High Inhaled Corticosteroids Research Articles

Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? A randomized, parallel group study

BackgroundWhile most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling.Methods22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.ResultsFP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP.Conclusions200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.

Adrenal suppression: A practical guide to the screening and management of this under-recognized complication of inhaled corticosteroid therapy

Inhaled corticosteroids (ICSs) are the most effective anti-inflammatory agents available for the treatment of asthma and represent the mainstay of therapy for most patients with the disease. Although these medications are considered safe at low-to-moderate doses, safety concerns with prolonged use of high ICS doses remain; among these concerns is the risk of adrenal suppression (AS). AS is a condition characterized by the inability to produce adequate amounts of the glucocorticoid, cortisol, which is critical during periods of physiological stress. It is a proven, yet under-recognized, complication of most forms of glucocorticoid therapy that can persist for up to 1 year after cessation of corticosteroid treatment. If left unnoticed, AS can lead to significant morbidity and even mortality. More than 60 recent cases of AS have been described in the literature and almost all cases have involved children being treated with ≥500 μg/day of fluticasone.The risk for AS can be minimized through increased awareness and early recognition of at-risk patients, regular patient follow-up to ensure that the lowest effective ICS doses are being utilized to control asthma symptoms, and by choosing an ICS medication with minimal adrenal effects. Screening for AS should be considered in any child with symptoms of AS, children using high ICS doses, or those with a history of prolonged oral corticosteroid use. Cases of AS should be managed in consultation with a pediatric endocrinologist whenever possible. In patients with proven AS, stress steroid dosing during times of illness or surgery is needed to simulate the protective endogenous elevations in cortisol levels that occur with physiological stress.This article provides an overview of current literature on AS as well as practical recommendations for the prevention, screening and management of this serious complication of ICS therapy.

Asthma and Pregnancy

Asthma is probably the most common serious medical disorder that may complicate pregnancy. A third of pregnant women with asthma will experience worsening of their symptoms, a third will see improvement of their symptoms and a third will see no change. The primary goal is to maintain optimal control of asthma for maternal health and well-being as well as fetal maturation. Vital patient education should cover the use of controller medication, avoidance of asthma triggers and early treatment of asthma exacerbations. Proper asthma management should ideally be started in the preconception period. Since smoking is probably the most modifiable risk factor of asthma, pregnant woman should avoid active and passive smoking. Acute asthma exacerbation during the first trimester is associated with an increased risk of congenital malformations. Poorly controlled asthma is associated with low birth weight, preeclampsia, and preterm birth. Medications used for asthma control in the non-pregnant population are generally the same in pregnancy with a few exceptions. Inhaled corticosteroids (ICS) are the preferred controller therapy. Budesonide is the preferred ICS. Long-acting B-agonists (LABA) are the preferred add-on therapy to medium to high dose ICS. Major triggers for asthma exacerbations during pregnancy are viral infections and ICS nonadherence.

Do migrant studies help to identify causes of asthma?

Do migrant studies help to identify causes of asthma?

Comparing the clinical efficacy and safety of high doses of beclomethasone inhaler with medium doses of beclomethasone inhaler combined with oral aminophylline or montelukast tablets in persistent asthmatic Iraqi patients.

Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The treatment guidelines recommend theuse of a second controller drug in addition to medium doses of inhaled corticosteroids (ICSs) rather than the use of high doses ICS alone in the treatment of moderate-severe persistent asthma. This study was conducted to compare the clinical efficacy and safety of three treatment regimens in Iraqi patients with moderate-severe persistent asthma.The study included three groups; each group included 15 patients. Patients were administered beclomethasone inhaler alone 1500-2000 μg/day, beclomethasone inhaler 750-1000 μg/day plus oral controlled release aminophylline tablets 450 mg/day or beclomethasone inhaler 750-1000 μg/dayplus oral montelukast tablets 10 mg/day for 4-5 weeks. Patients were followed 2 weeks and 4-5 weeks after the baseline visit. In all of the three groups,significant improvements were noticed in pulmonary function test parameters (FEV1, FVC, FEF50%) and the asthma symptom records (day-time symptoms,night-time symptoms, number of salbutamol puffs per 24 hours), while there were no significant differences among the groups. Regarding side effects, onlythe group of inhaled steroid plus aminophylline tablets showed discontinuation of drug therapy in some patients which could be attributed to the development of serious side effects.It was concluded that the administration of a second controller agent was important to use lower doses of inhaled beclomethasone. It was concluded alsothat montelukast was associated with a lower incidence of serious side effects than aminophylline which could make aminophylline an alternative to montelukast as combination therapy with medium doses ICS in the treatment of moderate-severe persistent asthma

Increased use of inhaled corticosteroids among young Danish adult asthmatics: An observational study

This population-based longitudinal study aimed to investigate trends in use of inhaled corticosteroids (ICS) and determinants of ICS use in young Danish adults with asthma. 106 757 users, aged 18-44 years, of anti-asthmatic drugs were identified in the Danish Register of Medical Product Statistics during 1997-2006. One year prevalences of ICS use were calculated in categories of gender, age, and annual consumption of inhaled beta-2-agonists (IBA) in defined daily doses (DDD) per year. Determinants of ICS use were estimated by logistic regression models. The one year prevalence of ICS use was constant, approximately 64%, during 1997-2000. An annual increase was observed from 67% in 2001 to 77% in 2006. This trend also existed when stratifying on gender, age and IBA use. Using 1997 as baseline, the adjusted odds ratios (ORs) of ICS use in 2000 was 0.98 (95% CI 0.96-1.01) compared to 1.12 (95% CI 1.09-1.15) in 2001, and 1.81 (95% CI 1.75-1.87) in 2006. Other determinants of high ICS use were female gender, young age, and high annual IBA consumption. Among those using at least 400 DDD of IBA per year (corresponding to 4.4 powder inhalations daily), nearly 20% had no ICS prescriptions in 2006. Treatment with ICS among young Danish adult asthmatics has increased since 2001. This apparent improvement was associated with the introduction of fixed dose combination inhalers with ICS and inhaled long-acting beta-2-agonists. However, there is still room for improvement.

A one-year prospective study of infectious etiology in patients hospitalized with acute exacerbations of COPD and concomitant pneumonia

SummaryAimThis study assessed the infectious etiology of patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) with concomitant pneumonia.MethodsPatients admitted to medical wards in an acute hospital were recruited prospectively from May 1, 2004 to April 30, 2005. Sputum culture, blood culture, paired serology, and nasopharyngeal aspirates (NPA) viral culture and polymerase chain reaction (PCR) studies were performed. Spirometry was assessed in stable phase at 2–3 months post-hospital discharge.ResultsSeventy eight subjects were admitted for AECOPD with concomitant pneumonia. The mean (SD) age was 77.1 (7.5) years, with FEV1 of 41.5 (20.8)% predicted normal. Overall, an infectious etiology could be established in 48.7% of the subjects. Among the 71 subjects with sputum collected, 40.8% had positive bacterial culture. The commonest bacteria identified were Streptococcus pneumoniae (8[11.3%]), Pseudomonas aeruginosa (7[9.9%]) and Haemophilus influenzae (7[9.9%]). Among the 66 subjects with NPA collected, 9.0 and 12.2% had positive viral culture and PCR results, respectively. The commonest viruses identified by NPA PCR were influenza A (4[6.1%] subjects) and rhinovirus (2[3.0%]). Paired serology was positive in 4.4%. Patients on high dose inhaled corticosteroid (ICS) (>1000 mcg beclomethasone-equivalent/day) had a higher rate of positive sputum bacterial culture than those on low-medium dose of ICS (50.0% vs 18.2%, p = 0.02).ConclusionAn infectious etiology could be established in about half of patients hospitalized with AECOPD and concomitant pneumonia. The majority of identifiable causes were bacterial. Patients on high dose ICS might have impaired airway defense as reflected by the higher rate of positive sputum culture.

A self-rating scale for patient-perceived side effects of inhaled corticosteroids

BackgroundPatient-reported side effect questionnaires offer a simple method for the systematic measurement of drug-related side effects. In order to measure patients' inhaled corticosteroids (ICS) related side effect perceptions the 14-day retrospective Inhaled Corticosteroid Questionnaire (ICQ) was developed. In this research we aim to assess the construct validity and reliability of the ICQ and test its responsiveness to dose changes in adult asthma patients.MethodsIn a cross-sectional study, current inhaler users with asthma completed the ICQ (27 with non ICS inhaler; 61 BDP equivalent daily ICS low dose ≤400 μg; 62 mid dose 401–800 μg; and 105 with high dose >800 μg). We generated 3 construct validity hypotheses: 1) a hierarchical dose-response pattern for scoring of the individual items on the ICQ, and statistically significant differences in the scores of each of the 15 ICQ domains by ICS dose group 2) an association between ICS dose and ICQ scoring after adjusting for appropriate confounders in multiple regression; 3) greater convergence between local side effect domains than between systemic and local domains of the scale. Test-retest reliability was assessed on a randomly selected subgroup of patients (n = 73) who also completed the ICQ a second time after 7 days. In a separate longitudinal study, 61 patients with asthma completed the ICQ at baseline and after changing their daily ICS dose, at 2- and 6- months, in order to test the ICQ's responsiveness.ResultsAll three construct validity hypotheses were well supported: 1) a statistically significant difference existed in scores for 14 domains, the high ICS dose group scoring highest; 2) ICS dose independently predicted ICQ scoring after adjusting for confounders; 3) greater convergence existed between local ICQ domains than between local and systemic domains. The ICQ had good reproducibility: test-retest intraclass correlation coefficients were ≥0.69 for all but the 'Facial Oedema' domain. In the longitudinal study, ICQ scores for 'Voice Problems' changed significantly at 2- and 6-months from baseline and other ICQ domains displayed trends in scoring change accordant with dose modulation at 6-months.ConclusionThe ICQ has good dose-related discriminative properties, is valid, reliable, and shows potential responsiveness to ICS dose change.

High-dose inhaled corticosteroids and add-on therapy use in adults with asthma in the UK in 2003: an observational study

To quantify use of high dose inhaled corticosteroids (ICS) and add-on therapy in adults, and children aged 12 and over, in the community. Cross-sectional observational survey of UK general practice prescribing records from July 2002 to June 2003 utilising the Doctors Independent Network clinical database. 30,895 patients aged 12 and over were treated for asthma with inhaled corticosteroids, with a quantifiable daily dose recommendation in 22,027 cases. Twenty-seven percent (95% Confidence Intervals 26-28%) were prescribed 'high-dose' ICS (>800 mcg/day beclomethasone or equivalent). Of these, 32% (31-33%) were not currently prescribed add-on therapy (long acting B2 agonists, leukotriene antagonists, theophylines), and most of these (84%, 82-86%) had never received a prior trial of add-on therapy. High dose ICS therapy was commonly prescribed to people with asthma, frequently without co-prescribed add-on therapy. Many adults with more severe asthma may be receiving treatment that does not accord with current evidence of best practice.

Higher patient perceived side effects related to higher daily doses of inhaled corticosteroids in the community: A cross-sectional analysis

The range and extent of inhaled corticosteroid (ICS) side effects experienced by patients in the general community are likely to be underestimated. To identify the side effects of ICS perceived by patients in the community and, through the use of a self-report questionnaire, measure their intensity, prevalence and relationship with daily medication dose. Focus groups and in-depth interviews were conducted to identify side effects that patients associated with their use of ICS. In an international multicentre cross-sectional survey, 395 inhaler users from community pharmacy (mean age 50, 53% female), divided into 4 daily dosage groups (beta2-agonist without ICS n=66, beclometasone dipropionate (BDP) equivalent ICS low dose 400 microg, n=109; mid dose 401-800 microg, n=151; and high dose>800 microg, n=69) reported how much they were affected by these side effects on a 7-point Likert scale. Focus groups and interviews revealed 57 side effects that were associated with ICS use. Cross-sectional survey results showed significant differences in side effect perception between the four dosage groups for 31 items (all P0.01) and a rising intensity with increasing ICS dose for total side effect score (P<0.001). For ICS users reporting the most bothersome side effects (scoring 3 on 0-6 scale) there was a rising prevalence as ICS dose increased for 34 items. A multivariate model confirmed that mid and high ICS dosages were statistically significantly associated with side effect perception after controlling for the other factors and covariates. Higher daily ICS doses were associated with a higher intensity and a higher prevalence of many patient perceived side effects, lending support to the call for dose titration in clinical practice. Results indicate the usefulness of patient self-report scales for understanding the burden of side effects of ICS in the community.

High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children.

Inhaled corticosteroids (ICS) form the basis of maintenance therapy in asthma and their efficacy is well established. However, the optimal starting dose of ICS is not clearly established. Recent reviews demonstrate a relatively flat efficacy curve for ICS and increasing side effects with increasing ICS doses. High doses are frequently prescribed and there are now reports of significant side effects occurring with high dose ICS use. These issues demonstrate the need to establish the optimal starting dose of ICS in asthma. To establish the optimal starting dose of ICS by evaluating the efficacy of initial high dose ICS with low dose ICS in subjects with asthma, not currently on ICS. We searched the Cochrane Airways Group trials register and reference lists of articles. Date of last search: January 2003 Randomised controlled trials of two different doses of the same ICS in adults and children with asthma with no concomitant ICS or OCS. Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. Trials were analysed according to the following ICS dose comparisons: step down vs constant dose ICS (n=7); high vs moderate (n=11); high vs low (n=9); moderate vs low (n=11); fold change in dose (all studies). 31 papers reporting the results of 26 trials were included in the review. For studies that compared a step down approach to a constant moderate/low ICS dose, there were no significant differences in lung function, symptoms, rescue medications or asthma control between the two treatment approaches. Significant but clinically small improvements in percent predicted FEV(1) ( WMD 5.32, 95% CI 0.65 to 9.99) and non significant improvements in the change in morning PEF were found for high dose ICS compared to moderate dose ICS. There were no significant differences in efficacy between high and low dose ICS. For moderate dose ICS, compared to low dose ICS, there were significant improvements in the change in morning PEF l/min from baseline (WMD 11.14, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06 ). Commencing ICS at double or quadruple a base moderate or low dose had no greater effect than commencing with the base dose. Several studies reported greater improvement in airway hyperresponsiveness for high dose ICS. For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.

Airway Responsiveness to Adenosine 5′-Monophosphate and Exhaled Nitric Oxide Measurements: Predictive Value as Markers for Reducing the Dose of Inhaled Corticosteroids in Asthmatic Subjects

To investigate the utility of the determination of airway responsiveness to inhaled adenosine 5'-monophosphate (AMP) and exhaled nitric oxide (ENO) levels as markers for safely reducing the dose of inhaled corticosteroids (ICS) in patients with asthma well controlled with a moderately high ICS dose. A total of 37 patients with asthma well controlled for at least 3 months by treatment with a moderately high ICS dose (beclomethasone dipropionate, 500 to 1,000 microg or equivalent daily) were included in the study. Patients were treated for a 2-week run-in (baseline) period with their usual dose of ICS. For the next 12 weeks, patients were treated with ICS at half the previous dose, maintaining the same inhalation device. At the end of the baseline period and after 2 weeks, 8 weeks, and 12 weeks of treatment with a reduced dose of ICS, measurements were made in the following order: ENO, spirometry, and AMP challenge. Furthermore, patients completed a diary twice daily recording peak expiratory flow, daytime and nighttime symptoms, and use of rescue albuterol. Ten patients had an asthma exacerbation. Using a Kaplan-Meier survival analysis, the significant predictors of a failure of ICS reduction were having both bronchoconstriction in response to AMP and ENO levels > or = 15 parts per billion (ppb) at baseline (p = 0.006), as well as having both bronchoconstriction in response to AMP and ENO levels > or = 20 ppb at baseline (p = 0.033). Having a decrease in the provocative concentration of AMP causing a 20% fall in FEV(1) of at least one doubling concentration 2 weeks after the dose of ICS was halved was a borderline significant predictor for failure of ICS reduction (p = 0.062). These observations suggest that in asthmatic patients well controlled with ICS, the determination of AMP responsiveness and ENO levels may be useful to identifying those subjects whose condition will or will not deteriorate when the dose of ICS is reduced.

Asthma Severity, Psychiatric Morbidity, and Quality of Life: Correlation with Inhaled Corticosteroid Dose

Objectives. Psychiatric phenomena in asthma has been debated for some time. Inhaled corticosteroids (ICS) are a significant part of treatment. We attempted to quantify the prevalence of psychiatric morbidity relative to asthma severity, quality of life (QOL), and ICS dose. Data Sources. Fifty asthmatic patients (18 ≥ X ≤ 75 years) on ICS, attending an urban clinic had asthma and ICS dose stratified by symptom severity and preparation potency. Peak flow and forced expiratory volume in 1 second (FEV1) were measured. Patients completed general QOL and disease-specific QOL questionnaires, along with psychiatric rating scales. Results. Patients (n = 50) clustered in the 40–59 year range (n = 27, 54%) and were predominantly female (n = 44, 88%) Hispanics (n = 30, 60%), with mild-moderate asthma (n = 18, 36%) and on low-dose ICS (n = 22, 44%). FEV1 ranged from 32 to 123 (mean 76.98, SE 3.01). Peak flow ranged from 210 to 590 (mean 407.83, SE 13.24). Prevalence of anxiety and depressive symptoms were higher than expected (Kendall's tau-c, n = 50, P < .01). Independently, high ICS dose and asthma severity correlated directly with all measures of psychiatric morbidity (Pearson's r 0.781, P < .01). High ICS dose correlated inversely with SF-36 Mental Component Scale (Pearson's r 0.681, P < .01) and directly with FEV1 and peak flow when age/sex adjusted (Spearman's rho: 0.660, P < .001). Conclusions. Psychiatric morbidity is more prevalent in this population and impacts negatively on QOL. Use of high-dose ICS benefited pulmonary function and “physical” QOL, yet may have negatively affected patients' mental well-being. Longitudinal follow-up, extension of sample size, and better study control would allow closer approximation of possible negative associations with ICS.

Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom

Background: Until recently, only two cases of acute adrenal crisis associated with inhaled corticosteroids (ICS) had been reported worldwide. We identified four additional cases and sought to survey the frequency...

TNF-alpha dysregulation in asthma: relationship to ongoing corticosteroidtherapy.

Tumour necrosis factor-alpha (TNF-alpha) is a major proinflammatory cytokine that is thought to be important in the pathogenesis of asthma. However, alterations in systemic regulation of this cytokine in asthma have not been examined in the context of corticosteroid therapy. To examine the ability of peripheral blood mononuclear cells (PBMC) from three different groups of patients with asthma requiring varying amounts of inhaled corticosteroids (ICS) for clinical control, and to examine cells from age- and sex-matched nonasthmatic patients to produce TNF-alpha. All patients with asthma had a positive methacholine challenge test. 'High dose' ICS patients with asthma required ICS greater than or equal to 800 microg/day. 'Medium dose' patients with asthma were on less than or equal to 500 microg/day of ICS, whereas 'no ICS' patients with asthma had received no ICS for at least three months. Each patient with asthma was examined in parallel with an age- and sex-matched, nonasthmatic, nonatopic control subject. Cells were cultured (with or without the addition of potential stimulators phytohemagglutinin, lipopolysaccharide, formyl-methionine-leucine-phenylalanine or antihuman CD3), and TNF-alpha production was assessed by ELISA. PBMC from both high dose ICS (n=8) and no ICS (n=11) patients with asthma produced more than twice the amount of TNF-alpha than cells from matched nonasthmatic control patients (P<0.01) when cultured alone or in the presence of each stimulus (P<0.05). In contrast, there was no significant difference in TNF-alpha production between medium dose ICS patients with asthma and control patients. A group of asymptomatic atopic patients (n=6) did not have an increased level of TNF-alpha production. Increases in TNF-a production within the PBMC compartment can be observed in both patients with asthma receiving high dose ICS and in a group of patients with mild asthma receiving no ICS therapy, but not in patients with asthma receiving a medium dose of ICS or atopic patients.