High Doses Of Inhaled Corticosteroids Research Articles

A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma

Studies in adults and adolescents have demonstrated that tiotropium is efficacious as an add-on therapy to inhaled corticosteroids (ICSs) with or without other maintenance therapies in patients with moderate or severe symptomatic asthma. We sought to assess the efficacy and safety of once-daily tiotropium Respimat add-on therapy to high-dose ICS with 1 or more controller medications, or medium-dose ICS with 2 or more controller medications, in the first phase III trial of tiotropium in children with severe symptomatic asthma. In this 12-week, double-blind, placebo-controlled, parallel-group trial, 401 participants aged 6 to 11years were randomized to receive once-daily tiotropium 5μg (2 puffs of 2.5μg) or 2.5μg (2 puffs of 1.25μg), or placebo (2 puffs), administered through the Respimat device as add-on to background therapy. Compared with placebo, tiotropium 5μg, but not 2.5μg, add-on therapy improved the primary end point, peak FEV1 within 3hours after dosing (5μg, 139mL [95% CI, 75-203; P<.001]; 2.5μg, 35mL [95% CI, -28 to 99; P=.27]), and the key secondary end point, trough FEV1 (5μg, 87mL [95% CI, 19-154; P=.01]; 2.5μg, 18mL [95% CI, -48 to 85; P=.59]). The safety and tolerability of tiotropium were comparable with those of placebo. Once-daily tiotropium Respimat 5μg improved lung function and was well tolerated as add-on therapy to ICSwith other maintenance therapies in children with severesymptomatic asthma.

Stepping down the dose of inhaled corticosteroids for adults with asthma.

Asthma is a condition of the airways affecting more than 300 million adults and children worldwide. National and international guidelines recommend titrating up the dose of inhaled corticosteroids (ICS) to gain symptom control at the lowest possible dose because long-term use of higher doses of ICS carries a risk of systemic adverse events. For patients whose asthma symptoms are controlled on moderate or higher doses of ICS, it may be possible to reduce the dose of ICS without compromising symptom control. To evaluate the evidence for stepping down ICS treatment in adults with well-controlled asthma who are already receiving a moderate or high dose of ICS. We identified trials from the Specialised Register of the Cochrane Airways Group and conducted a search of ClinicalTrials.gov (www.ClinicalTrials.gov) and the World Health Organization (WHO) trials portal (www.who.int/ictrp/en/). We searched all databases from their inception with no restriction on language. We also searched the reference lists of included studies and relevant reviews. We performed the most recent search in July 2016. We included randomised controlled trials (RCTs) of at least 12 weeks' duration and excluded cross-over trials. We looked for studies of adults (aged ≥ 18 years) whose asthma had been well controlled for a minimum of three months on at least a moderate dose of ICS. We excluded studies that enrolled participants with any other respiratory comorbidity.We included trials comparing a reduction in the dose of ICS versus no change in the dose of ICS in people with well-controlled asthma who a) were not taking a concomitant long-acting beta agonist (LABA; comparison 1), and b) were taking a concomitant LABA (comparison 2). Two review authors independently screened the search results for included studies, extracted data on prespecified outcomes of interest and assessed the risk of bias of included studies; we resolved disagreements by discussion with a third review author. We analysed dichotomous data as odds ratios (ORs) using study participants as the unit of analysis and analysed continuous data as mean differences (MDs). We used a random-effects model. We rated all outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system and presented results in 'Summary of findings' tables. We included six studies, which randomised a total of 1654 participants (ICS dose reduction, no concomitant LABA (comparison 1): n = 892 participants, three RCTs; ICS dose reduction, concomitant LABA (comparison 2): n = 762 participants, three RCTs). All included studies were RCTs with a parallel design that compared a fixed dose of ICS versus a 50% to 60% reduction in the dose of ICS in adult participants with well-controlled asthma. The duration of the treatment period ranged from 12 to 52 weeks (mean duration 21 weeks; median duration 14 weeks). Two studies were performed in the setting of primary care, two were performed in the secondary care setting and two reported no information on setting.Meta-analysis was hampered by the small number of studies contributing to each comparison, combined with heterogeneity among outcomes reported in the included studies. We found the quality of synthesised evidence to be low or very low for most outcomes considered because of a risk of bias (principally, selective reporting), imprecision and indirectness. Although we found no statistically significant or clinically relevant differences between groups with respect to any of the primary or secondary outcomes considered in this review, the data were insufficient to rule out benefit or harm. The strength of the evidence is not sufficient to determine whether stepping down the dose of ICS is of net benefit (in terms of fewer adverse effects) or harm (in terms of reduced effectiveness of treatment) for adult patients with well-controlled asthma. A small number of relevant studies and varied outcome measures limited the number of meta-analyses that we could perform. Additional well-designed RCTs of longer duration are needed to inform clinical practice regarding use of a 'stepping down ICS' strategy for patients with well-controlled asthma.

Inhaled corticosteroids: Effects on growth and bone health

BackgroundBoth slowed growth in children and reduced bone mineral density (BMD) are systemic effects of corticosteroids, and there is concern about the degree to which these systemic effects affect growth and BMD. ObjectiveTo engage in a data-driven discussion of the effects of inhaled corticosteroids (ICSs) on growth in children and BMD. MethodsArticles were selected based on their relevance to this review. ResultsStudies of ICSs in children in which growth was a secondary outcome have revealed slowed growth associated with low doses of budesonide, fluticasone propionate, and beclomethasone dipropionate. In the study of budesonide, the effect was permanent, and in the study of fluticasone propionate, the effect was long-lasting, but it is unclear whether the effect was permanent. However, the results of studies in which growth was the primary outcome were mixed. Slowed growth was detected in a study of beclomethasone dipropionate; however, slowed growth was not detected in a study of ciclesonide or flunisolide. A decrease in BMD acquisition in children was associated with high doses but not low to medium doses of ICSs. In adults, there was a dose-related effect of ICSs on BMD. Both higher daily dose and larger cumulative dose were associated with increased bone density loss. ConclusionBecause of the systemic effects on growth and bone health, children should be monitored for growth using stadiometry every 3 to 6 months and BMD should be monitored yearly in patients being treated with high doses of ICSs.

Factors associated with inhaled corticosteroids prescription in primary care patients with COPD: A cross-sectional study in the Balearic Islands (Spain)

Background: There is a worldwide over-prescription of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), off-label prescribing, and unnecessary prescription of high doses.Objectives: Our aim was to assess the prescription rate of ICS and to identify sociodemographic and clinical factors associated with ICS prescription among patients with COPD, treated in Balearic primary healthcare.Methods: This cross-sectional study included all patients with a clinical COPD diagnosis, who attended a primary care centre of the Balearic Islands (Spain) during 2012. Also, a sub-population with spirometry-confirmed COPD was defined. Data were obtained on patient demographics, smoking status, spirometry, ICS prescriptions, other respiratory medication, exacerbations and comorbidities. Associations with ICS and high-dose ICS prescription were assessed using multivariate regression analyses.Results: In total, 15,440 patients were included (70% men, mean age 68.6 years), and 44.6% were prescribed ICS. The largest association with ICS prescription was asthma comorbidity (OR: 3.50; 95%CI: 3.12–3.92), followed by exacerbation history (OR: 2.23; 95%CI: 2.07–2.47). In addition, smoking status, spirometry, atopic dermatitis, allergic rhinitis and mean age were significantly (P < 0.001) associated with ICS treatment. In the spirometry-confirmed population, asthma (OR: 2.89; 95%CI: 2.29–3.64) and exacerbations were also the major factors (OR: 2.85; 95%CI: 2.45–3.32) followed by severe bronchial-obstruction (OR: 2.63; 95%CI: 2.24–3.08). High-dose ICS prescription was mainly associated with severe obstruction (OR: 2.27; 95%CI: 1.93–2.68).Conclusion: The percentage of COPD patients prescribed ICS in Balearic primary care is relatively low. Asthma comorbidity, exacerbation history, severe bronchial-obstruction, smoking status and a spirometry-confirmed COPD diagnosis were significantly associated with ICS prescription.Key MessagesThe proportion of COPD patients with ICS prescriptions in Balearic primary care is lower than proportions observed in other studies.Asthma comorbidity, exacerbations, severe bronchial-obstruction, smoking status and spirometry-registered data were associated with ICS prescription.High-dose ICS prescription was associated with severe obstruction, exacerbations and co-morbid asthma.

Inhaled corticosteroid normalizes some but not all airway vascular remodeling in COPD.

BackgroundThis study assessed the effects of inhaled corticosteroid (ICS) on airway vascular remodeling in chronic obstructive pulmonary disease (COPD).MethodsThirty-four subjects with mild-to-moderate COPD were randomly allocated 2:1 to ICS or placebo treatment in a double-blinded clinical trial over 6 months. Available tissue was compared before and after treatment for vessel density, and expression of VEGF, TGF-β1, and TGF-β1-related phosphorylated transcription factors p-SMAD 2/3. This clinical trial has been registered and allocated with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 17/10/2012 with reference number ACTRN12612001111864.ResultsThere were no significant baseline differences between treatment groups. With ICS, vessels and angiogenic factors did not change in hypervascular reticular basement membrane, but in the hypovascular lamina propria (LP), vessels increased and this had a proportionate effect on lung air trapping. There was modest evidence for a reduction in LP vessels staining for VEGF with ICS treatment, but a marked and significant reduction in p-SMAD 2/3 expression.ConclusionSix-month high-dose ICS treatment had little effect on hypervascularity or angiogenic growth factors in the reticular basement membrane in COPD, but normalized hypovascularity in the LP, and this was physiologically relevant, though accompanied by a paradoxical reduction in growth factor expression.

Comorbidities and elevated IL-6 associate with negative outcome in adult-onset asthma.

The effect of systemic inflammation and comorbidities on treatment and outcome of adult-onset asthma remains unknown and is the objective of this study.As part of the Seinäjoki Adult Asthma Study (SAAS) with a 12-year follow-up, serum interleukin (IL)-6, high-sensitivity C-reactive protein (hsCRP) and lung function were measured and clinical information on comorbidities and medication collected from 170 patients with adult-onset asthma without chronic obstructive pulmonary disease.At follow-up visit, 54% of the patients had systemic inflammation as indicated by elevated IL-6 or hsCRP, 58% had at least one comorbidity and 30% at least two comorbidities (other than asthma related). Patients with systemic inflammation were treated with higher dose of inhaled corticosteroid (ICS) and they had lower lung function and higher blood neutrophils compared with patients without. Patients having ≥2 comorbidities had lower Asthma Control Test score and this association remained significant in adjusted analysis. Patients with both systemic inflammation and comorbidities showed poorest outcome of asthma. In multivariate regression analysis, high ICS dose was predicted by elevated IL-6, elevated blood neutrophils and eosinophils and poorer lung function at baseline and follow-up.Altogether, in patients with adult-onset asthma, elevated IL-6 was associated with use of high-dose ICS while multi-morbidity was linked to worse symptoms of asthma.

AB039. Pragmatic trial stepping down Flutiform® in patients maintained on high dose ICS

Background Global Initiative for Asthma (GINA) guidelines recommend a gradual step-down of asthma therapy if asthma has been well-controlled for at least 3 months. In real life, however, many well-controlled patients are prescribed high doses of inhaled corticosteroids (ICS), and are therefore unnecessarily at risk of systemic side effects associated with long-term ICS use. To encourage and facilitate step-down in a clinical setting, further pragmatic studies are required to demonstrate that good control of asthma can be maintained with a lower dose of ICS in stable and controlled patients, and to explore potential predictors for response to step-down.To test if good control of asthma can be maintained in adult patients previously stable on Flutiform® 250 (250 mcg fluticasone/10 mcg formoterol) for 12 weeks, after step-down to Flutiform® 125 (250 mcg fluticasone/5 mcg formoterol).

Inhaled corticosteroids can reduce osteoporosis in female patients with COPD.

BackgroundWhether the use of inhaled corticosteroids (ICSs) in patients with COPD can protect from osteoporosis remains undetermined. The aim of this study is to assess the incidence of osteoporosis in patients with COPD with ICS use and without.Patients and methodsThis is a retrospective cohort and population-based study in which we extracted newly diagnosed female patients with COPD between 1997 and 2009 from Taiwan’s National Health Insurance (TNHI) database between 1996 and 2011 (International Classification of Diseases, Ninth Revision – Clinical Modification [ICD-9-CM] 491, 492, 496). The patients with COPD were defined by the presence of two or more diagnostic codes for COPD within 12 months on either inpatient or outpatient service claims submitted to TNHI. Patients were excluded if they were younger than 40 years or if osteoporosis had been diagnosed prior to the diagnosis of COPD and cases of asthma (ICD-9 CM code 493.X) before the index date. These enrolled patients were followed up till 2011, and the incidence of osteoporosis was determined. The Cox proportional hazards regression model was also used to estimate hazard ratios (HRs) for incidences of lung cancer.ResultsTotally, 10,723 patients with COPD, including ICS users (n=812) and nonusers (n=9,911), were enrolled. The incidence rate of osteoporosis per 100,000 person years is 4,395 in nonusers and 2,709 in ICS users (HR: 0.73, 95% confidence interval [CI]: 0.63–084). The higher ICS dose is associated with lower risk of osteoporosis (0 mg to ≤20 mg, HR: 0.84, 95% CI: 0.69–1.04; >20 mg to ≤60 mg, HR: 0.78, 95% CI: 0.59–1.04; and >60 mg, HR: 0.72, 95% CI: 0.55–0.96; P for trend =0.0023) after adjusting for age, income, and medications. The cumulative osteoporosis probability significantly decreased among the ICS users when compared with the nonusers (P<0.001).ConclusionFemale patients with COPD using ICS have a dose–response protective effect for osteoporosis.

Genetic associations of the response to inhaled corticosteroids in children during an asthma exacerbation.

Genetic associations of the response to inhaled corticosteroids (ICSs) during an asthma exacerbation are unknown. To evaluate the role of genetic variants in the therapeutic response to high-dose ICS in children with moderate-to-severe asthma exacerbations. Eighty-two children (56 boys/26 girls, mean age 9.6 ± 3.2 years) with moderate-severe asthma exacerbation were genotyped for eight single-nucleotide polymorphisms that were a priori associated with ICS response in chronic asthma treatment: glucocorticosteroid receptor (NR3C1) rs41423247; corticotrophin-releasing hormone receptor1 (CRHR1) rs242939, rs242941, and rs1876828; T-box 21 (TBX21) rs2240017; glucocorticoid-induced transcript 1 (GLCCl1); and T gene rs3099266 and rs2305089. Children were treated with a single high-dose (4000 μg) fluticasone propionate given by a nebulizer followed by 1000 μg/day of inhaled fluticasone propionate for 6 days. Primary outcome measure was the improvement in FEV1 at 4 h. Mean FEV1 was 71.7 ± 14.2% at presentation. Overall, fluticasone treatment resulted in a significant improvement in asthma score and FEV1 (p < 0.0001 for both). Children with the GG genotype at NR3C1 rs41423247 (n = 26) had a higher improvement in FEV1 [24.2% (interquartile range 11.5-36.3)] compared to those with CG+CC (n = 19), [7.9% (interquartile range 6.1-24.6) (p = 0.006)]. Homozygosity for the G allele at rs41423247 of the glucocorticosteroid receptor (NR3C1) gene is associated with a higher improvement in FEV1 at 4 h in children with moderate-to-severe asthma exacerbation treated with high-dose ICS. This observation may have important clinical implications especially for children who use systemic steroids frequently for recurrent asthma exacerbations.

Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma.

Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

Fixed-Dose Combination Inhalers.

In asthma and chronic obstructive pulmonary disease (COPD), an important step in simplifying management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Fixed-dose combination (FDC) therapy might enhance compliance by decreasing the number of medications and/or the number of daily doses. Furthermore, they have the potential for enhancing, sensitizing, and prolonging the effects of monocomponents. Combination therapy with an inhaled corticosteroid (ICS) and a long-acting β-agonist (LABA) is considered an important approach for treating patients with asthma and patients with severe COPD who have frequent exacerbations. Several ICS/LABA FDCs are now commercially available or will become available within the next few years for the treatment of COPD and/or asthma. Several studies demonstrate that there are a number of added benefits in using combinations of β2-agonists and antimuscarinic agents. In particular, LABA/long-acting antimuscarinic agent (LAMA) combination seems to play an important role in optimizing bronchodilation. Several once-daily and twice-daily LABA/LAMA FDCs have been developed or are in clinical development. LAMA/ICS FDCs seem to be useful in COPD and mainly in asthma, in patients with severe asthma and persistent airflow limitation. The rationale behind the ICS/LABA/LAMA FDCs seems logical because all three agents work via different mechanisms on different targets, potentially allowing for lower doses of the individual agents to be used, accompanied by improved side effect profiles. In effect, in clinical practice, concomitant use of all three compounds is common, especially in more severe COPD but also in the treatment of adults with poorly controlled asthma despite maintenance treatment with high-dose ICS and a LABA.

Management of Preschool Children with Recurrent Wheezing: Lessons from the NHLBI's Asthma Research Networks

Recurrent wheezing in the preschool children is a common clinical problem, often associated with significant morbidity related to acute episodes. The management of these children has been complicated by a paucity of high-quality clinical trials in this age group. To fill this knowledge gap, National Heart, Lung,and Blood Institute's asthma research networks have performed a series of clinical trials in an effort to provide practitioners with guidance on appropriate management strategies. These studies establish daily inhaled corticosteroid (ICS) therapy in toddlers at high risk for subsequent asthma as an effective approach for the prevention of exacerbations and symptom reduction, but without evidence of disease-modifying properties. Additional studies have confirmed substantial heterogeneity in ICS response, in terms of both efficacy and effect on linear growth.Treatment with intermittent high-dose ICS was demonstrated to be an alternative approach to daily low-dose ICS for preventingsevere exacerbations in toddlers with intermittent butsignificant wheeze and a positive modified asthma predictive index. This review details the findings and clinical implications derived fromthese studies, discuss the utility of biomarkers andthe roleof oral corticosteroids during acute exacerbations, and summarizes ongoing clinical trials in this age group.

Reduced Antiviral Interferon Production in Poorly Controlled Asthma Is Associated With Neutrophilic Inflammation and High-Dose Inhaled Corticosteroids.

Asthma is a heterogeneous chronic inflammatory disease in which host defense against respiratory viruses such as human rhinovirus (HRV) may be abnormal. This is a matter of some controversy, with some investigators reporting reduced type I interferon (IFN) synthesis and others suggesting that type I IFN synthesis is relatively normal in asthma. The objective of this study was to examine the responsiveness of circulating mononuclear cells to HRV in a large cohort of participants with poorly controlled asthma and determine whether IFN-α and IFN-β synthesis varies across different inflammatory phenotypes. Eligible adults with asthma (n = 86) underwent clinical assessment, sputum induction, and blood sampling. Asthma inflammatory subtypes were defined by sputum cell count, and supernatant assessed for IL-1β. Peripheral blood mononuclear cells (PBMCs) were exposed to HRV serotype 1b, and IFN-α and IFN-β release was measured by enzyme-linked immunosorbent assay. Participants (mean age, 59 years; atopy, 76%) had suboptimal asthma control (mean asthma control questionnaire 6, 1.7). In those with neutrophilic asthma (n = 12), HRV1b-stimulated PBMCs produced significantly less IFN-α than PBMCs from participants with eosinophilic (n = 35) and paucigranulocytic asthma (n = 35). Sputum neutrophil proportion and the dose of inhaled corticosteroids were independent predictors of reduced IFN-α production after HRV1b exposure. Antiviral type I IFN production is impaired in those with neutrophilic airway inflammation and in those prescribed high doses of inhaled corticosteroids. Our study is an important step toward identifying those with poorly controlled asthma who might respond best to inhaled IFN therapy during exacerbations.

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

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

The efficacy of single-high dose inhaled corticosteroid versus oral prednisone treatment on exhaled leukotriene and 8-isoprostane levels in mild to moderate asthmatic children with asthma exacerbation

BackgroundThe anti-inflammatory effect of high-dose inhaled corticosteroids (ICS) in children with asthma exacerbation is unknown. We aimed to investigate the efficacy of single-high dose ICS versus oral prednisone treatment followed by a course of six day high-dose ICS or oral prednisone (P) treatment on the concentrations of Cys-LTs and 8-isoprostane levels in the exhaled breath condensate (EBC) of children with asthma exacerbation. MethodsNinety-four children with moderate–severe asthma exacerbation were evaluated with asthma scores, peak expiratory flow rate (PEF), forced expiratory volume in first second (FEV1) and exhaled Cys-LT and 8-isoprostane levels before and after treatment. EBC was collected from 52 patients before and four hours after treatment with inhaled fluticasone propionate (FP) (4000μg) or P and after six days of treatment with FP-1000μg/day or P. Cys-LTs and 8-isoprostane concentrations were determined using a specific immunoassay kit. ResultsBoth single high-dose FP (n=59) and p (n=35) treatment resulted in a significant improvement in asthma score (p<0.0001), PEF (p<0.0001), and FEV1 (p<0.0001). Cys-LT concentration in the EBC decreased significantly both after the initial treatment (p=0.001), and at the end of the six-day period in the FP group (p<0.0001). 8-Isoprostane concentration was lower only after six days of treatment with FP-1000μg/day in the FP group (p=0.023). There was a significant decrease in exhaled Cys-LTs after four hours (p=0.012) and six days of P treatment (p=0.018) in children with asthma exacerbation. ConclusionsHigh-dose ICS treatment may be useful in the treatment of children with asthma exacerbation. The effects start as early as after four hours. The suppression of Cys-LTs production contributes to the early effects. Suppression of both Cys-LTs and oxidants may favourably contribute to the effects observed later.

Evidence of hypothalamic-pituitary-adrenal axis suppression during moderate-to-high-dose inhaled corticosteroid use.

The possible risk of adverse effects due to regular use of inhaled corticosteroids (ICS) is a real concern. Our aim was to describe the factors that have an impact on hypothalamic-pituitary-adrenal axis suppression (HPA-AS) in children and adolescents taking ICS regularly. The HPA axis status of patients who were on moderate-to-high-dose ICS [>176 and >264 μg/day fluticasone propionate-hydrofluoroalkane (FP-HFA) for patients 0-11 and ≥12 years, respectively] was investigated. Various types of ICS were converted to FP-HFA equivalent according to National Asthma Education and Prevention Program (NAEPP) guidelines. Participants with a baseline (8 a.m.) serum cortisol <15 μg/dL underwent a low-dose ACTH stimulation test (LDAT) to diagnose HPA-AS. Among 91 patients, 60 (75.9 %) participants underwent LDAT, and seven (7.7, 95 % CI 3.5-15.3 %) were diagnosed with HPA-AS. Ciclesonide was more frequently used by the participants with HPA-AS compared to patients with a normal HPA axis (42.9 vs. 4.8 %, p = 0.009). Use of ICS at moderate-to-high doses for at least 7 months distinguished participants with HPA-AS from those with a normal HPA axis. Among the duration, type, and dose of ICS, solely the use of ICS with a body mass index (BMI)-adjusted daily dose of ≥22 μg FP was found to increase the risk for HPA-AS (odds ratio (OR) 7.22, 95 % confidence interval (CI) 1.23-42.26, p = 0.028). The receiver operating characteristics (ROC) curve analysis revealed a cutoff value of 291 μg/day FP (area under the curve (AUC) = 0.840, p = 0.003) for predicting HPA-AS Conclusion: The prevalence of HPA-AS was found to be 7.7 % in children taking not only high-dose ICS but also moderate-dose ICS. Dose alone was found to be an actual risk factor for HPA-AS.

Severe asthma in school-age children: evaluation and phenotypic advances.

Although the majority of children with asthma have a favorable clinical response to treatment with low to moderate doses of inhaled corticosteroids (ICS), a small subset of children have "severe" asthma characterized by ongoing symptoms and airway inflammation despite treatment with high doses of ICS and even oral corticosteroids. Although there is symptom heterogeneity in the affected children, children with severe asthma share the risk for adverse outcomes, including recurrent and potentially life-threatening exacerbations, which contribute to substantial economic burden. This article reviews current knowledge of severe asthma in school-age children (age 6-17 years) with a focus on recent literature published after January 2012. Clinical management approaches for children with severe asthma are discussed as well as current phenotyping efforts and emerging phenotypic-directed therapies that may be of benefit for subpopulations of children with severe asthma in the future.

Tiotropium Respimat®: A Review of Its Use in Asthma Poorly Controlled with Inhaled Corticosteroids and Long-Acting β2-Adrenergic Agonists

Tiotropium bromide (Spiriva®) solution for inhalation via the Respimat® Soft Mist™ inhaler is a long-acting anticholinergic agent approved in the EU for the add-on maintenance treatment of asthma in adults currently receiving maintenance therapy with an inhaled corticosteroid (ICS) (≥800 µg budesonide per day or equivalent) and a long-acting β2-adrenergic agonist (LABA) and who have experienced at least one severe exacerbation in the previous year. Tiotropium Respimat® added to maintenance ICS/LABA treatment significantly improved lung function after 6 months' treatment and extended the time to the first asthma exacerbation in two well-designed, replicate, phase III trials in patients with poorly controlled asthma despite treatment with an ICS (≥800 µg budesonide/day or equivalent) and a LABA. Tiotropium Respimat® was also associated with a reduced incidence of severe asthma exacerbations and an increase in the median time to asthma worsening. The drug was well tolerated in asthma patients throughout 48 weeks' treatment, with a generally similar incidence of serious adverse events in tiotropium Respimat® and placebo treatment groups. Thus, in patients with poorly controlled asthma despite receiving high-dose ICS and a LABA, tiotropium Respimat® provides a valuable treatment option.

Hot topics from the Assemblies.

INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD Authors: Rossi A, van der Molen T, Ricardo del Olmo, et al. Eur Respir J 2014; 44: 6, 1548-1556 SUMMARY: Inhaled corticosteroids (ICS) remain a highly controversial treatment for stable chronic obstructive pulmonary disease (COPD). Data linking high-dose ICS with complications, such as pneumonia and fractures, has necessitated a re-evaluation of their role in COPD management. Guidelines currently suggest ICS for patients with a forced expiratory volume in 1 s (FEV1) <50% predicted (or <60% in some regions) and a history of exacerbations. Nevertheless, it is well known that ICS and combination ICS/long-acting β-agonist (LABA) treatments are commonly used outside these groups. In view of the increasingly recognised dangers of ICS treatment, data demonstrating the safety of discontinuing ICS treatment is welcome.

Severe Asthma: Anti-IgE or Anti-IL-5?

Asthma is a common disease affecting more than 300 million people worldwide [1]. According to the recent ERS/ATS consensus severe asthma is defined as asthma that requires treatment with high dose Inhaled corticosteroids (ICS) plus one more controller (and/or oral corticosteroids) in order to be controlled or remains uncontrolled despite the above treatment or becomes uncontrolled with the reduction of high dose ICS or oral corticosteroids [2]. It is a prerequisite that the correct diagnosis of asthma has been confirmed and comorbidities have been identified and treated properly [2]. It is also extremely important to check inhaler technique and ensure good adherence to treatment. Current GINA document suggests that a referral to a specialist with expertise in the management of severe asthma is strongly encouraged for patients not controlled with treatment step 3 [1].