Moderate Doses Of Inhaled Corticosteroids Research Articles

Peripheral Blood Eosinophils as Marker of Sputum Eosinophilia and Outcome of COPD Exacerbation

Sputum eosinophils might predict response to inhaled corticosteroids (ICS) in patients with advanced chronic obstructive pulmonary disease (COPD). Induction of sputum requires expertise and may not always be successful. Aim was to investigate correlation and predictive relationship between peripheral blood eosinophils (bEo) and sputum eosinophils (sEo), and impact of peripheral blood eosinophilia on outcome of COPD exacerbation. 120 current smokers with COPD (GOLD group C) (57.4 ± 0.92 years, M/F ratio 1.4), with no blood (≥7% or >0.43x109/L) nor sputum (≥3%) eosinophilia, were treated with moderate dose of ICS and long-acting bronchodilatator during stable disease, but systemic corticosteroids and antibiotics during exacerbation. According to sputum eosinophilia (≥4%) during exacerbation, patients were divided into eosinophilic (n=45) and non-eosinophilic group (n=75). In stable disease, bEo and sEo were similar in both groups (p>0.05). During exacerbation, bEo and sEo were significantly higher in eosinophilic group (eosinophilic vs. non-eosinophilic: blood: 1.42 ± 0.39 x109/l vs. 0.23 ± 0.02 x109/l, p<0.001; sputum: 8% (4, 19) vs. 1% (0, 3), p<0.0001), but bEo correlated with sEo in both groups (eosinophilic: r=0.52, p<0.001; non-eosinophilic: r=0.25, p<0.05). Relative bEo predicted sputum eosinophilia (area under the curve=0.71, standard error=0.05; 95% confidence interval [CI] =0.61-0.81; p<0.001) and enabled identification of the presence or absence of sputum eosinophilia in 82% of the cases at a threshold of ≥4% (specificity=83.56%, sensitivity=93.83%, positive likelihood ratio=3.67). Eosinophilic group during exacerbation showed less frequent hospitalisations and shorter exacerbation (eosinophilic vs. non-eosinophilic: hospitalisations: 26.7% vs. 60.0%, p<0.001; duration of exacerbation (days): 8.1±0.35 vs. 10.13±0.31, p<0.0001). In COPD exacerbation, relative peripheral blood eosinophils ≥4% might identify sputum eosinophilia. Blood eosinophilia indicate better outcome of COPD exacerbation. Further investigations are needed to predict eosinophilic exacerbation in COPD patients, with prior absence of sputum or blood eosinophilia.

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.

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.

P229 Once-daily Tiotropium Respimat(R) As Add-on To At Least Medium- To High-dose Ics, With Or Without Laba, Improves Lung Function In Patients With Symptomatic Asthma, Independent Of Allergic Status

Background A substantial number of patients have symptomatic asthma despite treatment according to guidelines. Several studies have confirmed that tiotropium Respimat ® , a once-daily long-acting anticholinergic bronchodilator, improves lung function in symptomatic patients receiving at least medium-dose inhaled corticosteroids (ICS) + long-acting β 2 -agonist (LABA) (Kerstjens et al . NEJM 2012;367:1198–207; Bateman et al . JACI 2011;128:315–22). Here we examine whether the atopic and/or allergic status of patients in these trials influenced their response to tiotropium Respimat ® . Method Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients (n = 912) on high-dose ICS + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients (n = 2100) on moderate-dose ICS. Pre-planned analyses (pooled populations) were performed in two subgroups defined at baseline as total serum immunoglobulin E (IgE) ≤ or >430 μg/L or blood eosinophils ≤ or >0.6×10 9 /L or clinical judgement of allergic status (‘No’ or ‘Yes’). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results Tiotropium Respimat ® 5 µg or 2.5 µg improved peak and trough forced expiratory volume in 1 second versus placebo (Table) independent of IgE, eosinophil count and clinical judgement. Conclusion Once-daily tiotropium Respimat ® as add-on to ICS or ICS + LABA in patients with moderate to severe symptomatic asthma reduces airflow obstruction, apparently independent of their atopic and/or allergic status.

P231 Once-daily Tiotropium Respimat(R): Safety And Tolerability Results From Five Phase Iii Trials In Adults With Symptomatic Asthma

Background Tiotropium Respimat ® , a once-daily long-acting anticholinergic agent, is effective as add-on to inhaled corticosteroids (ICS) ± a long-acting β2-agonist (LABA) in adults with symptomatic asthma. Safety and tolerability are key issues in the development of new therapies or established therapies in new disease areas. We present key safety data from five Phase III, randomised, double-blind, parallel-group trials that evaluated the efficacy and safety of once-daily tiotropium Respimat ® versus placebo in adults with symptomatic asthma. Methods: Two 48-week trials of tiotropium Respimat ® 5 µg (PrimoTinA-asthma ® : NCT00776984, NCT00772538) in patients on high-dose ICS (≥800 µg budesonide or equivalent) + LABA; two 24-week trials of tiotropium Respimat ® 5 µg and 2.5 µg (MezzoTinA-asthma ® : NCT01172808, NCT01172821) in patients on moderate-dose ICS (400–800 µg budesonide or equivalent); one 12-week trial of tiotropium Respimat ® 5 µg and 2.5 µg (GraziaTinA-asthma ® : NCT01316380) in patients on low-dose ICS (200–400 µg budesonide or equivalent). All tiotropium doses were delivered via the Respimat ® SoftMist™ inhaler. Results: 3476 patients were treated. Incidence of any adverse events (AEs), serious AEs and investigator-defined drug-related AEs was similar across treatment groups within each trial. AEs reported by ≥5% of patients were similar across all treatment groups within each trial (Table). The number of cardiovascular AEs was small in all five studies and comparable between tiotropium Respimat ® and placebo. No deaths occurred in any trial. Conclusion: Once-daily tiotropium Respimat® is well tolerated and comparable with placebo in adult patients with symptomatic asthma receiving at least low- to high-dose ICS.

Dose Response of Inhaled Corticosteroids in Children With Persistent Asthma: A Systematic Review

To assess the dose-response relationship (benefits and harms) of inhaled corticosteroids (ICSs) in children with persistent asthma. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared ≥2 doses of ICSs in children aged 3 to 18 years with persistent asthma. Medline was searched for articles published between 1950 and August 2009. Main outcomes of our analyses included morning and evening peak expiratory flow, forced expiratory volume in 1 second, asthma symptom score, β(2)-agonist use, withdrawal because of lack of efficacy, and adverse events. Meta-analyses were performed to compare moderate (300-400 μg/day) with low (≤200 μg/day beclomethasone-equivalent) doses of ICSs. Fourteen RCTs (5768 asthmatic children) that evaluated 5 ICSs were included. The pooled standardized mean difference from 6 trials revealed a small but statistically significant increase of moderate over low doses in improving forced expiratory volume in 1 second (standardized mean difference: 0.11 [95% confidence interval: 0.01-0.21]) among children with mild-to-moderate asthma. There was no significant difference between 2 doses in terms of other efficacy outcomes. Local adverse events were uncommon, and there was no evidence of dose-response relationship at low-to-moderate doses. Compared with low doses, moderate doses of ICSs may not provide clinically relevant therapeutic advantage in children with mild-to-moderate persistent asthma. Additional RCTs are needed to clarify the dose-response relationship of ICSs in persistent childhood asthma.

Assessment of Adrenal Suppression in Children With Asthma Treated With Inhaled Corticosteroids: Use of Dehydroepiandrosterone Sulfate as a Screening Test

Dorsey MJ, Cohen LE, Phipatanakul W, Denufrio D, Schneider LC. Ann Allergy Asthma Immunol. 2006;97:182–186 PURPOSE OF THE STUDY. To evaluate dehydroepiandrosterone sulfate (DHEA-S), a corticotropin-dependent adrenal androgen precursor, as a possible marker for adrenal function and hypothalamic-pituitary-adrenal axis suppression in children treated with inhaled corticosteroids (ICSs) compared with low-dose (0.5 μg/m2 up to 1.0 μg) and standard-dose (250 μg) cosyntropin-stimulation testing. STUDY POPULATION. Twenty-two patients with moderate-to-severe–persistent asthma receiving a medium-to-high dose of ICSs for at least 6 months were enrolled (definition of median-to-high dose of ICS: budesonide &amp;gt;400 μg/day or fluticasone &amp;gt;176 μg/day for children &amp;lt;6 years old or &amp;gt;200 μg/day for those ≥6 years). Patients had received no more than 2 courses of systemic corticosteroid exposure of &amp;lt;10 days’ duration in the previous 6 months and no systemic corticosteroid in the 1 month before enrollment. The average age of the patients was 8.6 years (range: 2–12 years). METHODS. After a 12-hour fast, morning cortisol, corticotropin, DHEA-S, and fasting blood sugar levels were measured. Cortisol was measured after the stimulation tests. A cortisol level of ≤18 μg/dL was considered abnormal (adrenal suppression). RESULTS. Of 22 patients, 13 (59%) had an abnormal response to low-dose cosyntropin. One patient had an abnormal standard-dose cosyntropin test result. The normal and abnormal low-dose cosyntropin responders did not differ in age, height, BMI, predicted forced expiratory volume in 1 second, or morning cortisol, corticotropin, or fasting blood sugar levels. There was no difference between normal and abnormal low-dose cosyntropin responders in relation to type of ICS (fluticasone, fluticasone-salmeterol, or budesonide) or dose. DHEA-S levels were significantly lower in abnormal low-dose cosyntropin responders compared with normal responders (31 vs 91 μg/dL; P = .004). Age- and gender-specific mean DHEA-S z scores were significantly lower in abnormal low-dose cosyntropin responders. Receiver-operating-characteristic (ROC) curves for DHEA-S z scores were calculated to obtain optimal cutoff values for DHEA-S. The ROC curve for DHEA-S z scores reached 100% sensitivity with a DHEA-S z score of less than −1.5966 and 100% specificity with a DHEA-S z score &amp;gt;0.0225. CONCLUSIONS. Fifty-nine percent of the children on a medium-to-high dose of ICS had biochemical evidence of adrenal suppression according to the low-dose cosyntropin-stimulation test. Low DHEA-S levels can be used as a screening test to identify children who need more formal testing of the hypothalamic-pituitary-adrenal axis. The half-life of DHEA-S (10–20 hours) is substantially longer than that of cortisol (&amp;lt;2 hour) and, therefore, has less diurnal variation or fluctuating concentration depending on exogenous stress and time of day. REVIEWER COMMENTS. The cosyntropin-stimulation test is cumbersome, labor intensive, and not practical as a screening test, so the DHEA-S test may be more useful. The number of patients on a moderate dose of ICS found to have biochemical adrenal suppression by low-dose cosyntropin tests (59%) is higher than seen in most other studies. The authors speculated that the higher rates of adrenal suppression may be associated with “real-world” ICS use versus study-protocol use. The clinical significance of this biochemical suppression is not clear.

Reticular basement membrane thickening in airways of lung transplant recipients is not affected by inhaled corticosteroids

Chronic rejection is a major problem for all lung transplant programmes, which is functionally manifested by fixed airflow limitation, Bronchiolitis Obliterans Syndrome (BOS). The inclusion of a Pre-BOS category, BOS(0 approximately p), in newly revised guidelines, recognizes the potential importance of early changes. We have previously demonstrated reticular basement membrane (Rbm) thickening in clinically stable lung transplant recipients free from BOS. The present study extends this, testing the hypothesis that inhaled corticosteroid (ICS) therapy will lead to a decrease in Rbm thickness in lung transplant recipients. A parallel group, bronchoscopic intervention study of clinically stable lung allograft recipients, free from BOS, but with evidence of airway inflammation. Following baseline assessment of Rbm thickening, subjects were randomized to 3 months of either chlorofluorocarbon-driven beclomethasone diproprionate (BDP) 400 microg b.i.d., or a formulation designed to yield at least an equivalent dose, hydrofluoroalkane-driven BDP, 200 microg b.i.d. Three months treatment with a moderate dose of ICS, including a formulation designed for preferential small airway deposition, had no effect on Rbm thickening (13+/-3 vs. 14+/-5 microm post-ICS). Our data would suggest that airway remodelling can occur early in lung allografts and is not affected by moderate dose ICS therapy. Longitudinal studies are required to describe the pathophysiological processes involved in BOS, and specifically to elucidate potential relationships between airway remodelling, airflow obstruction and allograft failure.

MONTELULAST IMPROVES ASTHMA CONTROL IN ASTHMATIC CHILDREN MAINTAINED ON INHALED CORTICOSTEROIDS

Phipatanakul W, Greene C, Downes SJ, et al. Ann Allergy Asthma Immunol . 2003;91:49–54 To evaluate whether montelukast as adjunctive therapy improves asthma control and whether montelukast has corticosteroid-sparing effects among children treated with low or moderate inhaled corticosteroid (ICS) doses. Thirty-six children, 6 to 14 years of age, with mild/moderate persistent asthma who were being maintained with a stable low or moderate dose of ICS were randomly assigned …