Increasing Inhaled Corticosteroids Dose Research Articles

Urban-rural and socio-economic differences in inhaled corticosteroid treatment for chronic obstructive pulmonary disease: A nationwide register-based cross-sectional study

BackgroundUrban-rural disparities within chronic obstructive pulmonary disease (COPD) have been documented in USA, but not in Europe. Inhaled corticosteroids (ICS) are widely used in COPD despite strict recommendations. We aimed to investigate urban-rural and socioeconomic differences in ICS treatment for COPD. MethodsA Danish nationwide register-based cross-sectional study. All patients alive on the December 31, 2018 with a J44 ICD-10 diagnosis code (COPD) were included (99,057 patients). Daily average ICS dose was calculated from the accumulated ICS use during 2018 based on redeemed prescriptions. Patients were divided into groups: No ICS, low dose ICS, medium dose ICS, high dose ICS. A multinomial logistic regression model including educational level, co-habitation status, age, and sex was performed with “No ICS” as reference group. ResultsCompared to capital municipalities, living in other municipality types was associated with an increased probability of receiving medium and high dose ICS treatment, and increasing odds ratios (ORs) were seen with increasing ICS dose (medium dose ICS: ORs between 1.31 (95 % confidence interval (CI) 1.24–1.38) and 1.35 (95%CI 1.28–1.41), high dose ICS: ORs between 1.73 (95%CI 1.59–1.88) and 1.80 (95%CI 1.68–1.92)). Patients had increased probability of receiving ICS treatment if they were female, were co-habiting, or had completed only primary education. ConclusionPatients with a hospital-registered COPD diagnosis in non-capital municipalities receive more ICS, and in higher doses, compared to patients in capital municipalities. This is the first study to confirm that such urban-rural differences exist in Europe, and further research on this area is warranted.

Adrenal suppression in patients with chronic obstructive pulmonary disease treated with glucocorticoids: Role of specific glucocorticoid receptor polymorphisms.

Single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) gene NR3C1 have been associated with an altered sensitivity to glucocorticoids, and thus may alter the therapeutic effects of glucocorticoids. We investigated the prevalence of adrenal suppression after treatment with glucocorticoids and evaluated whether GR SNPs were associated with altered risks of adrenal suppression and metabolic disorders in patients with chronic obstructive pulmonary disease (COPD). In an observational prospective cohort study, we recruited 78 patients with severe COPD receiving 5 days glucocorticoid treatment for an exacerbation of COPD. In total, 55% of these patients were also receiving regular inhaled corticosteroids (ICS). Adrenal function was evaluated with a corticotropin test 30 days after the exacerbation. Patients were genotyped for Bcl1, N363S, ER22/23EK, and 9β SNPs. The prevalence of adrenal suppression (corticotropin-stimulated plasma-cortisol ≤ 420 nmol/L) 30 days after glucocorticoid treatment was 4/78 (5%). There was no difference between carriers and non-carriers of the polymorphisms (Bcl1, 9β, ER22/23K, and N363S) in corticotropin stimulated plasma-cortisol concentrations. In the haplotype analyses, we included the 50 patients who had a high-sensitivity (76%), a low-sensitivity (4%), or a wild-type (20%) GR haplotype. There was no difference in the frequency of adrenal suppression or metabolic disorders between the two stratified groups: (a) high-sensitivity (Bcl1 and/or N363S) haplotypes vs. (b) low-sensitivity (9β and/or ER22/23K) plus wild-type haplotypes (p > 0.05). Carriers of the high-sensitivity GR gene haplotype exhibited a steeper decline in stimulated P-cortisol with increased ICS dose (slope, -1.35 vs. 0.94; p = 0.17), compared to the group with low-sensitivity or wild-type haplotypes, respectively. In total, 5% of patients exhibited insufficient adrenal function. The Bcl1 and N363S polymorphisms did not seem to increase the risk of glucocorticoid suppression or metabolic disorders in adults treated with glucocorticoids for COPD exacerbations.

Hair cortisol and inhaled corticosteroid use in asthmatic children.

BackgroundAdrenal suppression is a side effect of long‐term use of inhaled corticosteroids (ICS). Hair cortisol concentration (HCC) measurement is a noninvasive tool for measuring adrenal function that may be useful for asthmatic patients who are on long‐term ICS treatment. The aim of this study was to compare HCC between children with and without asthma and to explore the association between HCC and ICS dose in asthmatic children.MethodsA cross‐sectional observational study in subjects with or without asthma (n = 72 and 226, respectively, age 6‐21 years). Hair samples were obtained from the posterior vertex for each subject and data on medication use were collected using questionnaires. HCC was analyzed by liquid chromatography‐mass spectrometry in the most proximal 3 cm of hair.ResultsMedian HCC was significantly lower in subjects with asthma than in subjects without asthma: 1.83 pg/mg and 2.39 pg/mg, respectively (P value after adjustment for age, sex, and body mass index: .036). Median HCC was 1.98 pg/mg in asthmatics using no ICS, 1.84 pg/mg in those using a low dose, 1.75 pg/mg in those on a medium dose, and 1.46 in those using a high ICS dose (P = .54).ConclusionWe observed a significantly lower HCC in asthmatics than in healthy controls and a nonsignificant trend of lower HCC with increasing ICS dose. Whether HCC measurement may be used to detect individuals at risk for hypocortisolism and may be useful to monitor adrenal function in asthmatic children using ICS needs to be further investigated.

Tiotropium bromide: additional options for the treatment of bronchial asthma

Bronchial asthma (BA) is one of the most common chronic diseases, characterized by airway inflammation and bronchospasm. Symptoms of BA are wheezing, shortness of breath, a feeling of constriction in the chest and cough, the frequency and severity of which vary greatly over time. Today studies of BA phenotypes allow selecting treatment depending on the particular pathogenesis of each phenotype individually, thereby helping to achieve control, which is the main goal of BA therapy. However, it is necessary to take into account the peculiarities of airway innervation, since an increased parasympathetic tone is characteristics of all BA phenotypes and plays an important role in the development of bronchoconstriction and inflammation. Therefore, tiotropium bromide, which is a long-acting blocker of muscarinic cholinergic receptors, is one of the main bronchodilators in the treatment of BA. It blocks bronchoconstriction, hypersecretion and swelling of the mucous membrane of the airway, which in turn prevents the progression of inflammation, and the prolonged action of tiotropium bromide, which allows it to be used once a day helps to achieve control of asthma in addition to basic inhalation therapy - inhaled corticosteroids (ICS) long-acting P2-agonists (LABA). According to GINA (Global Initiative for Asthma), tiotropium bromide is recommended as an additional treatment, starting from step 4, and in accordance with the Russian Federal Clinical Guidelines for Bronchial Asthma - from step 3. Currently, according to clinical studies, much is known about the mechanisms of action and biological properties of tiotropium bromide, which made it possible to substantiate the needs for its administration to patients with BA regardless of its phenotype. This strategy will contribute to a more successful control of BA considering risk factors and comorbidity, thereby reducing needs of increasing ICS dose.

Comparative Effectiveness of Step-up Therapies in Children with Asthma Prescribed Inhaled Corticosteroids: A Historical Cohort Study

In children with uncontrolled asthma prescribed low-dose inhaled corticosteroids (ICSs), various step-up options are available: fixed-dose combination ICS/long-acting β2-agonist (FDC), increasing ICS dose, or adding leukotriene receptor antagonist (LTRA). However, evidence of their relative effectiveness is limited. To compare the effectiveness of step-up treatment to FDC in children with asthma versus increased ICS dose, or LTRA. This matched cohort study used UK primary-care databases to study children prescribed their first step-up treatment to FDC, increased ICS dose, or LTRA. A year of baseline data was used for matching and identifying confounders. Outcomes over the following year were examined. The primary outcome was severe exacerbation rate; secondary outcomes included overall asthma control, derived from databases (no asthma-related admissions/hospital attendances/oral corticosteroids or antibiotics prescribed with a respiratory review, and average prescribed salbutamol ≤200 μg/day). There were 971 matched pairs in the FDC and increased ICS dose cohorts (59% males; mean age, 9.4 years) and 785 in the FDC and LTRA cohorts (60% males; mean age, 9.0 years). Exacerbation rates in the outcome year were similar between FDC and increased ICS (adjusted incidence rate ratio [95% CI], 1.09 [0.75-1.59]) and FDC and LTRA (incidence rate ratio, 1.36 [0.93-2.01]). Increased ICS and LTRA significantly reduced the odds of achieving overall asthma control, compared with FDC (odds ratios [95% CI], 0.52 [0.42-0.64] and 0.53 [0.42-0.66], respectively)-this was driven by reduced short-acting beta-agonist use. FDC is as effective as increased ICS or LTRA in reducing severe exacerbation rate, but more effective in achieving asthma control.

Predictive value of exhaled nitric oxide in the management of asthma: a systematic review.

The clinical value of measuring fractional exhaled nitric oxide (FeNO) in asthma is not clear. We aimed to assess whether FeNO can reliably predict clinical outcomes in asthma treated with inhaled corticosteroids (ICS). We also evaluated whether its predictive role is influenced by different inflammatory phenotypes of asthma.We conducted a systematic review focusing on five clinically relevant questions. Two authors independently screened search results, extracted data and assessed quality of the included studies. Data were synthesised by qualitative methods.12 prospective studies were included, answering partly three of the five questions. In steroid-naïve asthma, a high FeNO level probably predicts good response to ICS. In ICS-treated asthmatics, a low FeNO level probably predicts low risk of exacerbation, and the patient is unlikely to benefit from increasing ICS dose. There were scarce data to conclude whether FeNO predicts exacerbations when ICS treatment is stopped in well-controlled asthma. Only one study reported results separately in different asthma phenotypes.The current evidence on the predictive value of FeNO and its role in the management of asthma is incomplete. Future studies should focus on clinically meaningful questions and probably target only eosinophilic phenotypes where FeNO is best associated with the activity of airway inflammation.

Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children.

People with asthma may experience exacerbations or "attacks" during which their symptoms worsen and additional treatment is required. Written action plans may advocate doubling the dose of inhaled steroids in the early stages of an asthma exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. To compare the clinical effectiveness and safety of increased versus stable doses of inhaled corticosteroids (ICS) as part of a patient-initiated action plan for home management of exacerbations in children and adults with persistent asthma. We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) to March 2016. We handsearched respiratory journals and meeting abstracts. We included randomised controlled trials (RCTs) that compared increased versus stable doses of ICS for home management of asthma exacerbations. We included studies of children or adults with persistent asthma who were receiving daily maintenance ICS. Two review authors independently selected trials, assessed quality and extracted data. We contacted authors of RCTs for additional information. This review update added three new studies including 419 participants to the review. In total, we identified eight RCTs, most of which were at low risk of bias, involving 1669 participants with mild to moderate asthma. We included three paediatric (n = 422) and five adult (n = 1247) studies; six were parallel-group trials and two had a cross-over design. All but one study followed participants for six months to one year. Allowed maintenance doses of ICS varied in adult and paediatric studies, as did use of concomitant medications and doses of ICS initiated during exacerbations. Investigators gave participants a study inhaler containing additional ICS or placebo to be started as part of an action plan for treatment of exacerbations.The odds of treatment failure, defined as the need for oral corticosteroids, were not significantly reduced among those randomised to increased ICS compared with those taking their usual stable maintenance dose (odds ratio (OR) 0.89, 95% confidence interval (CI) 0.68 to 1.18; participants = 1520; studies = 7). When we analysed only people who actually took their study inhaler for an exacerbation, we found much variation between study results but the evidence did not show a significant benefit of increasing ICS dose (OR 0.84, 95% CI 0.54 to 1.30; participants = 766; studies = 7). The odds of having an unscheduled physician visit (OR 0.96, 95% CI 0.66 to 1.41; participants = 931; studies = 3) or acute visit (Peto OR 0.98, 95% CI 0.24 to 3.98; participants = 450; studies = 3) were not significantly reduced by an increased versus stable dose of ICS, and evidence was insufficient to permit assessment of impact on the duration of exacerbation; our ability to draw conclusions from these outcomes was limited by the number of studies reporting these events and by the number of events included in the analyses. The odds of serious events (OR 1.69, 95% CI 0.77 to 3.71; participants = 394; studies = 2) and non-serious events, such as oral irritation, headaches and changes in appetite (OR 2.15, 95% CI 0.68 to 6.73; participants = 142; studies = 2), were neither increased nor decreased significantly by increased versus stable doses of ICS during an exacerbation. Too few studies are available to allow firm conclusions on the basis of subgroup analyses conducted to investigate the impact of age, time to treatment initiation, doses used, smoking history and the fold increase of ICS on the magnitude of effect; yet, effect size appears similar in children and adults. Current evidence does not support increasing the dose of ICS as part of a self initiated action plan to treat exacerbations in adults and children with mild to moderate asthma. Increased ICS dose is not associated with a statistically significant reduction in the odds of requiring rescue oral corticosteroids for the exacerbation, or of having adverse events, compared with a stable ICS dose. Wide confidence intervals for several outcomes mean we cannot rule out possible benefits of this approach.

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

Long-acting muscarinic antagonists (LAMA), a class of drugs with proven effectiveness in chronic obstructive pulmonary disease (COPD), are being considered as an add-on option for adults with asthma whose condition is uncontrolled on inhaled corticosteroids (ICS). It is important to assess the safety and efficacy of LAMA add-on as an alternative to the prolonged use of higher doses of ICS, which are known to cause undesirable side effects in some people. To compare the effects of adding a LAMA to any dose of ICS versus increasing the dose of ICS, for uncontrolled asthma in adults. We searched the Cochrane Airways Group Specialised Register (CAGR) from its inception in 1995 to April 2015, imposing no restriction on language of publication. We also handsearched trial registries, reference lists of primary studies and existing reviews, as well as manufacturers' websites. We looked for parallel or cross-over randomised controlled trials lasting at least 12 weeks, in which adults whose asthma was not well controlled on ICS alone were randomised to treatment with LAMA add-on to ICS or with an increased dose of ICS. Trials were excluded if patients were taking long-acting beta2-agonists during the study period. Two review authors independently screened the searches and extracted data from studies meeting all the inclusion criteria. We used Covidence to manage duplicate screening, data extraction and risk of bias judgements, and to form a consensus where discrepancies arose. We used standard methods expected by The Cochrane Collaboration.The pre-specified primary outcomes were exacerbations requiring a course of oral corticosteroids (OCS), effects on quality of life and serious adverse events. One cross-over randomised controlled trial met the inclusion criteria. The trial was performed in 210 patients with moderate to severe asthma and compared the use of the LAMA tiotropium bromide with double dose beclomethasone (an ICS) using a cross-over design and 14-week treatment periods.Compared with people taking a double dose of ICS, fewer people taking a LAMA add-on had an exacerbation requiring treatment with OCS (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.22 to 1.43) or an exacerbation resulting in emergency department admission (OR 0.49, 95% CI 0.09 to 2.77), but the confidence intervals for both outcomes did not exclude the possibility that double dose ICS was more effective. Serious adverse events and exacerbations requiring hospitalisation occurred in similarly low numbers of people taking each treatment, but confidence intervals were too wide to suggest that the two treatment options were equivalent.Asthma-related quality of life was similar in both treatment groups (mean difference (MD) in change from baseline 0.10, 95% CI - 0.07 to 0.27). Those taking LAMA add-on scored slightly better on a scale measuring asthma control than those increasing their ICS dose (MD in change from baseline - 0.18, 95% CI - 0.34 to - 0.02), although the difference was clinically small. Evidence was deemed low quality for both quality of life and asthma control.There was moderate-quality evidence that participants' trough forced expiratory volume in one second (FEV1) was 100 mL better when taking LAMA add-on than with increased ICS dose (MD in change from baseline 0.10, 95% CI 0.03 to 0.17). Only one randomised trial was found, comparing tiotropium add-on to increased dose beclomethasone. Differences between the treatments were too small or imprecise to understand whether adding a LAMA to ICS is safer or more effective than increasing the dose of ICS, and there is a possibility of carry-over effects due to the study's cross-over design. LAMA add-on may lead to more improvement in lung function (FEV1) than an increased dose of ICS.The results of this review, alongside pending results from related reviews assessing the use of LAMA against other treatments, will help to define the role of these drugs in asthma management, and this review should be updated as results from future trials emerge. Studies assessing the role of LAMA add-on should be longer and include a double-ICS treatment arm so that the results can be interpreted in the context of the guideline-recommended treatment options that are available to physicians.

Early intervention with high-dose inhaled corticosteroids for control of acute asthma exacerbations at home and improved outcomes: A randomized controlled trial

Various studies have examined the efficacy of a temporary increase in the dose of inhaled corticosteroids (ICSs) during acute asthma exacerbations with conflicting results. This study was designed to investigate the efficacy of high-dose ICSs in controlling asthma exacerbations in children. Data were collected on asthmatic children, aged 2-17 years, who were maintained on ICSs. Participants were randomly assigned to a 12-day treatment protocol for acute asthma exacerbation at doses of ICS that were two, four, or eight times their maintenance ICS dose. The primary outcome was the frequency of need to progress to systemic steroid therapy. The secondary outcome was difference in symptom scores among the three treatment groups to determine if one dosing protocol was superior to another. Eighty-two of 197 enrolled patients experienced acute asthma exacerbation and completed the increased dosing protocol. No significant difference in systemic corticosteroid use was detected between patients treated with two, four, or eight times their maintenance dose of ICS, but we observed a trend toward a larger reduction in mean total symptom score with increasing ICS dose at the end of the study. We did not observe a significant difference in need for systemic corticosteroids between doubling the maintenance dose and increasing to four or eight times the dose, but we observed a trend suggesting that higher doses may improve symptoms better than doubling the dose. A more specific design may be needed to provide a more reliable answer to this question.

Inflammatory and functional effects of increasing asthma treatment with formoterol or double dose budesonide

Adding a long-acting beta(2)-agonist to inhaled corticosteroids (ICS) for asthma treatment is better than increasing ICS dose in improving clinical status, although there is no consensus about the impact of this regimen on inflammation. In this double-blind, randomized, parallel group study, asthmatics with moderate to severe disease used budesonide (400 mcg/day) for 5 weeks (run-in period); then they were randomized to use budesonide (800 mcg/day--BUD group) or budesonide plus formoterol (400 mcg and 24 mcg/day, respectively--FORMO group) for 9 weeks (treatment period). Home PEF measurements, symptom daily reporting, spirometry, sputum induction (for differential cell counts and sputum cell cultures), and hypertonic saline bronchial challenge test were performed before and after treatments. TNF-alpha, IL-4 and eotaxin-2 levels in the sputum and cell culture supernatants were determined. Morning and night PEF values increased in the FORMO group during the treatment period (p<0.01), from 435+/-162 to 489+/-169 and 428+/-160 to 496+/-173 L/min, respectively. The rate of exacerbations in the FORMO group was lower than in the BUD group (p<0.05). Neutrophil counts in sputum increased in both groups (p<0.05) and leukocyte viability after 48 h-culture increased in the FORMO group (p<0.05). No other parameter changed significantly in either group. This study showed that adding formoterol to budesonide improved home PEF and provided protection from exacerbations, although increase of leukocyte viability in cell culture may be a matter of concern and needs further investigation.

ABS006: Montelukast add-on therapy compared to high-dose inhaled corticosteroids in children age 2-5 yrs with asthma: a retrospective study

For children aged 2–5 with asthma uncontrolled on standard doses of inhaled corticosteroids (ICS), options include addition of montelukast or higher-dose ICS. To compare outcomes in children stepping up to either treatment, utilizing the General Practice Research Database. Asthmatic children aged 2–5 yrs. treated by ICS (200 mcg/day beclomethasone equivalent or less) whose first treatment increase was addition of montelukast or increased-dose ICS, having 12 months data before and after step-up were identified. Successful treatment was defined as: no recorded hospital attendance, no oral corticosteroids, average use of short acting B agonist (SABA) of under 1dose/day over 1 year. Montelukast (n = 127) and ICS (n = 3596) cohorts were similar in age and sex, and prior to step-up had similar asthma consultations, respiratory hospitalisations, antibiotics use for respiratory infections; montelukast cohort used more SABA devices, median (IQR) 3 (2–5) vs. 2 (1–4) p > 0.000, and more oral steroid courses, 0 (0–0) vs. 0 (0–0), average 0.68 v 0.52, p = 0.019, and a lower proportion had rhinitis (5% vs. 13%, p = 0.004). In the 12 month outcome period, the montelukast cohort showed non significant trends to fewer SABA devices: 2 (1–4) vs. 3 (1–4) p = 0.203 and oral steroid courses: 0 (0–0) vs. 0 (0–1), average 0.39 vs. 0.44, p = 0.431. No significant differencesvin asthma consultations, respiratory hospitalisation or use of antibiotics. Successful treatment was observed for 33% of LTRA and 25% of ICS cohort (p = 0.052). Adjusted for baseline differences, the odds ratio (95% CI) for success with LTRA compared to ICS was 1.9 (1.3–2.8) p = 0.002. In this ‘real-work’ database, patients stepped up by montelukast addition had an almost doubled chance of successful treatment over those increasing ICS dose. Conflict of interest and funding No conflict of interest declared. Funding: MSD UK.

High fractional concentration of nitric oxide in exhaled air despite steroid treatment in asthmatic children

The fractional concentration of nitric oxide in exhaled air (FENO) is elevated in atopic asthma and typically responds to treatment with inhaled corticosteroids (ICS). However, some patients have persistently high FENO levels despite treatment. We studied how optimizing the inhalation technique and increasing ICS doses would affect FENO in stable atopic asthmatic children who had elevated FENO while using ICS. In 41 stable asthmatic children who were treated with ICS (median daily dose 800 microg budesonide equivalent, range 100-1600 microg) and maintained FENO> or =20 p.p.b., we optimized the inhalation technique by thorough instruction and measured FENO 2 weeks later. Then, if FENO remained > or =20 p.p.b., we increased the ICS dose and reassessed FENO 2 weeks later. Improving the inhalation technique did not reduce FENO. Increasing ICS from a daily median dose of 800 to 1200 microg budesonide had no significant effect on FENO. FENO correlated positively with symptom scores in the following 2 and 4 weeks (P=0.001, 0.002) and beta2-agonist use the 2 and 4 weeks following FENO measurement (P=0.02, 0.004). We conclude that common steps in asthma treatment, i.e. inhalation instruction and increasing ICS dose, were both ineffective in reducing FENO in atopic asthmatic children with elevated FENO values despite treatment with ICS. This implies that FENO cannot simply be incorporated in current treatment guidelines.

Bone mineral density in women with asthma on long-term inhaled corticosteroid therapy.

Inhaled corticosteroids (ICS) have become first line agents in the management of moderate-to-severe asthma. Long-term use of ICS is associated with decreased bone mineral density (BMD). To investigate the prevalence of BMD loss and its severity in women with asthma on long-term ICS. Fifty-six women with asthma on long-term ICS, attending an inner-city allergy clinic were selected to undergo bone densitometry in order to evaluate the association between BMD and the long-term use of ICS at different dose ranges. Women (60.7%) had decreased BMD either at the lumbar spine or hip region. Among postmenopausal women, 17.1% of those <65 years and 42.9% of those > or =65 years had osteoporosis compared with 5.7% (95% CI-3.9% to 8.5%) of those <65 and 29.3% (95% CI-25.7%-33.5%) of those > or =65 years reported in the NHANES III survey. The prevalence of low BMD increased as ICS dose increased from 5% in the low dose group to 50% in the high dose group (P < .002). There were significant linear trends of decline by dose in mean BMD for the hip (P < .001) and the lumbar spine (P < .002). Women who received medium or high doses of ICS had significantly greater bone loss than those receiving low doses. The findings of increasing BMD loss with increasing ICS dose reinforce the necessity to monitor BMD periodically in women on ICS, particularly in the high risk postmenopausal group and those on medium to high doses. There should be a concurrent continual attempt to lower the dose by supplemental nonsteroidal controller medications and providing nutritional and pharmacologic treatment of identified BMD loss in these patients.