Withdrawal Of Inhaled Corticosteroids Research Articles

Effects of steroid therapy on inflammatory cell subtypes in asthma

RationaleAirway inflammation in asthma is heterogeneous with different phenotypes. The inflammatory cell phenotype is modified by corticosteroids and smoking. Steroid therapy is beneficial in eosinophilic asthma (EA), but evidence is...

Changes in Exhaled Nitric Oxide and Breath pH during Fluticasone Wean in Asthma

Background: Inhaled corticosteroid (ICS) therapy improves asthma outcome. Both the anti-inflammatory efficacy and toxicities of ICS therapy are dose dependent. Therefore, there is interest in monitoring airway inflammation during ICS dose adjustments. Objective: Fraction of expired nitric oxide (FENO) and exhaled breath condensate (EBC) pH were studied as noninvasive, corticosteroid-responsive markers of airway inflammation. Methods:We prospectively studied the effect of stepwise ICS wean on FENO and EBC pH over 6 months in otherwise healthy adults with moderate persistent asthma. Results:Eighteen subjects completed the initial dose titration and 13 completed the protocol. Of these, 7 weaned off ICS completely and 6 had exacerbations. FENO rose significantly with ICS withdrawal, though there was heterogeneity in the starting level and the degree of rise. EBC pH was collected at home in all subjects and fell more in subjects who had an exacerbation than in those who did not. The decrease in pH was associated with hazard of exacerbation. Conclusion: FENO can be a patient-specific index of airway inflammation during ICS dose titration; change in EBC pH is one home marker that might possibly be used during ICS dose titration. However, additional studies are required.

ICS and COPD: Time to clear the air

The debate about what constitutes the correct treatment for COPD has recently intensified.1 This discussion has grumbled on ever since the first multicenter trials using inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) such as the European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP) and Inhaled Steroids in Obstructive Lung Disease (ISOLDE) were published in the late 1990’s and the results of trials such as TORCH (TOwards a Revolution in COPD Health) using combination products has only added to the confusion. Complex debate predominantly pertaining to statistical methodology has muddied the waters. Concepts such as immortal time bias and selection bias introducing regression to the mean are often too difficult to grasp for the average reader. However, some of the methodological flaws identified by Suissa and colleagues2 are much easier to understand and solutions to these are potentially at hand. Firstly, it is clear trials investigating the effects of ICS on COPD may in fact be trials predominantly examining the effects of ICS withdrawal. It is not sufficient to state a treatment works simply because patients deteriorate when that treatment is withdrawn. Re-analysis of all data such that treatment effects are stratified according to pre-use of ICS is easy to do as all the data is there, as Suissa eloquently showed in his re-working of the OPTIMAL trial data.3 Even though most of the ICS/COPD trials have approximately 50% of subjects on ICS at randomization, some have a much lower rate, such as in Szfranski and colleagues4 (26%) and this may not necessarily skew the overall conclusions of the trial(s). Secondly, when assessing the impact of combination treatments it is imperative to present the correct 2 × 2 factorial analysis such that the impact of each individual component can be assessed as Suissa performed for TORCH.2 Thus it becomes clear the effect on mortality may be entirely long-acting β-agonists (LABA) dependant. The issue of systemic side effects and pneumonia in COPD patients treated with high doses of ICS over long periods also needs further careful evaluation. It would be disingenuous of us to suggest ICS have no place in the management of COPD. We know a proportion of patients benefit from their bronchoprotective effect and that this subset of patients with COPD has a higher mortality risk.5 ICS are also indicated in the patients with more reversible COPD who probably suffer from concomitant asthma. It is time that some fundamental issues are addressed. We strongly urge the pharmaceutical industry to re-analyze the underlying data and demystify at least some of the methodological smog.

Loss of Control of Asthma Following Inhaled Corticosteroid Withdrawal Is Associated With Increased Sputum Interleukin-8 and Neutrophils

The role of neutrophils in exacerbations of asthma is poorly understood. We examined the effect of withdrawal of inhaled corticosteroids on sputum inflammatory indexes in a double-blind study in patients with moderate, stable asthma. Following a 2-week run in period, 24 subjects were randomized to receive either budesonide (400 microg bid) or placebo, and the study was continued for another 10 weeks. Loss of asthma control developed in 8 of 12 patients over the 10-week period of steroid withdrawal, whereas only 1 of 10 patients with budesonide treatment had exacerbations. Those with an exacerbation had increased sputum interleukin (IL)-8 (p < 0.0001) and increased sputum neutrophil numbers (p < 0.0001) compared to those without an exacerbation. The significant elevation in sputum IL-8 and neutrophil counts initially occurred 2 weeks prior to an exacerbation. Sputum neutrophilia correlated positively with changes in IL-8 levels (r(2) = 0.76, p = 0.01). Rapid withdrawal of inhaled corticosteroids results in an exacerbation of asthma that is preceded by an increase in sputum neutrophils and IL-8 concentrations, in contrast to an increase in eosinophils reported in previous studies in which inhaled steroids are slowly tapered.

How do we measure the effectiveness of inhaled corticosteroids in clinical studies?

Inhaled corticosteroids (ICSs) are the gold standard anti-inflammatory therapy for asthma and have been studied using a variety of different clinical trial designs. In long-term comparative studies ICSs are more effective in controlling asthma than beta-agonists or leukotriene antagonists (LTAs). Efficacy has also been shown retrospectively, as patients frequently experience an exacerbation of their asthma upon withdrawal of ICSs, whilst the regular use of low dose ICSs prevents death from asthma. The combination of ICSs with long-acting beta2-agonists (LABAs) is effective for patients with asthma non-responsive to low doses of ICSs, particularly in reducing exacerbations. In shorter term studies a modest dose-response effect of ICSs has been shown for lung function, symptom control and oral corticosteroid use in asthmatic patients. ICSs are also effective in reducing airway hyperresponsiveness (AHR) to various stimuli, as well as reducing exhaled nitric oxide (NO) concentrations and the number and activation state of a wide variety of inflammatory cells. Finally, using allergen challenge models even single doses of ICSs have profound inhibitory effects on the late asthmatic reaction. Since ICSs are the mainstay of asthma management guidelines, it is important that novel therapies should be judged against ICSs in future clinical trials. There are many potential designs for these comparative studies.

Probability and determinants of relapse after discontinuation of inhaled corticosteroids in patients with COPD treated in general practice

The objective of the study was to assess the probability, and explore determinants of adverse respiratory outcome after discontinuation of inhaled corticosteroid (ICS) treatment in subjects with chronic obstructive pulmonary disease (COPD) diagnosed and treated in general practice. Prospective unblinded ICS withdrawal study. 201 ICS treated COPD patients with various degrees of airflow limitation from 45 Dutch general practices. Probability of and time to exacerbation or unremitting worsening of respiratory symptoms after ICS discontinuation. Mean age was 60.6 (S.D. 9.5) years, post-bronchodilator forced expiratory volume in 1s (FEV1) 65.6 (S.D. 15.7) % predicted. Overall probability of adverse respiratory outcome after ICS discontinuation was 0.37 (95% confidence interval (CI) 0.31, 0.44). Survival analysis showed that age, gender, smoking status and reversibility of airflow limitation were independent predictors of adverse respiratory outcome. For females, the adjusted hazard ratio was 2.14 (95% CI 1.31, 3.50) compared to males. For age, the hazard ratio was 1.05 (95% CI 1.02, 1.08) per year lived. Discontinuation of inhaled corticosteroids may harm patients with COPD. The probability of an adverse respiratory outcome may be higher in women, elderly patients, smokers and patients with higher bronchodilator reversibility while on inhaled steroid treatment.

Beyond our pages

Beyond our pages

An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease

Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease (COPD). We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents. We studied 272 patients of mean age 65 ( sd 0·8) years, mean FEV 1 42·8 ( sd 12·6)% predicted, entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. All had been clinically stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility, baseline lung function or pack-years of smoking between the 160 patients receiving inhaled corticosteroids and those not so treated. Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38% of those previously treated with these drugs had an exacerbation compared to 6% of the chronically untreated group. Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation. These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD.

Seasonal variations in house dust mite influence the circadian peak expiratory flow amplitude.

The aim of the study was to investigate whether seasonal differences in house dust mite (HDM) allergen exposure influence the circadian peak expiratory flow (PEF) amplitude in asthmatic children. Asthmatic children (n = 25) with a solitary allergy to HDM were studied in spring and in autumn. All used inhaled corticosteroids (ICS) regularly. Six days after withdrawal of ICS, PEF amplitude (every 4 h during 24 h, highest-lowest/percentage of mean value) was assessed. HDM allergen (HDMA) in living rooms, bedrooms, and mattresses was collected. HDMA levels were not always highest in autumn. PEF amplitudes in spring and autumn did not correlate with HDMA levels in the same season. However, the seasonal difference in PEF amplitude (autumn value - spring value) correlated positively and significantly with the seasonal difference in HDMA exposure levels from the mattresses (rho = 0.34, p < 0.05). Multivariate analysis showed that the seasonal difference in HDMA exposure in the mattress was the single parameter explaining seasonal difference in PEF amplitudes by 21.0% (p = 0.02). Our cross-sectional study showed a higher PEF amplitude not to be significantly associated with higher HDMA exposure in mattresses in a group of HDM-allergic asthmatic children. However, the change in HDMA exposure over seasons contributed significantly to the change in PEF amplitude after withdrawal of ICS in HDM-allergic asthmatic children.

Exogenous stimuli and circadian peak expiratory flow variation in allergic asthmatic children.

The influence of exogenous factors in the home on the circadian variation of airway obstruction has not been fully assessed in children with asthma. The aim of the present study was to investigate the contribution of exogenous stimuli to the degree of peak expiratory flow (PEF) variability during 24 h. Fifty-five children (33 boys and 22 girls; mean age, 9.3 +/- 1.7 yr) with symptoms of asthma, increased bronchial responsiveness, and a solitary allergy to house dust mite (HDM) participated. Their asthma symptoms were well-controlled for at least 4 mo with daily inhaled corticosteroids (ICS) and beta 2-adrenergic drugs if needed. Symptoms, peripheral blood eosinophils, total IgE, and specific IgE to HDM were assessed. Spirometry and PC20 histamine were performed. PEF amplitudes during 24 h (highest minus lowest as a percentage of the day's mean value) were obtained at home during and 6 d after withdrawal of ICS. Dust samples were collected from the total area of the living rooms, bedrooms, mattresses (n = 25), and classrooms to obtain the HDM allergen (HDMA) exposure to Der p I and Der p II. Family smoking habits, presence of pets, and types of floor-covering were recorded on a checklist. Mean PEF amplitude did not increase after withdrawal of ICS, but absolute PEF values were significantly lower (p = 0.05) at midnight and 4:00 A.M. Twenty-six children (47%) were exposed to environmental tobacco smoke (ETS), and 23 (42%) kept pets. Mattresses contained significantly higher amounts of HDMA compared with other locations. PEF amplitude after withdrawal of ICS was significantly higher in children exposed to ETS, a pet, or a high HDMA level in their mattress than in children who were not exposed (ETS: 29.7% [3.9 to 56.6] versus 19.4% [0.0 to 56.6], p < 0.05; pets: 31.4% [9.7 to 52.5] versus 21.9% [0.0 to 56.6], p < 0.05; high HDMA level in the mattress: 35.5% [10.2 to 56.6] versus 21.4% [3.9 to 56.6], p < 0.05). These factors combined with age and PC20 histamine and its interaction with ETS, especially in mild to moderate asthma, explained 48.4% of the variance of the PEF amplitude after withdrawal of ICS. Exogenous stimuli such as exposure to ETS, pets, and high HDMA levels in mattresses contribute to an increased circadian PEF amplitude after withdrawal of ICS and therefore to nocturnal worsening of asthma in HDM-allergic asthmatic children. Moreover, ETS exposure seems to especially worsen PEF variability in children with mild to moderately severe bronchial responsiveness.