Use Of Inhaled Corticosteroids Research Articles

The airway microbiome in patients with severe asthma: Associations with disease features and severity

Asthma is heterogeneous, and airway dysbiosis is associated with clinical features in patients with mild-to-moderate asthma. Whether similar relationships exist among patients with severe asthma is unknown. We sought to evaluate relationships between the bronchial microbiome and features of severe asthma. Bronchial brushings from 40 participants in the Bronchoscopic Exploratory Research Study of Biomarkers in Corticosteroid-refractory Asthma (BOBCAT) study were evaluated by using 16S ribosomal RNA-based methods. Relationships to clinical and inflammatory features were analyzed among microbiome-profiled subjects. Secondarily, bacterial compositional profiles were compared between patients with severe asthma and previously studied healthy control subjects (n = 7) and patients with mild-to-moderate asthma (n = 41). In patients with severe asthma, bronchial bacterial composition was associated with several disease-related features, including body mass index (P < .05, Bray-Curtis distance-based permutational multivariate analysis of variance; PERMANOVA), changes in Asthma Control Questionnaire (ACQ) scores (P < .01), sputum total leukocyte values (P = .06), and bronchial biopsy eosinophil values (per square millimeter, P = .07). Bacterial communities associated with worsening ACQ scores and sputum total leukocyte values (predominantly Proteobacteria) differed markedly from those associated with body mass index (Bacteroidetes/Firmicutes). In contrast, improving/stable ACQ scores and bronchial epithelial gene expression of FK506 binding protein (FKBP5), an indicator of steroid responsiveness, correlated with Actinobacteria. Mostly negative correlations were observed between biopsy eosinophil values and Proteobacteria. No taxa were associated with a TH2-related epithelial gene expression signature, but expression of TH17-related genes was associated with Proteobacteria. Patients with severe asthma compared with healthy control subjects or patients with mild-to-moderate asthma were significantly enriched in Actinobacteria, although the largest differences observed involved a Klebsiella genus member (7.8-fold increase in patients with severe asthma, adjusted P < .001). Specific microbiota are associated with and may modulate inflammatory processes in patients with severe asthma and related phenotypes. Airway dysbiosis in patients with severe asthma appears to differ from that observed in those with milder asthma in the setting of inhaled corticosteroid use.

Concentration of fractional excretion of nitric oxide (FENO): A potential airway biomarker of restored CFTR function

BackgroundLower airway biomarkers of restored cystic fibrosis transmembrane conductance regulator (CFTR) function are limited. We hypothesized that fractional excretion of nitric oxide (FENO), typically low in CF patients, would demonstrate reproducibility during CFTR-independent therapies, and increase during CFTR-specific intervention (ivacaftor) in patients with CFTR gating mutations. MethodsRepeated FENO and spirometry measurements in children with CF (Cohort 1; n=29) were performed during hospital admission for acute pulmonary exacerbations and routine outpatient care. FENO measurements before and after one month of ivacaftor treatment (150mg every 12h) were completed in CF patients with CFTR gating mutations (Cohort 2; n=5). ResultsCohort 1: Mean forced expiratory volume in 1s (FEV1 % predicted) at enrollment was 72.3% (range 25%–102%). Mean FENO measurements varied minimally over the two inpatient and two outpatient measurements (9.8–10.9ppb). There were no clear changes related to treatment of pulmonary exacerbations, gender, genotype or microbiology, and weak correlation with inhaled corticosteroid use (P<0.05). Between the two inpatient measurements, FEV1 % predicted increased by 7.3% (P<0.03) and FENO did not change. In Cohort 2, mean FENO increased from 6.6ppb (SD=2.19) to 11.8ppb (SD=4.97) during ivacaftor treatment. Mean sweat chloride dropped by 58mM and mean FEV1 % predicted increased by 10.2%. ConclusionsRepeated FENO measurements were stable in CF patients, whereas FENO increased in all patients with CFTR gating mutations treated with ivacaftor. Acute changes in FENO may serve as a biomarker of restored CFTR function in the CF lower airway during CFTR modulator treatment.

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Asthma exacerbations and lung function in patients with severe or difficult-to-treat asthma

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BackgroundChronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that ‘low dose’ theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of ‘low dose’ theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD.Method/DesignTWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either ‘low dose’ theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1–5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period.DiscussionThe demonstration that ‘low dose’ theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally.Trial registrationCurrent Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-0782-2) contains supplementary material, which is available to authorized users.

Self-reported osteoporosis prevention in inhaled corticosteroid users in community pharmacy setting.

Objectives:The use of inhaled corticosteroids is the standard maintenance therapy in asthma therapy and as adjunct therapy in moderate to severe chronic obstructive pulmonary disease. A dose-related increase in fracture risk is associated with inhaled corticosteroid use; there is an inverse relationship between bone mineral density and duration and cumulative dose of inhaled corticosteroid. Adequate intake of calcium and vitamin D are cornerstones of osteoporosis prevention. The objectives are to assess whether the proportion of patients receiving inhaled corticosteroids are taking calcium and vitamin D; the association between long-term inhaled corticosteroid use and abnormal bone mineral density or fractures; and how many qualified patients received bone mineral density scans.Methods:Patients who filled a prescription for inhaled corticosteroids at selected community pharmacies across Alberta were recruited for a survey of their osteoporosis prevention activities.Results:A total of 256 patients from 12 community pharmacies were included. The average age was 60 ± 17.4 years with 65% female. There were 21%, 51%, and 28% of patients on high, medium, and low dose inhaled corticosteroids, respectively. Only 17% of patients >50 years old received recommended calcium and vitamin D supplementation and 87 (73%) of the qualified patients received bone mineral density scan.Conclusion:Osteoporosis prevention in inhaled corticosteroid users is currently poorly addressed. More promotion is needed to raise pharmacist awareness of the risks of inhaled corticosteroids.

Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma

BackgroundThe pathogenesis of asthma in obese subjects is poorly understood and has been described as a specific phenotype in these patients. Weight loss improves asthma control and lung function. Whether...

Stepping down inhaled corticosteroid use in asthma ‐ who is responsible?

Asthma is a very common condition affecting 5.4 million people in the United Kingdom. Daily use of inhaled corticosteroids (ICS) prevents acute exacerbations and reduces need of other inhalers (ie Salbutamol). They are however amongst the most expensive prescription medicines in the UK, bearing a substantial financial burden on the NHS. ICS use is also linked with a higher risk of side effects such as developing oral thrush. Guidelines published by NICE stress that apt patient education is one necessary component of managing asthma, to increase adherence to treatment and subsequently improve symptomatic control. To assess the degree of adherence to ICS treatment, the files of all asthmatic patients currently prescribed ICS were analyzed, focusing on regularity of dispensing medicines. The results showed that the vast majority of patients were using their ICS inhaler in an ad-hoc fashion and not as prescribed; concluding that these patients did not require their ICS inhalers (either entirely, or at their current dosages). A significant cause of this was identified as being a lack of, or poor use of, communication between the practitioner and patient at the time of prescribing. In conclusion, insufficient patient education at time of starting medicines leads to poor adherence to treatment and causes financial inefficiencies regarding prescribing, for any given practice. Patient understanding must always be gauged, at the time of starting ICS treatment, and thereon, during subsequent consultations. To aid this process, a patient information leaflet should be used as means of signposting for the practitioner and as a treatment record for the patient.

A common variant in RAB27A gene is associated with fractional exhaled nitric oxide levels in adults.

Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N=610 adults) and the Hutterites (N=601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N=450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N=8858) consortium. We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P=1.6×10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P=8.9×10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.

The importance of atopy on exhaled nitric oxide levels in African American children

BackgroundFor physicians to be maximally effective in managing asthma in minority populations, a better understanding of the factors that affect fractional exhaled nitric oxide (FeNO) measurements in African Americans is needed. ObjectiveTo examine demographic, environmental, and physiologic factors that influence FeNO measurements in African American children with and without asthma. MethodsA cross-sectional study of 128 African American children aged 7 to 18 years (44% with asthma) was conducted. FeNO measurements, skin prick tests (as a measure of atopy), spirometry, and questionnaire data were obtained from all participants. Regression models were constructed after identifying factors significantly associated on univariate analysis. ResultsAmong all study participants, the mean FeNO measurement at baseline was 24.4 ppb. Children with asthma had a higher level than those without (30.9 vs 19.3 ppb, P = .002). When examining all children through logistic regression analysis, an elevated FeNO level was significantly associated with atopy, lower spirometric values, and current asthma (P < .05 for all). Among asthmatic children, univariate analysis revealed that an elevated FeNO level was associated with inhaled corticosteroid use, recent respiratory infection, and atopy (P < .05 for all). However, only atopy remained significant after regression analysis. For asthmatic and nonasthmatic children, FeNO levels were directly correlated with the number of positive skin test results. ConclusionIn African American children with and without asthma, FeNO levels are strongly influenced by atopy. Guidelines for FeNO measurements that incorporate atopic status are needed.

The Quasi-cohort approach in pharmacoepidemiology: upgrading the nested case-control.

Observational studies of drug effects conducted using health care mega-databases often involve large cohorts with multiple time-varying exposures and covariates. These present formidable technical challenges in data analysis, necessitating sampling approaches such as nested case-control designs. The nested case-control approach is, however, baffling to medical journal readers, particularly the comparisons involving "cases" versus "controls" and the convoluted way in which forward-looking relations from exposure to outcome are extracted from backward-looking data. I propose a "quasi-cohort" approach involving alternative ways of data presentation and analysis that are more in line with the underlying cohort design, including the computation of quasi-rates, rate ratios, and quasi-rate differences. I illustrate the quasi-cohort approach using data from a study of pneumonia risk associated with inhaled corticosteroid use in a cohort of 163,514 patients with chronic obstructive pulmonary disease, including 20,344 who had the outcome event of pneumonia hospitalization during more than 304 million person-days of follow-up.

Evaluating the impact of an integrated computer-based decision support with person-centered analytics for the management of asthma in primary care: a randomized controlled trial.

Background Computer-based decision support has been effective in providing alerts for preventive care. Our objective was to determine whether a personalized asthma management computer-based decision support increases the quality of asthma management and reduces the rate of out-of-control episodes.Methods A cluster-randomized trial was conducted in Quebec, Canada among 81 primary care physicians and 4447 of their asthmatic patients. Patients were followed from the first visit for 3–33 months. The physician control group used the Medical Office of the 21st century (MOXXI) system, an integrated electronic health record. A custom-developed asthma decision support system was integrated within MOXXI and was activated for physicians in the intervention group.Results At the first visit, 9.8% (intervention) to 12.9% (control) of patients had out-of-control asthma, which was defined as a patient having had an emergency room visit or hospitalization for respiratory-related problems and/or more than 250 doses of fast-acting β-agonist (FABA) dispensed in the past 3 months. By the end of the trial, there was a significant increase in the ratio of doses of inhaled corticosteroid use to fast-acting β-agonist (0.93 vs. 0.69: difference: 0.27; 95% CI: 0.02–0.51; P = 0.03) in the intervention group. The overall out-of-control asthma rate was 54.7 (control) and 46.2 (intervention) per 100 patients per year (100 PY), a non-significant rate difference of −8.7 (95% CI: −24.7, 7.3; P = 0.29). The intervention’s effect was greater for patients with out-of-control asthma at the beginning of the study, a group who accounted for 44.7% of the 5597 out-of-control asthma events during follow-up, as there was a reduction in the event rate of −28.4 per 100 PY (95% CI: −55.6, −1.2; P = 0.04) compared to patients with in-control asthma at the beginning of the study (−0.08 [95% CI: −10.3, 8.6; P = 0.86]).Discussion This study evaluated the effectiveness of a novel computer-assisted ADS system that facilitates systematic monitoring of asthma control status, follow-up of patients with out of control asthma, and evidence-based, patient-specific treatment recommendations. We found that physicians were more likely to use ADS for out-of-control patients, that in the majority of these patients, they were advised to add an inhaled corticosteroid or a leukotriene inhibitor to the patient s treatment regimen, and the intervention significantly increased the mean ratio of inhaled corticosteroids to FABA during follow-up. It also reduced the rate of out-of-control episodes during follow up among patients whose asthma was out-of-control at the time of study entry. Future research should assess whether coupling patient-specific treatment recommendations, automated follow-up, and home care with comparative feedback on quality and outcomes of care can improve guideline adoption and care outcomes.Conclusions A primary care-personalized asthma management system reduced the rate of out-of-control asthma episodes among patients whose asthma was poorly controlled at the study’s onset.Trial Registration Clinicaltrials.gov Identifier: NCT00170248 http://clinicaltrials.gov/ct2/show/NCT00170248?term=Asthma&spons=McGill+University&state1=NA%3ACA%3AQC&rank=2

Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids?

Inhaled corticosteroids are commonly prescribed for patients with severe chronic obstructive pulmonary disease. Although their use improves quality of life and reduces exacerbations, it is associated with increased risk of pneumonia. Curiously, their use has not been associated with increased risk of pneumonia-related or overall mortality. We review pertinent literature to further explore the effects of inhaled corticosteroids on incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. The association of use of inhaled corticosteroids and incident pneumonia is substantial and has been present in the majority of the studies on the topic. This includes both randomized controlled trials and observational studies. However, all of the studies have substantial risk of bias. Most randomized trials are limited by lack of systematic ascertainment of pneumonia; they depended on adverse event reporting. Many observational studies included proper radiographic assessment of pneumonia, but they are limited by their retrospective, observational design. The unadjusted higher risk of pneumonia is associated with longer duration of use, more potent ICS compounds, and higher doses. That implies a dose-effect relationship. Unlike pneumonia, mortality is a precise outcome. Despite the robust association of inhaled corticosteroid use with increased risk of pneumonia, all studies find either no difference or a reduction in pulmonary-related and overall mortality associated with the use of inhaled corticosteroids. These observations suggest a double effect of inhaled corticosteroids (i.e., an adverse effect plus an unexplained mitigating effect).

Association between allergic sensitization and exhaled nitric oxide in children in the School Inner-City Asthma Study

Association between allergic sensitization and exhaled nitric oxide in children in the School Inner-City Asthma Study

Long-term inhaled corticosteroid use not linked to fracture risk in asthma

Long-term inhaled corticosteroid use not linked to fracture risk in asthma

Journal Club

Introduction: COPD and Chronic infection In this issue of Journal Club we examine the relationship between inhaled corticosteroid use and the risk of pneumonia. Over the past several years, investigators have identified a pneumonia signal in COPD patients treated with inhaled corticosteroids. Furth

Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD.

Radiographically confirmed pneumonia risk with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD) has not been assessed to date. To determine the incidence of pneumonia, risk factors, and clinical attributes with inhaled fluticasone furoate (FF) in patients with COPD with an exacerbation history. Two replicate, 1-year, double-blind clinical trials enrolled subjects with COPD with moderate to very severe airflow limitation and at least one exacerbation within the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol (VI) 25 μg or VI 25 μg combined with 50, 100, or 200 μg FF. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Among 3,255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1,793 (70%) of the 2,545 moderate and severe exacerbations. For VI alone and the combination with 50, 100, or 200 μg FF, reported pneumonia incidence was 3, 6, 6, and 7%, respectively. However, for events with compatible parenchymal infiltrates, the respective incidences were 2, 4, 4, and 5%. Factors associated with at least a twofold increase in the risk of pneumonia with FF/VI treatment were being a current smoker, having prior pneumonia, body mass index <25 kg/m(2), and severe airflow limitation. Radiographically confirmed pneumonia risk is increased with inhaled FF/VI, although at less than investigator-defined rates. Modifiable pneumonia risk factors should be considered when attempting to optimize COPD management. Clinical trial registered with www.clinicaltrials.gov (NCT01009463 [HZC102871]; NCT01017952 [HZC102970]).

Inhaled corticosteroid use in infancy could stunt growth

Inhaled corticosteroid use in infancy could stunt growth

Lymphotoxin β receptor signaling induces IL-8 production in human bronchial epithelial cells.

Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin β receptor (LTβR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth-regulated protein α and IL-8. Specific siRNA for LTβR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-κB (NF-κB) signaling. LIGHT also induced luciferase activity of NF-κB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal-regulated kinase (Erk) and that of inhibitor κB attenuated IL-8 production, suggesting that LIGHT-LTβR signaling induces IL-8 production via the Erk and NF-κB pathways. LIGHT, via LTβR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells.

Rhinoviruses significantly affect day-to-day respiratory symptoms of children with asthma

BackgroundViruses are frequently associated with acute exacerbations of asthma, but the extent to which they contribute to the level of day-to-day symptom control is less clear.ObjectiveWe sought to explore the relationship between viral infections, host and environmental factors, and respiratory symptoms in children.MethodsSixty-seven asthmatic children collected samples twice weekly for an average of 10 weeks. These included nasal wash fluid and exhaled breath for PCR-based detection of viral RNA, lung function measurements, and records of medication use and asthma and respiratory symptoms in the previous 3 days. Atopy, mite allergen exposure, and vitamin D levels were also measured. Mixed-model regression analyses were performed.ResultsHuman rhinoviruses (hRVs) were detected in 25.5% of 1232 nasal samples and 11.5% of breath samples. Non-hRV viruses were detected in less than 3% of samples. hRV in nasal samples was associated with asthma symptoms (cough and phlegm: odds ratio = 2.0; 95% CI = 1.4-2.86, P = .0001; wheeze and chest tightness: odds ratio = 2.34, 95% CI = 1.55-3.52, P < .0001) and with cold symptoms, as reported concurrently with sampling and 3 to 4 days later. No differences were found between the 3 hRV genotypes (hRV-A, hRV-B, and hRV-C) in symptom risk. A history of inhaled corticosteroid use, but not atopic status, mite allergen exposure, or vitamin D levels, modified the association between viruses and asthma symptoms.ConclusionThe detection of nasal hRV was associated with a significantly increased risk of day-to-day asthma symptoms in children. Host, virus genotype, and environmental factors each had only a small or no effect on the relationship of viral infections to asthma symptoms.

Long-acting anticholinergic agents in patients with uncontrolled asthma: a systematic review and meta-analysis.

A novel effective treatment is necessary for severe asthma. To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long-acting β₂-agonists. A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included. Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events. The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma.