Inhaled Corticosteroids In Asthma Research Articles

GSDMB/ORMDL3 Rare/Common Variants Are Associated with Inhaled Corticosteroid Response among Children with Asthma.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response (DPP10, FBXL7, NDFIP1, TBXT, GLCCI1, HDAC9, TBXAS1, STAT6, GSDMB/ORMDL3, CRHR1, GNGT2, FCER2), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants (p-value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative (p-value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

The GLCCI1 rs37973 variant and the efficacy of inhaled corticosteroids in the treatment of asthma: A meta-analysis.

This study investigated the relationship between the glucocorticoid-induced transcript 1 (GLCCI1) gene variant and the degree of improvement in lung function with inhaled corticosteroids (ICS). We searched the PubMed, Embase, Cochrane Library, CBM, CNKI and Wanfang databases to obtain studies on the GLCCI1 rs37973 variant and the efficacy of ICS in asthma. The overall meta-analysis showed that patients with the GG phenotype (mutant homozygotes) exhibited significantly smaller forced expiratory volume in 1 sec (FEV1) change than patients with the AG phenotype (mutant heterozygous) (MD = -0.08, 95% CI [-0.12, -0.03], P = 0.001). Compared with the AA phenotype (wild homozygotes), the GG phenotype (MD = -4.23, 95% CI [-6.09, -2.38], P < 0.00001) and AG phenotype (MD = -1.92, 95% CI [-2.35, -1.49], P < 0.00001) had significantly smaller FEV1%pred changes. The FEV1 change subgroup analysis showed that the GG phenotype group was smaller than the AA phenotype group at 8 (MD = -0.53, 95% CI [-0.91, -0.14], P = 0.007), 12 (MD = -0.16, 95% CI [-0.30, -0.02], P = 0.02) and 24 (MD = -0.09, 95% CI [-0.17, -0.01], P = 0.02) weeks of treatment; the GG phenotype group was smaller than the AG phenotype group at 12 weeks (MD = -0.08, 95% CI [-0.15, -0.01], P = 0.02). This meta-analysis suggests that the GLCCI1 rs37973 variant affects the efficacy of ICS and that the presence of the G allele attenuates the improvement in lung function with ICS.

Pharmacogenomics of Leukotriene Modifiers: A Systematic Review and Meta-Analysis.

Pharmacogenetics research on leukotriene modifiers (LTMs) for asthma has been developing rapidly, although pharmacogenetic testing for LTMs is not yet used in clinical practice. We performed a systematic review and meta-analysis on the impact of pharmacogenomics on LTMs response. Studies published until May 2022 were searched using PubMed, EMBASE, and Cochrane databases. Pharmacogenomics/genetics studies of patients with asthma using LTMs with or without other anti-asthmatic drugs were included. Statistical tests of the meta-analysis were performed with Review Manager (Revman, version 5.4, The Cochrane Collaboration, Copenhagen, Denmark) and R language and environment for statistical computing (version 4.1.0 for Windows, R Core Team, Vienna, Austria) software. In total, 31 studies with 8084 participants were included in the systematic review and five studies were also used to perform the meta-analysis. Two included studies were genome-wide association studies (GWAS), which showed different results. Furthermore, none of the SNPs investigated in candidate gene studies were identified in GWAS. In candidate gene studies, the most widely studied SNPs were ALOX5 (tandem repeats of the Sp1-binding domain and rs2115819), LTC4S-444A/C (rs730012), and SLCO2B1 (rs12422149), with relatively inconsistent conclusions. LTC4S-444A/C polymorphism did not show a significant effect in our meta-analysis (AA vs. AC (or AC + CC): −0.06, 95%CI: −0.16 to 0.05, p = 0.31). AA homozygotes had smaller improvements in parameters pertaining to lung functions (−0.14, 95%CI: −0.23 to −0.05, p = 0.002) in a subgroup of patients with non-selective CysLT receptor antagonists and patients without inhaled corticosteroids (ICS) (−0.11, 95%CI: −0.14 to −0.08, p < 0.00001), but not in other subgroups. Variability exists in the pharmacogenomics of LTMs treatment response. Our meta-analysis and systematic review found that LTC4S-444A/C may influence the treatment response of patients taking non-selective CysLT receptor antagonists for asthma, and patients taking LTMs not in combination with ICS for asthma. Future studies are needed to validate the pharmacogenomic influence on LTMs response.

Does the use of inhaled corticosteroids in asthma benefit lung function in the long-term? A systematic review and meta-analysis.

While asthma is known to be associated with an increased risk of progressive lung function impairments and fixed airflow obstruction, there is ongoing debate on whether inhaled corticosteroids (ICS) modify these long-term risks. Searches were performed of the PubMed, Embase and CENTRAL databases up to 22 July 2019 for studies with follow-up ≥1 year that investigated the effects of maintenance ICS on changes in lung function in asthma.Inclusion criteria were met by 13 randomised controlled trials (RCTs) (n=11 678) and 11 observational studies (n=3720). Median (interquartile range) follow-up was 1.0 (1-4) and 8.4 (3-28) years, respectively. In the RCTs, predominantly in individuals with mild asthma, ICS use was associated with improved pre-bronchodilator (BD) forced expiratory volume in 1 s (FEV1) across all age groups (2.22% predicted (95% CI 1.32-3.12), n=8332), with similar estimates of strength in association for children and adults. Improvements in post-BD FEV1 were observed in adults (1.54% (0.87-2.21), n=3970), but not in children (0.20% (-0.49-0.90), n=3924) (subgroup difference, p=0.006). Estimates were similar between smokers and nonsmokers. There were no RCT data on incidence of fixed airflow obstruction. In the observational studies, ICS use was associated with improved pre-BD FEV1 in children and adults. There were limited observational data for post-BD outcomes.In patients with mild asthma, maintenance ICS are associated with modest, age-dependent improvements in long-term lung function, representing an added benefit to the broader clinical actions of ICS in asthma. There is currently insufficient evidence to determine whether treatment reduces incidence of fixed airflow obstruction in later life.

E-Monitoring of Asthma Therapy to Improve Compliance in children (e-MATIC): a randomised controlled trial.

Real-time medication monitoring (RTMM) is a promising tool for improving adherence to inhaled corticosteroids (ICS), but has not been sufficiently tested in children with asthma. We aimed to study the effects of RTMM with short message service (SMS) reminders on adherence to ICS, asthma control, asthma-specific quality of life and asthma exacerbation rate; and to study the associated cost-effectiveness.In a multicentre, randomised controlled trial, children (aged 4-11 years) using ICS were recruited from five outpatient clinics and were given an RTMM device for 12 months. The intervention group also received tailored SMS reminders, sent only when a dose was at risk of omission. Outcome measures were adherence to ICS (RTMM data), asthma control (childhood asthma control test questionnaire), quality of life (paediatric asthma quality of life questionnaire) and asthma exacerbations. Costs were calculated from a healthcare and societal perspective.We included 209 children. Mean adherence was higher in the intervention group: 69.3% versus 57.3% (difference 12.0%, 95% CI 6.7%-17.7%). No differences were found for asthma control, quality of life or asthma exacerbations. Costs were higher in the intervention group, but this difference was not statistically significant.RTMM with tailored SMS reminders improved adherence to ICS, but not asthma control, quality of life or exacerbations in children using ICS for asthma.

Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus the same dose of ICS alone for adults with asthma.

Despite the availability of several evidence-based therapies and non-pharmacological strategies to improve control of symptoms and prevent exacerbations of asthma, patients with asthma continue to be at risk for mortality and morbidity.Previous trials have demonstrated the potentially beneficial effects of the long-acting muscarinic antagonist (LAMA) tiotropium on lung function in patients with asthma; however, a definitive conclusion on the benefit of LAMA in asthma is lacking, as is information on where in the current step-wise management strategy they would be most beneficial. To assess the efficacy and safety of a LAMA added to any dose of an inhaled corticosteroid (ICS) compared with the same dose of ICS alone for adults whose asthma is not well controlled. We searched the Cochrane Airways Group Specialised Register (CAGR) from inception to April 2015, and we imposed no restriction on language of publication. We also searched clinicaltrials.gov, the World Health Organization (WHO) trials portal and drug company registries to identify unpublished studies. We searched for parallel and cross-over randomised controlled trials in which adults whose asthma was not well controlled by ICS alone were randomly assigned to receive LAMA add-on or placebo (both combined with ICS) for at least 12 weeks. Two review authors independently screened the searches and extracted data from study reports. We used Covidence for duplicate screening, extraction of study characteristics and numerical data and risk of bias ratings. Pre-specified primary outcomes included exacerbations requiring oral corticosteroids, quality of life and all-cause serious adverse events. We identified five studies that met the inclusion criteria. All studies applied a double-blind, double-dummy design, and the population of all studies totalled 2563 adult participants. Study duration ranged from 12 weeks to 52 weeks, and risk of bias across domains in all studies was low. Trials included more women than men (33% to 47% male), and mean age of participants ranged from 41 to 48 years. Participants generally had a long history of asthma, and mean baseline predicted forced expiratory volume in one second (FEV1) was between 72% and 75% in three studies reporting pre-bronchodilator values.The rate of exacerbations requiring oral corticosteroids (OCS) was lower in patients prescribed an LAMA add-on than in those receiving the same dose of ICS alone (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.46 to 0.93; 2277 participants; four studies; I(2) = 0%; high-quality evidence), meaning that 27 fewer people per 1000 would have an exacerbation over 21 weeks requiring OCS with LAMA compared with ICS alone (95% CI 42 fewer to 6 fewer).All-cause serious adverse events (SAEs) and exacerbations requiring hospital admission were rare and the effects too imprecise to permit firm conclusions, but effects suggested that LAMA add-on may be associated with fewer of both compared with ICS alone (SAEs: OR 0.60, 95% CI 0.23 to 1.57; 2532 participants; four studies; low-quality evidence; exacerbations requiring hospital admission: OR 0.42, 95% CI 0.12 to 1.47; 2562 participants; five studies; moderate-quality evidence). Additional therapy with a LAMA showed no clear benefit in terms of quality of life compared with ICS given alone; high-quality evidence showed only a small mean improvement in quality of life as measured on the Asthma Quality of Life Questionnaire (AQLQ), which was not statistically significant. The same was true for asthma control as measured on the Asthma Control Questionnaire (ACQ), which was based on moderate-quality evidence. LAMA combined with ICS showed consistent benefit in a range of lung function measures compared with the same dose of ICS alone, and LAMA was not associated with significantly higher rates of adverse events than were reported with placebo. For adults taking ICS for asthma without a long-acting beta₂-agonist (LABA), LAMA given as add-on treatment reduces the likelihood of exacerbations requiring treatment with OCS and improves lung function. The benefits of LAMA combined with ICS for hospital admissions, all-cause serious adverse events, quality of life and asthma control remain unknown.Results of this review, along with findings of related reviews conducted to assess the use of LAMA in other clinical scenarios involving asthma, can help to define the role of LAMA in the management of asthma. Trials of longer duration (up to 52 weeks) would provide a better opportunity to observe rare events such as serious adverse events and exacerbations requiring hospital admission.

Asthma and adherence to inhaled corticosteroids: current status and future perspectives.

Inhaled corticosteroids (ICS) are the cornerstone of maintenance asthma therapy. However, in spite of this, adherence to ICS remains low. The aim of this systematic literature review was to provide an overview of the current knowledge of adherence to ICS, effects of poor adherence, and means to improve adherence. A total of 19 studies met the inclusion criteria: 9 focusing on the level of adherence, 6 focusing on effects of poor adherence, and 7 focusing on interventions to improve adherence. Three of the studies focused on more than one of these end points. The mean level of adherence to ICS was found to be between 22 and 63%, with improvement up to and after an exacerbation. Poor adherence was associated with youth, being African-American, having mild asthma, < 12 y of formal education, and poor communication with the health-care provider, whereas improved adherence was associated with being prescribed fixed-combination therapy (ICS and long-acting β2 agonists). Good adherence was associated with higher FEV1, a lower percentage of eosinophils in sputum, reduction in hospitalizations, less use of oral corticosteroids, and lower mortality rate. Overall, 24% of exacerbations and 60% of asthma-related hospitalizations could be attributed to poor adherence. Most studies have reported an increase in adherence following focused interventions, followed by an improvement in quality of life, symptoms, FEV1, and oral corticosteroid use. However, 2 studies found no difference in health-care utilization, one observed no effect on symptoms, and one observed more symptoms in subjects in the intervention group compared with the control group. Good adherence to ICS in asthma improves outcome but remains low. Interventions to improve adherence show varying results, with most studies reporting an increase in adherence but unfortunately not necessarily an improvement in outcome. Even following successful interventions, adherence remains low. Further research is needed to explore barriers to adherence and interventions for improvement.

Asthma outcomes and costs of therapy with extrafine beclomethasone and fluticasone

Characteristics of inhaled corticosteroids (ICSs) differ, but data comparing the real-life effectiveness of various ICSs for asthma are lacking. We sought to compare real-life asthma outcomes and costs of extrafine hydrofluoroalkane (HFA)-beclomethasone and fluticasone administered through a pressurized metered-dose inhaler. This retrospective matched cohort study examined database markers of asthma control from a large US longitudinal health care claims database over 1 baseline and 1 outcome year for 10,312 patients with asthma aged 12 to 80 years receiving their first ICS as HFA-beclomethasone or fluticasone and matched on baseline demographic characteristics and asthma severity. Patients started on HFA-beclomethasone had significantly higher odds (adjusted odds ratio, 1.19; 95% CI; 1.08-1.31) of achieving overall control (risk and impairment), which was defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection and less than 2 puffs per day of short-acting β-agonist; they also experienced a lower rate of respiratory-related hospitalizations or referrals (adjusted rate ratio, 0.82; 95% CI, 0.73-0.93) than patients started on fluticasone. Other database outcome measures were similar in the 2 cohorts. Prescribed HFA-beclomethasone doses were lower (P< .001) than fluticasone doses (median, 320 μg/d [interquartile range, 160-320 μg/d] vs 440 μg/d [interquartile range, 176-440 μg/d]). Adjusted respiratory-related health care costs were significantly lower for HFA-beclomethasone than fluticasone (mean, $1869 [95% CI, $1727-$2032] vs $2259 [95% CI, $2111-$2404]), representing a mean annual savings of $390 (95% CI, $165-$620) per patient prescribed HFA-beclomethasone rather than fluticasone. Asthma treatment outcomes were similar or better with HFA-beclomethasone prescribed at significantly lower doses and with lower costs than fluticasone.

E-Monitoring of Asthma Therapy to Improve Compliance in children using a real-time medication monitoring system (RTMM): the e-MATIC study protocol

BackgroundMany children with asthma do not have sufficient asthma control, which leads to increased healthcare costs and productivity loss of parents. One of the causative factors are adherence problems. Effective interventions improving medication adherence may therefore improve asthma control and reduce costs. A promising solution is sending real time text-messages via the mobile phone network, when a medicine is about to be forgotten. As the effect of real time text-messages in children with asthma is unknown, the primary aim of this study is to determine the effect of a Real Time Medication Monitoring system (RTMM) with text-messages on adherence to inhaled corticosteroids (ICS). The secondary objective is to study the effects of RTMM on asthma control, quality of life and cost-effectiveness of treatment.MethodsA multicenter, randomized controlled trial involving 220 children (4–11 years) using ICS for asthma. All children receive an RTMM-device for one year, which registers time and date of ICS doses. Children in the intervention group also receive tailored text-messages, sent only when a dose is at risk of omission. Primary outcome measure is the proportion of ICS dosages taken within the individually predefined time-interval. Secondary outcome measures include asthma control (monthly Asthma Control Tests), asthma exacerbations, healthcare use (collected from hospital records, patient reports and pharmacy record data), and disease-specific quality of life (PAQLQ questionnaire). Parental and children’s acceptance of RTMM is evaluated with online focus groups and patient questionnaires. An economic evaluation is performed adopting a societal perspective, including relevant healthcare costs and parental productivity loss. Furthermore, a decision-analytic model is developed in which different levels of adherence are associated with clinical and financial outcomes. Also, sensitivity analyses are carried out on different price levels for RTMM.DiscussionIf RTMM with tailored text-message reminders proves to be effective, this technique can be used in daily practice, which would support children with suboptimal adherence in their asthma (self)management and in achieving better asthma control and better quality of life.Trial registrationNetherlands Trial Register NTR2583.

S6 The FENOtype Trial: Inhaled Corticosteroid Dose-Response Using Domiciliary Exhaled Nitric Oxide in Persistent Asthma

Background International guidelines advocate a standard approach to asthma management for all despite its heterogeneity. ‘Personalised’ treatment for inflammatory asthma phenotypes confers superior benefits. We wished to evaluate dose-response to inhaled corticosteroids (ICS) in asthmatics with an elevated exhaled nitric oxide (FeNO) phenotype using domiciliary measurements. Methods We performed a randomised, cross-over trial in 21 mild-to-moderate persistent asthmatics receiving ICS with elevated FeNO (>30ppb) that increased further (>10ppb) after ICS washout. Patients were randomised to 2 weeks of either fluticasone propionate 50µg twice-daily (FP100) or 250µg twice-daily (FP500). The primary outcome was response in diurnal domiciliary FeNO levels. Secondary outcomes included: mannitol challenge; serum eosinophilic cationic protein (ECP); blood eosinophil count; and asthma control questionnaire (ACQ). Results We found significant dose-related reductions of diurnal FeNO compared to baseline - morning FeNO: baseline=71ppb (95%CI:61–83ppb); FP100=34ppb (95%CI:29–40ppb), p 0.5) with values in keeping with controlled asthma ( Conclusions There is a significant dose-response of diurnal FeNO to ICS in asthmatics with an elevated FeNO phenotype, which translates into well-controlled asthma. Further interventional studies are warranted using domiciliary FeNO in this specific phenotype.

Nebulized Corticosteroids in Asthma and COPD. An Italian Appraisal

Inhaled corticosteroids (ICSs) are the mainstay of anti-inflammatory treatment in subjects with asthma and COPD. This review evaluates the role of nebulizers as an alternative to inhalers for delivering ICSs in asthma and COPD. I selected 16 randomized, placebo-controlled, blinded, long-term studies, mostly carried out in asthma (n = 14) and COPD. Nebulized budesonide has been demonstrated to be effective and safe in children ages 1-8 years, and, with less evidence, in infants and adults with asthma. Other investigations, with the addition of in vitro and in vivo comparison studies, have shown that nebulized beclomethasone, fluticasone, and flunisolide are effective alternatives to nebulized budesonide in asthma and COPD. Efficient delivery of nebulized ICSs requires that the nebulizer system, the nebulized drug formulation, and the inhaling subject interact properly. The practices of mixing nebulized ICSs with bronchodilators and using nebulized ICSs in acute settings are promising, but require further confirmations, and at present cannot be recommended. I conclude that nebulizers may be considered as an effective alternative to inhalers for delivering ICSs and can be recommended to asthmatic and COPD subjects who are unwilling or unable to use inhalers. Newer formulations could possibly offer a relevant advance for a more efficient nebulization of ICSs.

Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid.

To determine the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression in asthmatic children on inhaled corticosteroids (ICS). Clinical and demographic variables were recorded on preconstructed, standardized forms. HPA axis suppression was measured by morning serum cortisol levels and confirmed by low-dose adrenocorticotropic hormone stimulation testing. In total, 214 children participated. Twenty children (9.3%, 95% CI 5.3% to 13.4%) had HPA axis suppression. Odds of HPA axis suppression increased with ICS dose (OR 1.005, 95% CI 1.003 to 1.009, P<0.001). All children with HPA axis suppression were on a medium or lower dose of ICS for their age (200 μg/day to 500 μg/day). HPA axis suppression was not predicted by drug type, dose duration, concomitant use of long-acting beta-agonist or nasal steroid, or clinical features. Laboratory evidence of HPA axis suppression exists in children taking ICS for asthma. Children should be regularly screened for the presence of HPA axis suppression when treated with high-dose ICS (>500 μg/day). Consideration should be given to screening children on medium-dose ICS.

New Measure of Adherence Adjusted for Prescription Patterns: The Case of Adults with Asthma Treated with Inhaled Corticosteroid Monotherapy

Common measures of adherence to prescribed medications derived from administrative databases reflect both patients' and physicians' behavior, even if the measures are often interpreted as reflecting only the patient's adherence. Adherence to inhaled corticosteroids (ICSs) has been shown to be low among patients with asthma. To develop a new measure of patients' adherence adjusted for prescription patterns and to evaluate the extent to which the low use of ICSs in asthma is due to patients' nonadherence or suboptimal prescribing practices. The new measure of adherence, called the proportion of prescribed days covered (PPDC), is defined as the ratio of the total days' supply dispensed to the total days' supply prescribed during the study period. The PPDC is a modification of an existing adherence measure, the proportion of days covered (PDC). The PPDC and PDC for ICSs, therapy that should be prescribed for chronic daily use to patients with persistent asthma, were compared within a cohort of 4190 ICS-naïve patients with asthma aged 18-45 years derived from the administrative health databases of Quebec, Canada. We estimated the mean and the 95% confidence interval of the PPDC and PDC for ICSs over 1 year, and we calculated the part of nonadherence attributed to patients when measured with the PDC that can be attributed to nonoptimal prescribing of ICSs for chronic daily use with the following formula: [(1-PDC)-(1-PPDC)]/(1-PDC). The mean PPDC and PDC during the 1-year study were 52.6% (95% CI 51.6 to 53.6) and 19.1% (95% CI 18.6 to 19.6), respectively. Forty-one percent of nonadherence attributed to patients when measured with the PDC could be, in fact, attributed to nonprescribing of ICSs for chronic daily use. Our new adherence measure, the PPDC, may be considered as another way to assess patient adherence, taking into account differing prescribing patterns.

Cost Effectiveness of Leukotriene Receptor Antagonists versus Long-Acting Beta-2 Agonists as Add-On Therapy to Inhaled Corticosteroids for Asthma

Information is lacking on the relative effectiveness and cost effectiveness--in a real-life primary-care setting--of leukotriene receptor antagonists (LTRAs) and long-acting beta2 adrenergic receptor agonists (beta2 agonists) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids (ICS). To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS. An economic evaluation was conducted alongside a 2-year, pragmatic, randomized controlled trial set in 53 primary-care practices in the UK. Patients aged 12-80 years with asthma insufficiently controlled with ICS (n = 361) were randomly assigned to add-on LTRAs (n = 176) or long-acting beta2 agonists (n = 185). The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), per point improvement in the Asthma Control Questionnaire (ACQ) and per QALY gained from perspectives of the UK NHS and society. Over 2 years, the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists, a (significant, adjusted) increase of pounds sterling 214 (95% CI 2, 411) [year 2005 values]. Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs (95% CI -0.077, 0.103). The incremental cost per QALY gained from the societal (NHS) perspective was pounds sterling 22,589 (pounds sterling 11,919). Uncertainty around this point estimate suggested that, given a maximum willingness to pay of pounds sterling 30,000 per QALY gained, the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52% from both societal and NHS perspectives. On balance, these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma. However, there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs. UK National Research Register N0547145240; Controlled Clinical Trials ISRCTN99132811.

Steroids in COPD: still up in the air?

Inhaled corticosteroids (ICS) have had a wild and controversial rollercoaster ride in chronic obstructive pulmonary disease (COPD). With the success of ICS in asthma and with the advent of the Dutch Hypothesis, suggesting that asthma and COPD had a similar pathogenic origin, there was great hope that ICS would be the saviour for millions of patients suffering from COPD, by palliating symptoms and changing its natural history. Based on this promise, by the mid 1980s, clinicians were routinely recommending ICS therapy to their patients, even though there was an absence of compelling grade A evidence from large randomised controlled trials (RCTs) demonstrating efficacy 1. By the late 1990s, the promise was shattered by the publication of several seminal RCTs that clearly showed that ICS did not modify the rate of decline in forced expiratory volume in 1 s (FEV1) and had only a modest effect on symptoms 2–4. These data re-inforced the notion that COPD was a steroid-resistant state and many leading experts in the field concluded that ICS had no role in COPD, except during exacerbations 5. Ostensibly, ICS were dead and buried. However, the new millennium brought new hope for ICS. Proponents argued that while ICS may not alter the rate of decline in FEV1, it improved patient based outcomes including survival. This optimism was fuelled by several large observational studies and meta-analyses 6–9 that demonstrated a distinct survival benefit for patients who were prescribed ICS. This enthusiasm, however, was dashed in 2007 by the publication of the long-awaited TORCH (TOwards a Revolution in COPD Health) Study, which failed to show an unequivocal survival advantage for patients assigned to a steroid-containing treatment …

Dose–response relationship of inhaled corticosteroids and cataracts: A systematic review and meta‐analysis

The risk of cataracts associated with the long-term use of inhaled corticosteroids (ICS) is poorly recognized, yet may be of major public health importance. The aim of this study was to determine the dose-response relationship of ICS use and risk of cataracts in adults. A systematic review and meta-analysis was performed of case-control studies of cataracts and ICS use, which included at least two doses of ICS and in which the number of cases and controls using each dose of ICS was reported. The primary outcome variable was risk of cataracts. Four case-control studies were identified, with a total of 46 638 cases and 146 378 controls. There was a significant relationship between the risk of cataracts and ICS dose, with a random effects pooled odds ratio for risk of cataracts per 1000 microg increase in daily beclomethasone dipropionate dose of 1.25 (95% CI: 1.14-1.37). The risk of cataracts was increased by approximately 25% for each 1000 microg per day increase in the dose of beclomethasone dipropionate or equivalent. These findings reinforce the importance of prescribing within the therapeutic dose-response range for ICS in asthma and the need to determine the dose-response relationship for the efficacy of ICS in COPD. Screening for the presence of cataracts could usefully be undertaken in older subjects with asthma and COPD, particularly current or ex-smokers.

Exhaled nitric oxide for monitoring childhood asthma inflammation compared to sputum analysis, serum interleukins and pulmonary function

The level of fractional exhaled nitric oxide (FENO) is significantly elevated in uncontrolled asthma and decreases after anti-inflammatory therapy. The aim of this prospective study was to analyze the behavior of FENO in the follow-up and management of the inflammation in asthmatic pediatric patients treated with inhaled corticosteroids (ICS), compared to sputum cellularity, serum interleukins (IL), and pulmonary function. Twenty-six clinically stable asthmatic children aged from 6 to 18 years, previously treated or not with ICS were included. Following an international consensus (GINA), the patients were submitted to standard treatment with inhaled fluticasone for 3 months according to the severity of the disease. During this period, each patient underwent three assessments at intervals of approximately 6 weeks. Each evaluation consisted of the measurement of FENO, determination of serum interleukins IL-5, IL-10, IL-13, and interferon gamma (INF-gamma), spirometry and cytological analysis of spontaneous or induced sputum. A significant reduction in mean FENO and IL-5, without concomitant changes in FEV1, was observed along the study. There was no significant correlation between FeNO and FEV1 in the three assessments. A significant correlation between FeNO and IL-5 levels was only observed in the third assessment (r = 0.499, P = 0.025). In most patients, serum IL-10, IL-13, and INF-gamma concentrations were undetectable throughout the study. Sputum samples were obtained spontaneously in 11 occasions and in 56 by induction with 3% hypertonic saline solution (success rate: 50.8%), with 39 (69.9%) of them adequate for analysis. Only two of the 26 patients produced adequate samples in the three consecutive evaluations, which impaired the determination of a potential association between sputum cellularity and FeNO levels throughout the study. In conclusion, among the parameters of this study, it was difficult to perform and to interpret the serial analysis of spontaneous or induced sputum. Serum interleukins, which remained at very low or undetectable levels in most patients, were not found to be useful for therapeutic monitoring, except for IL-5 that seems to present some correlation with levels of FeNO exhaled. Monitoring of the mean FEV1 indicated no significant variations during the treatment, demonstrating that functional stability or the absence of obstruction may not reflect the adequate management of asthma. Serial measurement of FeNO seemed to best reflect the progressive anti-inflammatory action of ICS in asthma.

Concurrent therapy (long acting beta agonists and inhaled corticosteroids) in the management of asthma

Asthma is a clinical syndrome characterised by chronic inflammation of the lower respiratory tract in which many cells and cellular elements play a role, in particular mast cells, eosinophils, T-lymphocytes, macrophages, neutrophils and epithelial cells. Patients often require long-term anti-inflammatory and reliever drugs to achieve a normal life. This review aims to highlight role of concurrent therapy in the optimal management of asthma. A review of relevant literature was conducted using available medical journals and Science direct via the Internet. The key words employed were: asthma, concurrent therapy, long acting beta agonists and corticosteroids. British Thoracic Society and The National Heart, Lung and Blood Institute websites were also used in sourcing information for this review. Several studies support adding long acting beta agonists (LABA) to inhaled corticosteroids (ICS) than doubling the dose of ICS. This improves lung function, symptoms control and allows the dose of each drug to be adjusted to the patients'needs. This review was able to show that concurrent use LABA and ICS in asthmatics helps in adjusting their treatment within limits hence achieving control of the condition with minimal side effects.

The treatment of asthma in children: Inhaled corticosteroids

The evidence that asthma is characterized by extensive inflammation of the airways has warranted the use of inhaled corticosteroid (ICS) in asthma maintenance therapy. Corticosteroid treatment, especially if high or frequent doses are required, is associated with a range of adverse effects including adrenal suppression and impairment in growth and bone metabolism. New corticosteroids are in development, including mometasone furoate, and some of these are predicted to have reduced adverse effects such as the soft steroid ciclesonide. Soft steroids are designed for delivery near to their site of action, to exert their effect and then to undergo controlled and predictable metabolism to inactive metabolites. This review points out the anti-inflammatory effects of corticosteroid in asthmatic airways and the clinical efficacy and safety of ICS in asthmatic children. The development of a soft steroid should help to achieve the aim of improving the therapeutic profile of ICS in asthma and thus alleviate the ongoing problem of poor patient compliance especially in childhood.

Effects of Inhaled Corticosteroids on Mortality and Hospitalisation in Elderly Asthma and Chronic Obstructive Pulmonary Disease Patients

Asthma and chronic obstructive pulmonary disease (COPD) are common conditions that have substantial effects on daily functioning and medical resource utilisation. In elderly populations, the use of inhaled corticosteroids (ICS) as a mainstay of treatment in asthma has long been accepted whereas the appropriateness and extent of use of ICS in COPD is not as clear. This paper reviews data associated with ICS treatment in the elderly, specifically characteristics of ICS users, rates of adherence, hospitalisation and mortality associated with ICS treatment. Studies examining the use of ICS in asthma and COPD have generally found that ICS may be underused compared with guideline recommendations or that there are substantial differences between patients who receive ICS and those who do not. Among elderly asthma or COPD patients who receive ICS, there are lower rates of hospitalisation among those who adhere to their treatment plan. Among elderly patients with asthma, the combination of ICS plus long-acting beta-adrenoceptor agonists has been shown to be superior in terms of mortality and hospitalisation compared with either treatment alone. There may be an interaction effect between oral corticosteroids and ICS among elderly COPD patients, although important differences may be present in the clinical characteristics of patients who receive one versus both forms of corticosteroids. A dose-response relationship between ICS and both all-cause and pulmonary-specific mortality has been shown among older COPD patients. Several existing studies are subject to selection bias, as they have identified patients who survived for a specified period, for example, long enough to have received a specified number of prescriptions for ICS. This bias must be further explored. Future research should also clearly delineate asthma and COPD populations in order to identify different benefits from ICS. The use of a claims database that also includes clinical metrics would be useful to identify additional possible outcomes of ICS use. Further, symptom diaries or other patient-reported outcomes, such as health-related quality of life and health status, should be included in studies of ICS among the elderly to identify other benefits that should be considered in treatment selection.