Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs) Predictors of symptoms are different from predictors of severe exacerbations from asthma in children. Management of Asthma in School age Children On Therapy (MASCOT): a randomised, double-blind, placebo-controlled, parallel study of efficacy and safety. Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma Management Program study. Effect of Vitamin D Supplementation on Moderate to Severe Bronchial Asthma Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Severe exacerbations and decline in lung function in asthma. Omalizumab in children with inadequately controlled severe allergic (IgE-mediated) asthma Does continuous use of inhaled corticosteroids improve outcomes in mild asthma? A double-blind randomised controlled trial. The safety of inactivated influenza vaccine in adults and children with asthma. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial Factors associated with asthma exacerbations during a long-term clinical trial of controller medications in children. Efficacy of omalizumab in cat-allergic patients with moderate-to-severe persistent asthma. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. DO IT Trial: vitamin D Outcomes and Interventions in Toddlers – a TARGet Kids! randomized controlled trial Omalizumab, a recombinant humanized anti-IgE antibody, reduces asthma-related emergency room visits and hospitalizations in patients with allergic asthma. Temperature-controlled laminar airflow in severe asthma for exacerbation reduction (The LASER Trial): study protocol for a randomised controlled trial Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial Use of sputum eosinophil counts to guide management in children with severe asthma
IMPORTANCE In asthma and other diseases , vitamin D insufficiency is associated with adverse outcomes . It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency . OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels . DESIGN , SETTING , AND PARTICIPANTS The VIDA ( Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma ) r and omized , double-blind , parallel , placebo-controlled trial study ing adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart , Lung , and Blood Institute 's AsthmaNet network , with enrollment starting in April 2011 and follow-up complete by January 2014 . After a run-in period that included treatment with an inhaled corticosteroid , 408 patients were r and omized . INTERVENTIONS Oral vitamin D3 ( 100,000 IU once , then 4000 IU/d for 28 weeks ; n = 201 ) or placebo ( n = 207 ) was added to inhaled ciclesonide ( 320 µg/d ) . If asthma control was achieved after 12 weeks , ciclesonide was tapered to 160 µg/d for 8 weeks , then to 80 µg/d for 8 weeks if asthma control was maintained . MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure ( a composite outcome of decline in lung function and increases in use of β-agonists , systemic corticosteroids , and health care ) . RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks ( 28 % [ 95 % CI , 21%-34 % ] with vitamin D3 vs 29 % [ 95 % CI , 23%-35 % ] with placebo ; adjusted hazard ratio , 0.9 [ 95 % CI , 0.6 - 1.3 ] ) . Of 14 prespecified secondary outcomes , 9 were analyzed , including asthma exacerbation ; of those 9 , the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control ( 111.3 µg/d [ 95 % CI , 102.2 - 120.4 µg/d ] in the vitamin D3 group vs 126.2 µg/d [ 95 % CI , 117.2 - 135.3 µg/d ] in the placebo group ; difference of 14.9 µg/d [ 95 % CI , 2.1 - 27.7 µg/d ] ) . CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency . These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01248065 Rationale Asthma exacerbations are commonly precipitated by viral upper respiratory infections ( URIs ) . Vitamin D insufficiency associates with susceptibility to URI in patients with asthma . Trials of vitamin D in adults with asthma with incidence of exacerbation and URI as primary outcome are lacking . Objective To conduct a r and omised controlled trial of vitamin D3 supplementation for the prevention of asthma exacerbation and URI ( co primary outcomes ) . Measurements and methods 250 adults with asthma in London , UK were allocated to receive six 2-monthly oral doses of 3 mg vitamin D3 ( n=125 ) or placebo ( n=125 ) over 1 year . Secondary outcomes included asthma control test and St George 's Respiratory Question naire scores , fractional exhaled nitric oxide and concentrations of inflammatory markers in induced sputum . Subgroup analyses were performed to determine whether effects of supplementation were modified by baseline vitamin D status or genotype for 34 single nucleotide polymorphisms in 11 vitamin D pathway genes . Main results 206/250 participants ( 82 % ) were vitamin D insufficient at baseline . Vitamin D3 did not influence time to first severe exacerbation ( adjusted HR 1.02 , 95 % CI 0.69 to 1.53 , p=0.91 ) or first URI ( adjusted HR 0.87 , 95 % CI 0.64 to 1.16 , p=0.34 ) . No clinical ly important effect of vitamin D3 was seen on any of the secondary outcomes listed above . The influence of vitamin D3 on co primary outcomes was not modified by baseline vitamin D status or genotype . Conclusions Bolus-dose vitamin D3 supplementation did not influence time to exacerbation or URI in a population of adults with asthma with a high prevalence of baseline vitamin D insufficiency . Trial registration number NCT00978315 ( Clinical Trials.gov ) BACKGROUND Asthma therapy is typically prescribed and titrated based on patient or parent self-report of symptoms . No longitudinal studies have assessed the relationship between symptoms and severe asthma exacerbations in children . The goal of our study was ( 1 ) to assess the association of asthma symptoms with severe asthma exacerbations and ( 2 ) to compare predictors of persistent asthma symptoms and predictors of severe asthma exacerbations . METHODS The Childhood Asthma Management Program was a multicenter clinical trial of 1,041 children r and omized to receive budesonide , nedocromil , or placebo ( as-needed β-agonist ) . We conducted a post hoc analysis of diary cards that were completed by subjects on a daily basis to categorize subjects as having persistent vs intermittent symptoms . We defined a severe asthma exacerbation as an episode requiring ≥ 3 days use of oral corticosteroids , hospitalization , or ED visit due to asthma based on self-report at study visits every 4 months . RESULTS While accounting for longitudinal measures , having persistent symptoms from asthma was significantly associated with having severe asthma exacerbations . Predictors of having persistent symptoms compared with intermittent symptoms included not being treated with inhaled corticosteroids , lower FEV(1)/FVC ratio , and a lower natural logarithm of provocative concentration of methacholine producing a 20 % decline in FEV(1 ) ( lnPC(20 ) ) . Predictors of having one or more severe asthma exacerbations included younger age , history of hospitalization or ED visit in the prior year , ≥ 3 days use of oral corticosteroids in the prior 3 months , lower FEV(1)/FVC ratio , lower lnPC(20 ) , and higher logarithm to the base 10 eosinophil count ; treatment with inhaled corticosteroids was predictive of having no severe asthma exacerbations . CONCLUSIONS Patients with persistent symptoms from asthma were more likely to experience severe asthma exacerbations . Nevertheless , demographic and laboratory predictors of having persistent symptoms are different from predictors of severe asthma exacerbations . Although symptoms and exacerbations are closely related , their predictors are different . The current focus of the National Asthma Education and Prevention Program guidelines on the two separate domains of asthma control , impairment and risk , are supported by our analysis BACKGROUND Asthma affects one in eight children in the UK . National management guidelines have been available for many years but , unlike in adults , studies in children have been few , with their method ologies often based on inappropriate adult models . Sound medical evidence in support of the national guidelines for asthma management in children is lacking . The MASCOT study has been developed to address this need . OBJECTIVES To determine whether adding salmeterol or montelukast to low-dose inhaled corticosteroids ( ICSs ) can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma . DESIGN A r and omised , double-blind , placebo-controlled trial with a 4-week run-in period on a fluticasone propionate inhaler ( 100 µg twice daily ) with inhaler technique correction . Patients who met the post run-in period eligibility criteria were r and omised in the ratio of 1 : 1 : 1 and were followed for 48 weeks . SETTING Secondary care hospitals based in Engl and and Scotl and with recruitment from primary and secondary care . PARTICIPANTS Children aged 6 - 14 years with asthma requiring frequent short-acting beta-2 agonist relief , with symptoms of asthma result ing in nocturnal wakening and /or asthma that has interfered with usual activities . INTERVENTIONS Three groups were compared : ( 1 ) inhaled fluticasone propionate 100 µg twice daily plus placebo tablet once daily ; ( 2 ) inhaled fluticasone propionate 100 µg and salmeterol 50 µg twice daily ( combination inhaler ) plus placebo tablet once daily ; and ( 3 ) inhaled fluticasone propionate 100 µg twice daily plus montelukast 5-mg tablet once daily . MAIN OUTCOME MEASURES The primary outcome was the number of exacerbations requiring treatment with oral corticosteroids over 48 weeks . Secondary outcome measures included quality of life as measured by the Paediatric Asthma Quality of Life Question naire with St and ardised Activities [ PAQLQ(S ) ] and the Paediatric Asthma Caregiver 's Quality of Life Question naire ( PACQLQ ) ; time from r and omisation to first exacerbation requiring treatment with a short course of oral corticosteroids ; school attendance ; hospital admissions ; amount of rescue beta-2 agonist therapy prescribed ; time from r and omisation to treatment withdrawal ( because of lack of efficacy or side effects ) ; lung function at 48 weeks ( as assessed by spirometry ) ; cost-effectiveness ; adverse events . RESULTS The study was closed prematurely because of poor recruitment and the target sample size of 450 was not achieved . In total , 898 children were screened to enter the trial , 166 were registered for the 4-week run-in period and 63 were r and omised ( group 1 : 19 , group 2 : 23 , group 3 : 21 ) , with 38 contributing data for the primary outcome analysis . There were no significant differences between groups for any of the outcomes . Adverse events were similar between the groups except for nervous system disorders , which were more frequently reported on fluticasone plus montelukast . CONCLUSIONS Based on the results of the MASCOT study it is not possible to conclude whether adding salmeterol or montelukast to ICSs can reduce the number of exacerbations requiring treatment with oral corticosteroids in children with uncontrolled asthma . TRIAL REGISTRATION Current Controlled Trials IS RCT N03556343 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 17 , No. 4 . See the HTA programme website for further project information BACKGROUND Asthma exacerbations , most often caused by respiratory tract infections , are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs . Vitamin D status might play a role in preventing asthma exacerbations . OBJECTIVES We sought to assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations . METHODS We measured  25-hydroxyvitamin D levels in sera collected from 1024 children with mild-to-moderate persistent asthma at the time of enrollment in a multicenter clinical trial of children r and omized to receive budesonide , nedocromil , or placebo ( as-needed beta-agonists ) : the Childhood Asthma Management Program . Using multivariable modeling , we examined the relationship between baseline vitamin D levels and the odds of any hospitalization or emergency department visit over the 4 years of the trial . RESULTS Thirty-five percent of all subjects were  vitamin D insufficient , as defined by a level of 30 ng/mL or less 25-hydroxyvitamin D. Mean vitamin D levels were lowest in African American subjects and highest in white subjects . After adjusting for age , sex , body mass index , income , and treatment group , insufficient vitamin D status was associated with a higher odds of any hospitalization or emergency department visit ( odds ratio , 1.5 ; 95 % CI , 1.1 - 1.9 ; P = .01 ) . CONCLUSION Vitamin D insufficiency is common in this population of North American children with mild-to-moderate persistent asthma and is associated with higher odds of severe exacerbation over a 4-year period Objective To define the therapeutic role of vitamin D in children with moderate to severe bronchial asthma as an adjunct to st and ard treatment . Methods Hundred asthmatic children of either sex , attending the respiratory and asthma clinic were enroled in the study . Diagnosis was made on the basis of history and clinical examination . R and omization was done using sealed opaque envelop method . In addition to the treatment as per GINA guidelines , one group received oral vitamin D3 ( Cholecalciferol ) 60,000 IU per month for 6 mo and the other group received placebo powder in the form of glucose sachet with a double blinded design . Monthly follow up of every patient was done and during every visit change in severity , level of control , Peak expiratory flow rate ( PEFR ) , steroid dosage , number of exacerbations and number of emergency visits were assessed . Results Monthly doses of 60,000 IU vitamin D significantly reduced the number of exacerbations as compared to placebo ( p = 0.011 ) . PEFR significantly increased in the treatment group ( p = 0.000 ) . Monthly doses of vitamin D significantly reduced the requirement of steroids ( p = 0.013 ) and emergency visits ( p = 0.015 ) . Control of asthma was achieved earlier in patients who received monthly vitamin D. Vitamin D significantly reduced the level of severity of asthma patients over 6 mo of treatment ( p = 0.016 ) . Conclusions Vitamin D has a definite role in the management of moderate to severe persistent bronchial asthma as an adjunct to st and ard treatment BACKGROUND Many children with asthma continue to experience symptoms despite available therapies . OBJECTIVE This study evaluated the efficacy and safety of omalizumab , a humanized anti-IgE mAb , in children with moderate-to-severe persistent allergic ( IgE-mediated ) asthma that was inadequately controlled despite treatment with medium-dose or high-dose inhaled corticosteroids ( ICSs ) with or without other controller medications . METHODS A r and omized , double-blind , placebo-controlled trial enrolled children age 6 to < 12 years with perennial allergen sensitivity and history of exacerbations and asthma symptoms despite at least medium-dose ICSs . Patients were r and omized 2:1 to receive omalizumab ( 75 - 375 mg sc , q2 or q4 wk ) or placebo over a period of 52 weeks ( 24-week fixed-steroid phase followed by a 28-week adjustable-steroid phase ) . RESULTS A total of 627 patients ( omalizumab , n = 421 ; placebo , n = 206 ) were r and omized , with efficacy analyzed in 576 ( omalizumab , n = 384 ; placebo , n = 192 ) . Over the 24-week fixed-steroid phase , omalizumab reduced the rate of clinical ly significant asthma exacerbations ( worsening symptoms requiring doubling of baseline ICS dose and /or systemic steroids ) by 31 % versus placebo ( 0.45 vs 0.64 ; rate ratio , 0.69 ; P = .007 ) . Over a period of 52 weeks , the exacerbation rate was reduced by 43 % versus placebo ( P < .001 ) . Omalizumab significantly reduced severe exacerbations . Over a period of 52 weeks , omalizumab had an acceptable safety profile , with no difference in overall incidence of adverse events compared with placebo . CONCLUSION Add-on omalizumab is effective and well tolerated as maintenance therapy in children ( 6 to < 12 years ) with moderate-to-severe persistent allergic ( IgE-mediated ) asthma whose symptoms are inadequately controlled despite medium to high doses of ICSs BACKGROUND Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation . Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations . We aim ed to establish efficacy , safety , and patient characteristics associated with the response to mepolizumab . METHODS We undertook a multicentre , double-blind , placebo-controlled trial at 81 centres in 13 countries between Nov 9 , 2009 , and Dec 5 , 2011 . Eligible patients were aged 12 - 74 years , had a history of recurrent severe asthma exacerbations , and had signs of eosinophilic inflammation . They were r and omly assigned ( in a 1:1:1:1 ratio ) to receive one of three doses of intravenous mepolizumab ( 75 mg , 250 mg , or 750 mg ) or matched placebo ( 100 mL 0·9 % NaCl ) with a central telephone-based system and computer-generated r and omly permuted block schedule stratified by whether treatment with oral corticosteroids was required . Patients received 13 infusions at 4-week intervals . The primary outcome was the rate of clinical ly significant asthma exacerbations , which were defined as vali date d episodes of acute asthma requiring treatment with oral corticosteroids , admission , or a visit to an emergency department . Patients , clinicians , and data analysts were masked to treatment assignment . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT01000506 . FINDINGS 621 patients were r and omised : 159 were assigned to placebo , 154 to 75 mg mepolizumab , 152 to 250 mg mepolizumab , and 156 to 750 mg mepolizumab . 776 exacerbations were deemed to be clinical ly significant . The rate of clinical ly significant exacerbations was 2·40 per patient per year in the placebo group , 1·24 in the 75 mg mepolizumab group ( 48 % reduction , 95 % CI 31 - 61 % ; p<0·0001 ) , 1·46 in the 250 mg mepolizumab group ( 39 % reduction , 19 - 54 % ; p=0·0005 ) , and 1·15 in the 750 mg mepolizumab group ( 52 % reduction , 36 - 64 % ; p<0·0001 ) . Three patients died during the study , but the deaths were not deemed to be related to treatment . INTERPRETATION Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma . FUNDING GlaxoSmithKline Not all asthma can be adequately controlled , despite the use of high-dose inhaled corticosteroids . Because cysteinyl-leukotrienes ( Cys-LT ) have been implicated in the pathogenesis of asthma , we hypothesized that the leukotriene receptor antagonist zafirlukast , in combination with high-doses of inhaled corticosteroids , might be efficacious in severe asthma . In a double-blind , parallel group study , 368 chronic adult asthmatic patients treated with inhaled corticosteroids ( 1,000 to 4,000 microgram/d ) , who had a predefined level of asthma symptoms during the run in period of the study , were r and omly assigned to receive additional treatment with a high dose of zafirlukast ( 80 mg twice daily ) ( n = 180 ) or placebo ( n = 188 ) for 6 wk . Compared with placebo , zafirlukast produced a significant improvement over baseline in the primary study endpoint of mean morning peak expiratory flow rate ( PEFR ) ( 18.7 L/min versus 1.5 L/min , p < 0.001 ) , as well as in evening PEFR ( p < 0.01 ) , FEV(1 ) ( p < 0.05 ) , daytime symptom score ( p < 0.001 ) , and beta(2)-agonist use ( p < 0.001 ) . Furthermore , zafirlukast significantly reduced the risk of an exacerbation of asthma ( odds ratio [ OR ] : 0.61 ; 95 % confidence interval [ CI ] : 0.38 to 0.99 ) and the risk of patients requiring a further increase in asthma controller therapy ( OR : 0.4 ; 95 % CI : 0.2 to 0.8 ) . In conclusion , in patients taking high-dose inhaled corticosteroids , zafirlukast improves pulmonary function and asthma symptoms , and reduces the risk of an asthma exacerbation , suggesting that the contribution of leukotrienes to asthma symptoms and exacerbations is not adequately controlled by high-dose inhaled corticosteroids RATIONALE To evaluate the association between asthma exacerbations and the decline in lung function , as well as the potential effects of an inhaled corticosteroid , budesonide , on exacerbation-related decline in patients with asthma . OBJECTIVES To determine whether severe asthma exacerbations are associated with a persistent decline in lung function . METHODS The START ( inhaled steroid treatment as regular therapy in early asthma ) study was a 3-year , r and omized , double-blind study of 7,165 patients ( 5 - 66 yr ) with persistent asthma for less than 2 years , to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events ( exacerbations requiring hospitalization or emergency treatment ) and decline in lung function . MEASUREMENTS AND MAIN RESULTS There were 315 patients who experienced at least one severe asthma exacerbation , of which 305 were analyzable , 190 in the placebo group and 115 in the budesonide group . In the placebo group , the change in post-bronchodilator FEV(1 ) % predicted from baseline to the end of the study , in patients who did or did not experience a severe exacerbation was -6.44 % and -2.43 % , respectively ( P < 0.001 ) . A significant difference was seen in both children and in adults , but not in adolescents . In the budesonide group , the change in the post-bronchodilator FEV(1 ) % predicted in patients who did or did not experience a severe exacerbation was -2.48 % and -1.72 % , respectively ( P = 0.57 ) . The difference in magnitude of reduction afforded by budesonide , in patients who experienced at least one severe asthma-related event compared with those who did not , was statistically significant ( P = 0.042 ) . CONCLUSIONS Severe asthma exacerbations are associated with a more rapid decline in lung function . Treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline Abstract Background : Many children with severe persistent allergic ( IgE-mediated ) asthma remain inadequately controlled despite treatment with high-dose inhaled corticosteroids ( ICS ) plus a long-acting β2-agonist ( LABA ) . Research and design methods : This pre-specified analysis of a r and omized , double-blind , placebo-controlled trial evaluated the efficacy and safety of omalizumab  in children ( 6–<12 years ) with perennial allergen sensitivity , and history of asthma exacerbations and symptoms despite treatment with ICS ( fluticasone ≥500 µg · day−1 or equivalent ) plus a LABA . Patients received omalizumab ( 75–375 mg once or twice a month by subcutaneous injection , as determined from dosing tables ) or placebo over 52 weeks ( 24-week fixed-steroid then 28-week adjustable-steroid phases ) . Results : Out of 246 r and omized patients ( omalizumab , n = 166 ; placebo , n = 80 ) , efficacy  was analysed in 235 (  omalizumab , n = 159 ; placebo , n = 76 ) . Over the 24-week fixed-steroid phase , omalizumab reduced the rate of clinical ly significant asthma exacerbations ( worsening symptoms requiring doubling of baseline ICS dose and /or systemic steroids ) by 34 % versus placebo ( 0.42 vs 0.63 , rate ratio 0.662 ; P = 0.047 ) . Over 52 weeks , the exacerbation rate was reduced by 50 % ( P < 0.001 ) . Omalizumab had an acceptable safety profile , with no statistically significant ( P < 0.05 ) differences in adverse events observed between omalizumab and placebo . Conclusion : Add-on omalizumab is well-tolerated and reduces exacerbations in children ( 6–<12 years ) with severe persistent allergic asthma , inadequately controlled despite high-dose ICS plus a LABA . It should be noted that the sample size was not based on providing statistical power in the severe subgroup , and no corrections were made for multiple comparisons ; however , outcomes consistently favoured omalizumab . Trial registration : Clinical Trials.gov identifier : NCT00079937 AIM To compare the effects of fluticasone and placebo on asthma control in patients with mild asthma . METHOD Adults with FEV1 > 80 % predicted and reliever use < or=2 times/week were r and omised to receive fluticasone 250 mcg/day or placebo double-blind for 11 months . Exacerbations were treated with four weeks ' fluticasone 500 mcg/day . Primary outcomes were electronically-recorded morning PEF and FEV1 , analysed by mixed model regression . RESULTS 44 subjects were r and omised ( 23-fluticasone , 21-placebo ) . Fluticasone led to significantly better morning FEV1 ( mean difference 5.4 % predicted , p<0.0001 ) , morning PEF , clinic spirometry , exhaled nitric oxide levels , and airway hyperresponsiveness , but there were no differences in reliever use , symptoms or quality of life . Fewer patients had mild exacerbations on fluticasone ( 22 % vs 62 % , p=0.02 ) . CONCLUSION The goals of asthma treatment include not only control of symptoms , but also prevention of future adverse outcomes such as exacerbations - which can occur even in mild asthma . This study showed that treatment with low dose inhaled corticosteroids led to significant improvements in lung function , exacerbations , and in pathophysiological predictors of future risk , even though symptoms were minimal at entry . For patients with mild asthma , discussion about treatment needs to consider not only short-term benefit , side effects and cost , but also long-term reduction of risk . This study was completed prior to m and atory registration for clinical trials BACKGROUND Influenza causes substantial morbidity in adults and children with asthma , and vaccination can prevent influenza and its complications . However , there is concern that vaccination may cause exacerbations of asthma . METHODS To investigate the safety of the inactivated trivalent split-virus influenza vaccine in adults and children with asthma , we conducted a multicenter , r and omized , double-blind , placebo-controlled , cross-over trial in 2032 patients with asthma ( age range , 3 to 64 years ) . The order of injection of vaccine and placebo was assigned r and omly , with a mean of 22 days between the injections . Each day during the two weeks after each injection , the patients recorded peak expiratory flow rates , symptoms thought to be related to the injection , use of asthma medications , unscheduled health care visits for asthma , and asthma-related absences from school or work . The primary outcome measure was an exacerbation of asthma in the two weeks after the injections . RESULTS The frequency of exacerbations of asthma was similar in the two weeks after the influenza vaccination and after placebo injection ( 28.8 percent and 27.7 percent , respectively ; absolute difference , 1.1 percent ; 95 percent confidence interval , -1.4 percent to 3.6 percent ) . The exacerbation rates were similar in subgroups defined according to age , severity of asthma , and other factors . Among symptoms thought to be associated with the injection , only body aches were more frequent after the vaccine injection than after placebo injection ( 25.1 percent vs. 20.8 percent , P<0.001 ) . CONCLUSIONS The inactivated influenza vaccine is safe to administer to adults and children with asthma , including those with severe asthma . Given the morbidity of influenza , all those with asthma should receive the vaccine annually Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections ( LRTI ) . Severe asthma is heterogeneous , encompassing eosinophilic and non-eosinophilic ( mainly neutrophilic ) phenotypes . Patients with neutropilic airway diseases may benefit from macrolides . Methods We performed a r and omised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma . Subjects received low-dose azithromycin ( n=55 ) or placebo ( n=54 ) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months . The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase . Secondary efficacy outcomes included lung function and scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) . Results The rate of primary endpoints ( PEPs ) during 6 months was not significantly different between the two treatment groups : 0.75 PEPs ( 95 % CI 0.55 to 1.01 ) per subject in the azithromycin group versus 0.81 PEPs ( 95 % CI 0.61 to 1.09 ) in the placebo group ( p=0.682 ) . In a predefined subgroup analysis according to the inflammatory phenotype , azithromycin was associated with a significantly lower PEP rate  than placebo in subjects with non-eosinophilic severe asthma ( blood eosinophilia ≤200/µl ) : 0.44 PEPs ( 95 % CI 0.25 to 0.78 ) versus 1.03 PEPs ( 95 % CI 0.72 to 1.48 ) ( p=0.013 ) . Azithromycin  significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function . Azithromycin was well tolerated , but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci . Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma . However , the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study . Clinical Trials.gov number NCT00760838 BACKGROUND Asthma exacerbations are a common cause of critical illness in children . OBJECTIVE To determine factors associated with exacerbations in children with persistent asthma . METHODS Regression modeling was used to identify historical , phenotypic , treatment , and time-dependent factors associated with the occurrence of exacerbations , defined by need for oral corticosteroids or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study . Children age 6 to 14 years with mild-to-moderate persistent asthma were r and omized to receive either fluticasone propionate 100 microg twice daily ( FP monotherapy ) , combination fluticasone 100 microg AM and salmeterol twice daily , or montelukast 5 mg once daily . RESULTS Of the 285 participants r and omized , 48 % had 231 exacerbations . Using a multivariate analysis , which included numerous demographic , pulmonary , and inflammatory parameters , only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year ( odds ratio [ OR ] , 2.10 ; P < .001 ) was associated with a subsequent exacerbation during the trial . During the trial , treatment with montelukast versus FP monotherapy ( OR , 2.00 ; P = .005 ) , season ( spring , fall , or winter vs summer ; P < or = .001 ) , and average seasonal 5 % reduction in AM peak expiratory flow ( OR , 1.21 ; P = .01 ) were each associated with exacerbations . Changes in worsening of symptoms , beta-agonist use , and low peak expiratory flow track together before an exacerbation , but have poor positive predictive value of exacerbation . CONCLUSION Children with mild-to-moderate persistent asthma with previous exacerbations are more likely to have a repeat exacerbation despite controller treatment . Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk . Available physiologic measures and biomarkers and diary card tracking are not reliable predictors of asthma exacerbations Cat allergen ( Fel d 1 ) is a pervasive and common trigger of exacerbations in sensitized patients with IgE-mediated asthma . This study was design ed to evaluate the effect on asthma-related outcome measures of adding omalizumab to current treatment in patients with moderate-to-severe persistent asthma and cat allergen sensitivity . A pooled analysis was conducted of two double-blind , placebo-controlled , 28-week pivotal U.S. registration trials . In all patients , asthma was inadequately controlled with moderate-high dose inhaled corticosteroids . Patients were r and omized to receive subcutaneous omalizumab ( minimum , 0.016 mg/kg per IgE IU/mL every 4 weeks ) or matched placebo . The effects of omalizumab on asthma-related outcomes were assessed for patients with cat allergen sensitivity ( n = 811 ) , identified by positive skin-prick test . The mean number of asthma exacerbations requiring treatment with systemic steroid bursts in cat allergen-sensitive patients was lower in those receiving omalizumab versus placebo ( 0.6 versus 1.3 , respectively ; relative risk = 0.50 , p < 0.001 ) . Compared with placebo , omalizumab treatment led to significantly lower asthma symptom scores ( least squares means ( LSMs ) treatment difference [ 95 % confidence interval { CI } ] : -0.57 [ -0.77 , -0.37 ] ; p < 0.001 ) , less rescue medication use ( LSMs treatment difference [ 95 % CI ] : -0.75 puffs of rescue beta-agonist per day [ -1.04 , -0.46 ] ; p < 0.001 ) , and improvement in forced expiratory volume in 1 second ( LSMs treatment difference [ 95 % CI ] : 100.84 mL [ 51.86 , 149.81 ] ; p < 0.001 ) . Patient and investigator global evaluations of treatment effectiveness paralleled these outcomes . Omalizumab improved asthma control by reducing exacerbations and decreasing symptoms in cat-allergic patients with moderate-to-severe persistent IgE-mediated asthma RATIONALE Asthma exacerbations are unpredictable , disruptive , and frightening , and are therefore important to prevent . OBJECTIVES We investigated whether a policy of quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate reduces asthma exacerbations requiring treatment with oral corticosteroids . METHODS A total of 403 people with asthma were given a self-management plan and r and omized to take an active or placebo corticosteroid inhaler in addition to their usual asthma treatment when their PEF fell by 15 % on 2 consecutive days or by 30 % on 1 day . The study inhalers provided a quadrupling or no change in corticosteroid dose . MEASUREMENTS AND MAIN RESULTS Eighteen of 197 ( 9 % ) and 29 of 203 ( 14 % ) participants had an exacerbation of asthma requiring treatment with oral corticosteroids  in the active and placebo groups , respectively , giving a risk ratio of 0.64 ( 95 % confidence interval , 0.37 - 1.11 , P = 0.11 ) . Of the 94 participants who started the study inhaler far fewer required treatment with oral corticosteroids in the active compared with the placebo group : 12 of 56 ( 21 % ) in the active group and 19 of 38 ( 50 % ) in the placebo group , giving a risk ratio of 0.43 ( 95 % confidence interval , 0.24 - 0.78 , P = 0.004 ) . CONCLUSIONS Although our primary outcome did not reach statistical significance , quadrupling the dose of inhaled corticosteroid when asthma control starts to deteriorate appears to reduce acute exacerbations of asthma and deserves further investigation . Clinical trial registered with www.controlled-trials.com ( IS RCT N 46018181 ) BACKGROUND Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma . To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies , stratifying patients by different baseline blood eosinophil thresholds . METHODS We did a post-hoc analysis of data , which was completed on Sept 25 , 2015 , from two r and omised , double-blind , placebo-controlled studies of at least 32 weeks duration ( NCT01000506 [ DREAM ] and NCT01691521 [ MENSA ] ) done between 2009 and 2014 . In these studies , mepolizumab ( DREAM 75 mg , 250 mg , or 750 mg intravenously ; MENSA : 75 mg intravenously or 100 mg subcutaneously ) versus placebo was given at 4-week intervals in addition to st and ard care ( high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids ) to patients aged 12 years or older with a clinical diagnosis of asthma , a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment , and evidence of eosinophilic airway inflammation . The primary endpoint in both studies was the annual rate of clinical ly significant exacerbations ( defined as worsening of asthma that required the use of systemic corticosteroids , or admission to hospital , or an emergency-room visit , or a combination of these occurrences ) . In our analysis , the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts ( ≥150 cells per μL , ≥300 cells per μL , ≥400 cells per μL , and ≥500 cells per μL ) and baseline blood eosinophil ranges ( < 150 cells per μL , ≥150 cells per μL to < 300 cells per μL , ≥300 cells per μL to < 500 cells per μL , and ≥500 cells per μL ) . We based our analysis on the intention-to-treat population s of the two original studies , and all mepolizumab doses were combined for analysis . FINDINGS Of 1192 patients , 846 received mepolizumab and 346 received placebo  . The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab ( 47 % reduction ; rate ratio [ RR ] 0·53 , 95 % CI 0·44 - 0·62 ; p<0·0001 ) . The exacerbation rate reduction  with mepolizumab versus placebo increased progressively from 52 % ; 0·48 , 0·39 - 0·58 ) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70 % ; 0·30 , 0·23 - 0·40 ] ) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL , predicted efficacy of mepolizumab was reduced . INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations . We noted clinical ly relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline . The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab . FUNDING GlaxoSmithKline Background Vitamin D levels are alarmingly low ( < 75 nmol/L ) in 65 - 70 % of North American children older than 1 year . An increased risk of viral upper respiratory tract infections ( URTI ) , asthma-related hospitalizations and use of anti-inflammatory medication have all been linked with low vitamin D. No study has determined whether wintertime vitamin D supplementation can reduce the risk of URTI and asthma exacerbations , two of the most common and costly illnesses of early childhood . The objectives of this study are : 1 ) to compare the effect of ‘ high dose ’ ( 2000 IU/day ) vs. ‘ st and ard dose ’ ( 400 IU/day ) vitamin D supplementation in achieving reductions in laboratory confirmed URTI and asthma exacerbations during the winter in preschool-aged Canadian children ; and 2 ) to assess the effect of ‘ high dose ’ vitamin D supplementation on vitamin D serum levels and specific viruses that cause URTI . Methods / Design This study is a pragmatic r and omized controlled trial . Over 4 successive winters we will recruit 750 healthy children 1–5 years of age . Participating physicians are part of a primary healthcare research network called TARGet Kids!. Children will be r and omized to the ‘ st and ard dose ’ or ‘ high dose ’ oral supplemental vitamin D for a minimum of 4 months ( 200 children per group ) . Parents will obtain a nasal swab from their child with each URTI , report the number of asthma exacerbations and complete symptom checklists . Unscheduled physician visits for URTIs and asthma exacerbations will be recorded . By May , a blood sample will be drawn to determine vitamin D serum levels . The primary analysis will be a comparison of URTI rate between study groups using a Poisson regression model . Secondary analyses will compare  vitamin D serum levels , asthma exacerbations and the frequency of specific viral agents between groups . Discussion Identifying whether vitamin D supplementation of preschoolers can reduce wintertime viral URTIs and asthma exacerbations and what dose is optimal may reduce population wide morbidity and associated health care and societal costs . This information will assist in determining practice and health policy recommendations related to vitamin D supplementation in healthy Canadian preschoolers BACKGROUND Prevention of serious asthma exacerbations is an important therapeutic goal in patients with asthma . OBJECTIVE The purpose of this study was to investigate the effect of omalizumab ( Xolair ) , a recombinant humanized monoclonal anti-IgE antibody , on the rate of serious exacerbations during long-term therapy . METHODS A pooled analysis was completed of 3 multicenter , r and omized , double-blind , placebo-controlled phase III studies with omalizumab  in adults/adolescents aged > or = 12 years ( n = 1071 ) and in children aged 6 to 12 years ( n = 334 ) who required treatment with inhaled corticosteroids for allergic asthma .  Rates of serious asthma exacerbations were computed and compared between omalizumab- and placebo-treated patients . Serious exacerbations were those leading to unscheduled outpatient visits , emergency room treatment , or hospitalization during 1 year of treatment . RESULTS In all , 767 patients were treated with omalizumab ( at least 0.016 mg/kg/IgE [ IU/mL ] , administered subcutaneously every 4 weeks ) . Another 638 patients were treated with placebo .  The rate of unscheduled , asthma-related outpatient visits was lower for the omalizumab-treated patients than for the placebo-treated patients ( rate ratio [ 95 % CI ] , 0.60 [ 0.44 , 0.81 ] ; P < .01 ) , as were asthma-related emergency room visits ( rate ratio [ 95 % CI ] , 0.47 [ 0.24 , 1.01 ] ; P = .05 ) . Importantly , hospitalizations for asthma were markedly reduced in patients receiving omalizumab ( rate ratio [ 95 % CI ] , 0.08 [ 0.00 , 0.25 ] ; P < .01 ) . CONCLUSION Omalizumab reduces the rate of serious asthma exacerbations and the need for unscheduled outpatient visits , emergency room treatment , and hospitalization in patients with moderate-to-severe allergic asthma Background Asthma affects more than 5 million patients in the United Kingdom . Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments . The burden of severe asthma on the NHS is enormous , accounting for 80 % of the total asthma cost ( £ 1 billion ) , with frequent exacerbations and expensive medications generating much of this cost . Of those patients with severe asthma , 70 % are sensitised to indoor aeroallergens , and the level of exposure to allergens determines the symptoms ; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions . The LASER trial aims to assess whether a new treatment , temperature controlled laminar airflow ( TLA ) delivered by the Airsonett ™ device , can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight . Methods This multicentre study is a placebo-controlled , blinded , r and omised controlled , parallel group trial . A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a r and om element in a 1:1 ratio to receive either an active device for one year or a placebo device . The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period , defined in accordance with the American Thoracic Society/European Respiratory Society ( ATS/ERS ) guidelines . Secondary outcomes include changes in asthma control , lung function , asthma-specific and global quality of life for participants and their carers , adherence to intervention , healthcare re source use and costs , and cost-effectiveness . Qualitative interviews will be conducted to elicit participant ’s and their partner ’s perceptions of the treatment . Discussion Effective measures of allergen avoidance have , to date , proved elusive . The LASER trial aims to address this . The study will ascertain whether home-based nocturnal TLA usage over a 12-month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo , whilst being cost-effective and acceptable to adults with poorly controlled , severe allergic asthma . The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally . Trial registration Current controlled trials IS RCT N46346208 ( Date assigned 22 January 2014 ) BACKGROUND Although inhaled glucocorticosteroids are recommended for persistent asthma , their long-term effect on recent onset , mild , persistent asthma has yet to be established . METHODS We did a r and omised , double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide  in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids . Patients aged 5 - 66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications . The daily budesonide dose was 400 microg , or 200 microg for children younger than 11 years . The primary outcome was time to first severe asthma-related event , and analysis was by intention to treat . FINDINGS 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation ; hazard ratio 0.56 ( 95 % CI 0.45 - 0.71 , p<0.0001 ) . Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo . Compared with placebo , budesonide increased postbronchodilator forced expiratory volume in 1 s ( FEV1 ) from baseline by 1.48 % ( p<0.0001 ) after 1 year and by 0.88 % ( p=0.0005 ) after 3 years ( expressed as percent of the predicted value ) . The corresponding increase in prebronchodilator FEV1 was 2.24 % after 1 year and 1.71 % after 3 years ( p<0.0001 at both timepoints ) . The effect of treatment on all outcome variables was independent of the baseline lung function ( prebronchodilator or postbronchodilator ) or baseline medication . In children younger than 11 years , 3-year growth was reduced in the budesonide group by 1.34 cm . The reduction was greatest in the first year of treatment ( 0.58 cm ) than years 2 and 3 ( 0.43 cm and 0.33 cm , respectively ) . INTERPRETATION Long-term , once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset Background Previous studies in adults with asthma incorporating the control of sputum eosinophils into management strategies have shown significant reductions in exacerbations . A study was undertaken to investigate whether this strategy would be successful in children with severe asthma . Methods 55 children ( 7–17 years ) with severe asthma were r and omised to either a conventional symptom-based management strategy or to an inflammation-based strategy ( principally sputum eosinophils ) . Children were seen 3-monthly over a 1-year period . Results The annual rate of total and major exacerbations ( courses of oral corticosteroids ) was non-significantly lower in the inflammatory management group compared with the symptom management group ( 3.6 vs 4.8 , incident rate ratio ( IRR ) 0.75 , 95 % CI 0.54 to 1.04 , p=0.082 ; and 1.9 vs 2.7 IRR 0.73 , 95 % CI 0.42 to 1.28 , p=0.274 for total and major exacerbations , respectively ) . Significantly fewer subjects in the inflammatory management group experienced an exacerbation within 28 days of a study visit . There were small non-significant differences in measures of asthma control ( symptom-free days and short-acting β agonist use ) favouring the inflammatory management group . There was no significant difference in the inhaled corticosteroid dose prescribed over the course of the study . Conclusion Incorporating the control of sputum eosinophils into the management algorithm did not significantly reduce overall exacerbations or improve asthma control . Exacerbations were reduced in the short term , suggesting that more frequent measurements would be needed for a clinical ly useful effect and that controlling inflammation may have a role to play in subgroups of children with severe asthma
Meta- analysis of a modest number of trials in people with predominantly mild to moderate asthma suggests that vitamin D is likely to reduce both the risk of severe asthma exacerbation and healthcare use .
Children and people with frequent severe asthma exacerbations were under-represented ; additional primary trials are needed to establish whether vitamin D can reduce the risk of severe asthma exacerbation in these groups
BACKGROUND Several clinical trials of vitamin D to prevent  asthma exacerbation  and improve  asthma control  have been conducted in children and adults , but a meta- analysis restricted to double-blind , r and omised , placebo-controlled trials of this intervention is lacking .
OBJECTIVES To evaluate the efficacy of administration of vitamin D and its hydroxylated metabolites in reducing the risk of severe asthma exacerbations ( defined as those requiring treatment with systemic corticosteroids ) and improving asthma symptom control .