), or withdrawals due to poor asthma control (RR 1.3; 95% CI 0.5 to 3.4). AUTHORS' CONCLUSIONS: In steroid-naive patients with mild to moderate airway obstruction, the initiation of inhaled corticosteroids in combination with long-acting beta2-agonists does not significantly reduce the rate of exacerbations over that achieved with inhaled corticosteroids alone; it does improve lung function and symptom-free days but does not reduce rescue beta2-agonist use as compared to inhaled steroids alone. Both options appear safe. There is insufficient evidence at present to recommend use of combination therapy rather than ICS alone as a first-line treatment.

Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators.

BACKGROUND: Since the advent of inhaled beta2-agonists, anticholinergic agents and glucocorticoids, the role of aminophylline in paediatric acute asthma has become less clear. There remains some consensus that it is beneficial in children with acute severe asthma, receiving maximised therapy (oxygen, inhaled bronchodilators, and glucocorticoids). OBJECTIVES: To determine if the addition of intravenous aminophylline produces a beneficial effect in children with acute severe asthma receiving conventional therapy. SEARCH STRATEGY: The Cochrane Airways Group register of trials was used to identify relevant studies. The latest search was carried out in December 2004 SELECTION CRITERIA: Randomised-controlled trials comparing intravenous aminophylline with placebo in addition to usual care in children met the inclusion criteria. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies and extracted data. Disagreement in the selection of trials was resolved by consensus. Attempts were made to contact authors to verify accuracy of data. MAIN RESULTS: Seven trials met the inclusion criteria (380 participants). Methodological quality was high. All studies recruited children with acute severe asthma and requiring hospital admission. Six studies sought participants who were unresponsive to nebulised short-acting beta-agonist and administered systemic steroids to study participants. In two studies where some children were able to perform spirometry, baseline FEV1 was between 35 and 45% predicted. The addition of aminophylline to steroids and beta2-agonist significantly improved FEV1% predicted over placebo at 6-8 hours, 12-18 hours and 24 hours. Aminophylline led to a greater improvement in PEF% predicted over placebo at 12-18 hours. There was no significant difference in length of hospital stay, symptoms, frequency of nebulsations and mechanical ventilation rates. There were insufficient data to permit aggregation for oxygenation and duration of supplemental oxygen therapy. Aminophylline led to a three-fold increase in the risk of vomiting. There was no significant difference between treatment groups with regard to hypokalaemia, headaches, tremour, seizures, arrhythmias and deaths. AUTHORS' CONCLUSIONS: In children with a severe asthma exacerbation, the addition of intravenous aminophylline to beta2-agonists and glucocorticoids (with or without anticholinergics) improves lung function within 6 hours of treatment. However there is no apparent reduction in symptoms, number of nebulised treatment and length of hospital stay. There is insufficient evidence to assess the impact on oxygenation, PICU admission and mechanical ventilation. Aminophylline is associated with a significant increased risk of vomiting.

Long-acting beta2-agonists versus anti-leukotrienes as add-on therapy to inhaled corticosteroids for chronic asthma.

BACKGROUND: Patients who continue to experience asthma symptoms despite taking regular inhaled corticosteroids (ICS) represent a management challenge. Leukotriene receptor antagonists (LTRA) and long-acting beta2-agonists (LABA) agents may both be considered as add-on therapy to inhaled corticosteroids (ICS). OBJECTIVES: We compare the efficacy and safety profile of adding either daily LABA or LTRA in asthmatic patients with asthma who remained symptomatic on ICS. SEARCH STRATEGY: MEDLINE, EMBASE, CINAHL databases were searched for randomised controlled trials up to and including January 2004. Reference lists of all included studies and reviews were screened to identify potentially relevant citations. Inquiries regarding other published or unpublished studies supported by the authors of the included studies or pharmaceutical companies who manufacture these agents were made. Conference proceedings of major respiratory meetings were also searched. SELECTION CRITERIA: Only randomised controlled trials conducted in adults or children with recurrent asthma where a LABA (for example, salmeterol or formoterol) or LTRA (for example, montelukast, pranlukast, zafirlukast) was added to ICS for a minimum of 28 days were considered for inclusion. Inhaled short-acting beta2-agonists and short courses of oral steroids were permitted as rescue medications. Other daily asthma treatments were permitted, providing the dose remained constant during the intervention period. Two reviewers independently reviewed the literature searches. DATA COLLECTION AND ANALYSIS: Data extraction and trial quality assessment were conducted independently by two reviewers. Whenever possible, primary study authors were requested to confirm methodology and data extraction and to provide additional information and clarification when needed. Where necessary, expansion of graphic reproductions and estimation from other data presented in the paper was performed. MAIN RESULTS: Twelve randomised controlled trials met the inclusion criteria; only eight trials including 5,895 patients, provided data in sufficient details to allow aggregation. All eight trials pertained to adults with moderate airway obstruction (% predicted FEV1 66-76%) at baseline. Montelukast (n=6) or Zafirlukast (n=2) was compared to Salmeterol (n=7) or Formoterol (n=1) as add-on therapy to 400-565 mcg of beclomethasone or equivalent. Risk of exacerbations requiring systemic corticosteroids was significantly lower with LABA+ICS when compared to LTRA+ICS (RR= 0.83, 95% Confidence Interval (95%CI): 0.71, 0.97): the number needed to treat with LABA compared to LTRA, to prevent one exacerbation over 48 weeks, was 38 (95% CI: 23 to 247). The following outcomes also improved significantly with the addition of LABA compared to LTRA to inhaled steroids (Weighted Mean Difference; 95%CI): morning PEFR (16 L/min; 13 to 18), evening PEFR (12 L/min; 9 to 15), FEV(1) (80 mL; 60 to 100), rescue-free days (9%; 4 to 14), symptom-free days (6%; 2 to 11), rescue beta2-agonists (-0.4 puffs/day; -0.2 to -0.5), quality of life (0.1; 0.05 to 0.2), symptom score (Standard Mean Difference -0.2; -0.1 to -0.3), night awakenings (-0.1/week; -0.06 to -0.2) and patient satisfaction (RR 1.12; 1.07 to 1.16). Risk of withdrawals due to any reason was significantly lower with LABA+ICS compared to LTRA+ICS (Relative Risk 0.84, 95% CI 0.74 to 0.96). Withdrawals due to adverse events or due to poor asthma control, hospitalisation, osteopenia, serious adverse events, overall adverse events, headache or cardiovascular events were not significantly different between the two study groups. AUTHORS' CONCLUSIONS: In asthmatic adults inadequately controlled on low doses of inhaled steroids, the addition of LABA is superior to LTRA for preventing exacerbations requiring systemic steroids, and for improving lung function, symptoms, and use of rescue beta2-agonists.

Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children.

BACKGROUND: Ketotifen is an antihistamine which may be used to treat asthma. Since administering inhaled therapy to younger children can be difficult, an oral agent such as ketotifen offers potential advantages. OBJECTIVES: The objective of this review is to determine, whether ketotifen alone or in combination with other co-interventions results in better control of asthma in children with asthma and/or wheezing and examine its safety profile. SEARCH STRATEGY: We searched the Cochrane Airways Group register of trials (based on MEDLINE, EMBASE, CINAHL and handsearched respiratory journals) and reference lists of articles. The latest search was carried out in October 2002. SELECTION CRITERIA: Clinical studies had to be randomised-controlled and double-blinded, comparing oral ketotifen with placebo in children with asthma and/or wheeze for at least eight weeks at a dose not less than one mg daily. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed selection of trials, quality assessment and data extraction; a third reviewer was included in the consensus process if necessary. MAIN RESULTS: A total of 26 relevant studies involving 1826 participants were included in this review. Children's age ranged from 4 months to 18 years and ketotifen was given between 10 and 32 weeks. The proportion of children able to reduce or stop their bronchodilator use within 12 to 16 weeks of treatment was significantly higher in the ketotifen group (relative risk 2.39, 95% CI 1.64 to 3.48) based on four trials; this result was statistically significant in a subgroup of two trials with well described and adequate method of blinding. Statistically significant beneficial effects of ketotifen were also observed in the following secondary outcomes: efficacy evaluated by physician (10 trials) and parents/patients (7 trials), asthma symptom score (4 trials), asthma exacerbations (2 trials), and reduction in use of oral steroids (4 trials). However, sub-group analyses of trials with well described and adequate method of blinding was only significant for the outcome asthma symptom score and non-significant for the remaining secondary outcomes. Reported side effects were more frequent in the ketotifen group (sedation: 21%, weight gain: 27%) than in the placebo group (sedation: 12%, weight gain: 17%). REVIEWER'S CONCLUSIONS: Evidence from randomised controlled trials indicates that ketotifen alone or in combination with other co-interventions improves control of asthma and wheezing in children with mild and moderate asthma. However due to the high proportion of children with atopy in some trials the results cannot necessarily be generalised to all asthmatic children. The benefit is obtained at the cost of minor side effects, namely sedation and weight gain. The validity of this conclusion is limited by the low reported, methodological quality of included trials.

Inhaled sodium cromoglycate for asthma in children.

BACKGROUND: Sodium cromoglycate has been recommended as maintenance treatment for childhood asthma for many years. Its use has decreased since 1990, when inhaled corticosteroids became popular, but it is still used in many countries. OBJECTIVES: To determine the efficacy of sodium cromoglycate compared to placebo in the prophylactic treatment of children with asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group Asthma trials register (November 2002), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2002), MEDLINE (January 1966 to November 2002), EMBASE (January 1985 to November 2002) and reference lists of articles. We also contacted the pharmaceutical company manufacturing sodium cromoglycate SELECTION CRITERIA: All double-blind placebo-controlled randomised trials, which addressed the effectiveness of inhaled sodium cromoglycate as maintenance therapy, studying children aged 0 up to 18 years with asthma. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. Study results were pooled. MAIN RESULTS: Of 3500 titles retrieved from the literature, 25 papers reporting on 24 studies could be included in the review. The studies were published between 1970 and 1997 and together included 1074 participants. Most were cross-over studies. Few studies provided sufficient information to judge the concealment of allocation. Four studies provided results for the proportion of symptom-free days. Pooling the results did not reveal a statistically significant difference between sodium cromoglycate and placebo. For most of the other outcomes, the results were similar: small effect size and a confidence interval including the point of no difference. The funnel plot showed an under representation of small studies with negative results, suggesting publication bias. REVIEWER'S CONCLUSIONS: The evidence of the efficacy of sodium cromoglycate over placebo is not proven. Publication bias is likely to have overestimated the beneficial effects of sodium cromoglycate as maintenance therapy in childhood asthma.

Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children.

BACKGROUND: Anti-leukotrienes agents are currently being studied as alternative first line agents to inhaled corticosteroids in mild to moderate chronic asthma. OBJECTIVES: To compare the safety and efficacy of anti-leukotriene agents with inhaled glucocorticoids (ICS) and to determine the dose-equivalence of anti-leukotrienes to daily dose of ICS. SEARCH STRATEGY: Medline (1966 to Jan 2002), Embase (1980 to Jan 2002), and Cinahl (1982 to Jan 2002) were searched and reference lists of review articles and trials. We contacted colleagues and international headquarters of anti-leukotrienes producers. SELECTION CRITERIA: Randomised controlled trials that compared leukotriene antagonists with inhaled corticosteroids during a minimal 30-day intervention period in asthmatic patients aged 2 years and older. DATA COLLECTION AND ANALYSIS: Two reviewers performed assessments of methodological quality and data extraction independently and blindly. The primary outcome was the rate of exacerbations requiring systemic corticosteroids. Secondary outcomes included lung function, indices of chronic asthma control, adverse effects and withdrawal rates. MAIN RESULTS: 14 trials met the inclusion criteria; 10 were of high methodological quality; 8 are published in full-text. All were in mild-to-moderate chronic asthma, Two included children or adolescents. Trial duration was 4 - 37 weeks. In most trials, daily dose of ICS was 400 mcg of beclomethasone-equivalent. Patients treated with anti-leukotrienes were 60% more likely to suffer an exacerbation requiring systemic steroids [12 trials; Relative Risk 1.61; 95% Confidence Interval (CI) 1.15, 2.25]. Significant differences favouring ICS were noted in most secondary outcomes, eg improvement in FEV1 [7 trials; Weighted Mean Difference 120 ml; 95% CI: 80, 170 ml ]; symptom scores [5 trials: Standardized Mean Difference 0.3; 95% CI 0.2, 0.4]. Other significant benefits of ICS were seen for nocturnal awakenings, rescue medication use, and quality of life. Risk of side effects was not different between groups, but anti-leukotriene therapy was associated with 30% increased risk of "withdrawals for any cause" or "withdrawals due to poor asthma control". REVIEWER'S CONCLUSIONS: For most asthma outcomes, ICS at 400 mcg/day of beclomethasone-equivalent are more effective than anti-leukotriene agents given in the usual licensed doses. The exact dose-equivalence of anti-leukotriene agents in mcg of ICS remains to be determined.

Cow's milk protein avoidance and development of childhood wheeze in children with a family history of atopy.

BACKGROUND: In infants with a family history of atopy, food allergen avoidance has been advocated as means of preventing the development of atopic disease when breast-feeding is not possible or supplemental feeding is needed. Most infant formulas are based on cow's milk protein. Alternative choices include soya based and hydrolysed cows milk formulas. OBJECTIVES: To estimate the effect of dietary avoidance of cow's milk protein on the development of asthma or wheeze in children. SEARCH STRATEGY: The Cochrane database was searched for eligible trials until February 2002. The full text papers of all abstracts identified as RCTs were obtained and reviewed independently by two reviewers. SELECTION CRITERIA: Randomised controlled trials involving children with a family history of atopy in at least one first degree relative were considered if feeding with cow's milk based standard formula was compared to dietary avoidance of cow's milk protein using soya or other hypoallergenic formula during the initial four months of life or longer. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently. A priori defined subgroups were the types of hypoallergenic artificial feed and dietary restrictions on mother and/or child's diet. MAIN RESULTS: Six trials used hydrolysed formula for at least 4 months in addition to dietary restrictions and in some cases dust-mite reduction measures. The risk of infants experiencing asthma or wheeze during the first year of life was reduced compared to standard cow's milk based formula (Relative Risk =0.40, 95% Confidence Intervals 0.19, 0.85). Feeding soya-based formula as opposed to standard cow's milk formula did not reduce the risk of having asthma or wheeze at any age. REVIEWER'S CONCLUSIONS: Breast-milk should remain the feed of choice for all babies. In infants with at least one first degree relative with atopy, hydrolysed formula for a minimum of 4 months combined with dietary restrictions and environment measures may reduce the risk of developing asthma or wheeze in the first year of life. There is insufficient evidence to suggest that soya-based milk formula has any benefit.