Successful withdrawal of inhaled corticosteroids in childhood asthma

OBJECTIVE: Although inhaled corticosteroids are useful and effective in the prophylaxis of childhood asthma, there is a dearth of information regarding the duration of treatment. The present study was undertaken to assess the possibility of successful withdrawal of inhaled corticosteroids in childhood asthma following good control of the disease. METHODOLOGY: The study was carried out at the Asiri Hospital, Colombo, Sri Lanka and was a prospective observational clinical study. The participants were consecutive children with documented moderately severe and severe asthma seen over a period of 4 years from January 1990 and followed up to December 2003. Patients were allocated randomly to receive either beclomethasone dipropionate or budesonide. Initial dose of the selected drug was 300, 400 or 600 microg/day, depending on the child's age. After a period of stabilization, the dose was reduced from the starting dose to a maintenance level of 200, 300 or 400 microg/day, respectively. Once sustained control had been maintained for a period ranging from 9 to 18 months, gradual withdrawal was attempted. The dosage was reduced by 50-100 microg each time, at intervals of 3 months. Long-term follow up was maintained following withdrawal of inhaled corticosteroids. Breakthrough wheezing, acute severe attacks, hospitalization for wheezing and absence from school were used to assess the response. RESULTS: Eighty-six children were recruited into the study. Eighty children responded well. The initial period on a high dose of corticosteroid was 8.4 months (range 4-12 months) and the average period of maintenance dosing was 11.7 months (range 9-18 months). The average time taken for withdrawal was 12.6 months (range 9-18 months). Successful withdrawal was achieved in 73 children. In this group, the mean total duration of treatment was 27.4 months (range 20-44 months). Up to December 2003, the subjects had been observed for an average period of 97.1 months (range 86-121 months) following withdrawal of inhaled corticosteroids. Of the 73 children in whom corticosteroids were withdrawn, 57 (78%) have remained well without any episodes of wheezing, and 14 (19%) have had mild episodes of wheezing that were easily controlled by bronchodilators. No patient needed hospitalization, long-term treatment or systemic corticosteroids. In two (3%) patients, it was necessary to restart inhaled corticosteroids because of troublesome recurrences. CONCLUSION: It is possible to gradually withdraw inhaled corticosteroids in a significant proportion of asthmatic children once good control has been sustained on a maintenance dose for a considerable period.     

Addition to inhaled corticosteroids of leukotriene receptor antagonists versus theophylline for symptomatic asthma: a meta-analysis

Background

Inhaled corticosteroids (ICSs) are widely used in combination with second controller medications in the management of asthma in adults and children. There lacks a systematic comparison between addition of leukotriene receptor antagonists (LTRAs) and theophylline to ICS. The purpose of this meta-analysis was to evaluate the difference of the efficacy and safety profile of adding either LTRAs or theophylline to ICS in adults and children with symptomatic asthma.

Methods

Randomised controlled trials (RCTs) published prior to November 2014 were acquired through systematically searching and selected based on the established inclusion criteria for publications. The data extracted from the included studies were further analyzed by a meta-analysis.

Results

We included eight RCTs, of which six recruited adults and two recruited children aged 5 to 14 years. The primary outcomes were changes in lung function from baseline, including forced expiratory volume in the first second (FEV₁) and peak expiratory flow (PEF). Overall, addition of LTRAs led to significantly better morning PEF {mean difference (MD) 16.94 [95% confidence interval (CI): 11.49-22.39] L/min, P<0.01} and FEV₁ [MD 0.09 (95% CI: 0.03-0.15) L, P=0.005] as compared to addition of theophylline. There were no differences between the two treatments in terms of evening PEF, adverse events, rescue medication use and asthma exacerbation.

Conclusions

The combination of LTRA and ICS leads to modestly greater improvement in lung function than the combination of theophylline and ICS in the treatment of symptomatic asthma. Long-term trials are required to assess the efficacy and safety of these two therapies.     

哮喘儿童吸入性糖皮质激素使用情况及用药依从性评价

目的探讨哮喘儿童吸入性糖皮质激素(Inhaled corticosteroids,ICS)使用情况及用药依从性。方法选择2016年1月至2018年1月期间本院儿科住院部和门诊收治的哮喘儿童共350例。采用问卷调查了解哮喘儿童的一般情况下、ICS使用情况和用药依从性,并分析用药依从性差的影响因素。结果350例儿童哮喘病例中,布地奈德、氟替卡松和倍氯卡松的使用率分别为81.14%、10.29%、8.57%。雾化器、压力定量气雾剂和干粉吸入剂的使用率分别为62.29%、27.43%和10.29%。哮喘儿童ICS用药依从性差占74.86%,而用药依从性佳仅占25.14%。儿童哮喘ICS用药依从性差的原因主要包括担心ICS的安全性、家庭经济困难、不配合治疗、自认痊愈而停药和吸入方法不正确等。单因素分析显示,哮喘严重程度、父母受教育程度、掌握ICS吸入装置、家庭经济困难、父母对哮喘认知、父母对医护人员的信任程度与ICS用药依从性具有紧密的关系。多因素logistic回归分析显示,哮喘病情程度、父母受教育程度、父母对哮喘认知程度和父母对医护人员的信任程度越高,儿童哮喘ICS用药依从性越高。结论哮喘儿童ICS的使用以布地奈德雾化吸入为主,但用药依从性与多种因素具有紧密的关系,针对上述因素进行有效干预可有利于提高用药依从性,最终改善治疗效果。     

Cost analysis of the use of inhaled corticosteroids in the treatment of asthma: a 1-year follow-up

A retrospective cohort using pharmacy and medical claims was analysed to determine whether the differences in efficacy of various inhaled corticosteroids demonstrated in clinical trials lead to differences in costs of care observed in clinical practice. Subjects that had an ICD-9 (493.XX) code for asthma and a new pharmacy claim for inhaled fluticasone propionate 44 mcg (FP), beclomethasone dipropionate (BDP), triamcinolone acetonide (TAA), budesonide (BUD) or flunisolide (FLU) were identified and followed for 12 months. Annual asthma care charges (pharmacy and medical) over the 12-month observation period were significantly (P < 0.03) higher in patients treated with BDPTAA, BUD and FLU compared to FP, 24%, 27%, 34% and 45% respectively In addition, patients treated with BDPTAA, and FLU were associated with significantly (P < 0.005) higher total healthcare (asthma + non-asthma) charges compared to patients on FP, 53%, 46% and 39% respectively Asthma care and total healthcare charges remained lower for FP after including FP110 mcg and excluding patients who were extreme cost outliers (+/- 2 SD from the mean) in a univariate sensitivity analysis. This analysis supports recent randomized control trials that FP offers a superior efficacy profile at lower asthma care as well as total healthcare charges compared to other inhaled corticosteroids.     

Bone mineral density and bone metabolism of prepubertal children with asthma after long-term treatment with inhaled corticosteroids

Little is known about the effect of long-term treatment with inhaled corticosteroids (ICS) on bone mineral density (BMD) in asthmatic children. In the present cross-sectional study BMD, bone metabolism, height, body composition, and bone age were evaluated in 40 prepubertal children (21 boys) with asthma, treated with a moderate to high dose of ICS over a period of 3 to 8 years. Body composition and BMD of the lumbar spine and total body were measured by Dual Energy X-ray Absorptiometry. BMD results were compared with 148 prepubertal healthy children of the same population. Blood samples were taken for the determination of biochemical bone parameters. The asthmatic children had decreased height, lean tissue mass and fat mass, and a delay of bone maturation, indicating growth retardation. ICS-treated asthma was negatively correlated with total body BMD in a multiple regression model with adjustment for age, gender, height and weight (P = 0.01). Duration of ICS therapy correlated negatively with total body BMD when it was added to the model (P = 0.01). Lumbar spine BMD was not affected by ICS in children with ICS-treated asthma. If age of the asthmatic children was replaced by their bone age in the model, no significant correlation was found between ICS-treated asthma and total body or lumbar spine BMD. The biochemical parameters of bone metabolism were within normal limits. In conclusion, children with asthma who have used ICS daily for 3 to 8 years had lower total body BMD than healthy controls. Long-term longitudinal studies are needed to investigate whether these children attain a normal peak bone mass. Pediatr. Pulmonol. 1997; 24:379–384. © 1997 Wiley-Liss, Inc.     

Effectiveness of an asthma integrated care program on asthma control and adherence to inhaled corticosteroids

Objective: To measure the effectiveness of an integrated care program for individuals with asthma aged 12–45 years, on asthma control and adherence to inhaled corticosteroids (ICS). Methods: Researchers used a theoretical model to develop the program and assessed effectiveness at 12 months, using a pragmatic controlled clinical trial design. Forty-two community pharmacists in Quebec, Canada recruited participants with either uncontrolled or mild-to-severe asthma. One group was exposed to the program; another received usual care. Asthma control was measured with the Asthma Control Questionnaire; ICS adherence was assessed with the Morisky medication adherence scale and the medication possession ratio. Program effectiveness was assessed with an intention-to-treat approach using multivariate generalized estimating equation models. Results: Among 108 exposed and 241 non-exposed, 52.2% had controlled asthma at baseline. At 12-months, asthma control had improved in both groups but the interaction between study groups and time was not significant (p?=?0.09). The proportion of participants with good ICS adherence was low at baseline. Exposed participants showed improvement in adherence and the interaction between study groups and time was significant (p?=?0.02). Conclusion: An integrated intervention, with healthcare professionals collaborating to optimize asthma control, can improve ICS adherence.     

Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids

Objective: Eosinophilic inflammation in the respiratory tract is a hallmark of bronchial asthma. In naïve cases, the inflammatory profile is associated with disease severity and reactivity to inhaled corticosteroids (ICS). Sustained airway eosinophilia has been reported during ICS treatment. However, the immunological characteristics of these cases are not known and it is unclear if this situation contributes to asthma control. This study was performed to determine the answer of these questions. Methods: To compare phenotypes of eosinophilic and non-eosinophilic asthma (EA and NEA, respectively) under ICS treatment, clinical data were obtained from asthmatic subjects (n?=?22) and healthy controls (n?=?10), and the leukocyte compositions of induced sputum and peripheral blood were determined. T lymphocyte profiles in systemic blood were assessed by flow cytometry. Results: A higher frequency of emergency room visits was observed in the NEA group, which had a higher neutrophil count relative to the total inflammatory cell population in induced sputum than the EA group (59.5 versus 36.6%; p?<?0.01). The fraction of helper T (Th)17 lymphocytes as well as the ratio of Th17 to regulatory T cells (Treg) in the peripheral blood was higher in the NEA than in the EA group (0.24 versus 0.13; p?<?0.05). Conclusions: Th17 were more prevalent than Treg cells in the peripheral blood of NEA patients under ICS treatment, corresponding to neutrophil-dominant airway inflammation and a severe asthmatic phenotype. Thus, an imbalance in Th17/Treg may be associated with the pathogenesis of NEA in patients undergoing ICS treatment.     

DP_2拮抗剂对哮喘模型气道炎症的影响及与激素的比较

目的了解DP2受体拮抗剂对气道炎症影响,并比较其同吸入性激素作用的差异。方法 24只SPF级BALB/c小鼠,随机分为正常对照组、哮喘组。DP2拮抗剂干预组和吸入激素干预组,每组6只。用卵白蛋白(OVA)雾化诱喘。用ELISA测定小鼠支气管灌洗液中PGD2、DP2、IL-4与IL-5水平;肺组织病理切片,HE染色镜检。Real time RT-PCR(Taq Man)方法检测小鼠肺组织PGD2、DP2与DP1mRNA表达。结果哮喘组支气管灌洗液炎症水平,PGD2,DP2显著高于正常对照组(P0.01),DP2拮抗剂干预组与吸入激素组小鼠支气管灌洗液炎症水平均较哮喘组减少。结论 DP2受体拮抗剂能抑制哮喘模型小鼠IL-4、IL-5水平;DP2受体拮抗剂改善小鼠哮喘作用与吸入糖皮质激素类似,或可作为新的药物用于支气管哮喘的治疗。     

Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge‐induced cough

Background and Aims: Bronchial provocation tests may be utilised to monitor the efficacy of the corticosteroid treatment. Unfortunately, these measurements necessitate good patient cooperation during the spirometry. Coughing during such tests is related to the degree of the bronchoconstriction and occurs involuntarily, i.e. independent of patient cooperation. This study aimed to evaluate the utility of a hypertonic histamine challenge‐induced cough in assessing the efficacy of inhaled corticosteroid treatment. Methods: A total of 16 steroid‐naïve asthmatics and 10 non‐asthmatic, symptomatic controls received 800‐µg beclomethasone (Beclomet Easyhaler®, Orion Ltd., Orion Pharma, Helsinki, Finland) via powder inhaler per day for 8 weeks. Videoed inhalation challenge with hypertonic histamine solution was performed before and after the treatment. Symptom questionnaire was completed before both challenges. The airway responsiveness to hypertonic histamine was expressed as the cumulative number of coughs divided by the final histamine concentration administered [coughs/concentration ratio (CCR)] and as the provocative concentration of histamine to induce a 20% fall in FEV₁(PC₂₀). Results: CCR [geometric mean; 95% confidence interval (CI)] of the asthmatic subjects decreased from 494 (209–1168) to 73.6 (29.8–182) coughs per mg/mL (P = 0.002). Their PC₂₀ levels were 1.31 (1.07–1.60) and 1.91 (1.33–2.74) mg/mL over the treatment period (P = 0.01). The symptom frequency also decreased significantly in the asthmatics (P = 0.039). There were no significant changes in PC₂₀ level, in CCR level or in symptom frequency in non‐asthmatic subjects during the treatment. Conclusions: Hypertonic histamine challenge‐induced cough and PC₂₀ are sensitive measures in assessing the treatment effect in asthma. The cough response may be especially useful in subjects who cannot perform spirometry reliably. Please cite this paper as: Purokivi M, Koskela H, Koistinen T, Peuhkurinen K and Kontra KM. Assessment of inhaled corticosteroid treatment response in asthma using hypertonic histamine challenge‐induced cough. The Clinical Respiratory Journal 2010; 4: 67–73.     

Benefits of fixed-dose combination therapy with inhaled corticosteroids and long-acting bronchodilators as initial maintenance therapy in the management of asthma

Background and objective:   Revised Australian guidelines for asthma management were released by the National Asthma Council (NAC) in 2006. One area where clinical opinion and trial data have changed recently concerns the place of fixed-dose combination (FDC) therapy with inhaled corticosteroid (ICS) and long-acting β₂-agonists as initial maintenance therapy.
Methods:   A systematic review of the literature commissioned by the NAC and undertaken by the University of Tasmania addressed several questions, including whether there was evidence for the use of FDC therapy as first-line asthma treatment in steroid-naïve patients.
Results:   Nineteen relevant studies were identified, from which 20 comparisons contributed to the analyses. The definition of steroid-naïve ranged from no ICS therapy over the preceding 1 month to no ICS therapy ever. FDC therapy was effective in subjects who were steroid-naïve and was more effective than an equivalent dose of ICS, irrespective of the definition of steroid-naïvety. Compared with ICS alone, FDC therapy increased mean FEV₁ by 140 mL, mean morning PEF by 21 L/min and mean evening PEF by 20 L/min. There was a mean increase of 9.8% in symptom-free days, associated with a greater reduction in rescue medication use of −0.12 puff/24 h. FDC therapy was not superior to ICS alone for prevention of withdrawals or exacerbations requiring systemic corticosteroids. Adverse events were similar for FDC therapy and ICS, whether ICS were administered at the same or an increased dose.
Conclusions:   FDC therapy is effective as first-line treatment in steroid-naïve subjects and is superior to ICS alone for most outcomes, irrespective of the period of time since last exposure to ICS.     

Comparison of inhaled corticosteroids and leukotriene receptor antagonists in adolescents and adults with mild to moderate asthma: a meta‐analysis

Introduction: Inhaled corticosteroids (ICS) and oral leukotriene receptor antagonists (LTRA) are effective drugs used in the management of asthma as controller monotherapy in adolescents and adults, although there are debates as to which one is better. Objectives: To thoroughly compare the efficacy and tolerability of ICS vs LTRA in adolescents and adults with mild to moderate asthma. Methods: Relative database were searched for the review. Randomized controlled trials of more than or equal to 4 weeks' treatment duration comparing ICS with LTRA were reviewed. Results and Conclusion: Twenty‐four trials with 6197 randomized adolescents and adults with mild to moderate asthma met the inclusion criteria with a minimum duration of 4 weeks' treatment. Significant differences favouring ICS were found in all indices of pulmonary function. Other significant benefits of ICS were shown in symptoms, nocturnal awakenings, rescue‐medication use, symptom‐free days and quality of life. As to each special symptom of adverse effects, ICS was similar to LTRA in the incidence of headache, nausea and throat discomfort, but significantly higher in the incidence of hoarseness and oral pharyngeal candidiasis. Concerning withdrawal because of adverse events potentially related to treatment, ICS was similar to LTRA but significantly superior to LTRA in decreasing the asthma exacerbations or attacks during the treatment period. These results show that ICS may be the better drug in terms of efficacy and tolerability, except hoarseness and oral pharyngeal candidiasis, and should thus have priority over LTRA in asthma monotherapy in adolescents and adults. Please cite this paper as: Yang D, Luo H, Wang J, Bunjhoo H, Xu Y and Xiong W. Comparison of inhaled corticosteroids and leukotriene receptor antagonists in adolescents and adults with mild to moderate asthma: a meta‐analysis. Clin Respir J 2013; 7: 74–90.     

Dose–response relationship of inhaled corticosteroids and cataracts: A systematic review and meta-analysis

Background and objective:   The risk of cataracts associated with the long-term use of inhaled corticosteroids (ICS) is poorly recognized, yet may be of major public health importance. The aim of this study was to determine the dose–response relationship of ICS use and risk of cataracts in adults.
Methods:   A systematic review and meta-analysis was performed of case–control studies of cataracts and ICS use, which included at least two doses of ICS and in which the number of cases and controls using each dose of ICS was reported. The primary outcome variable was risk of cataracts.
Results:   Four case–control studies were identified, with a total of 46 638 cases and 146 378 controls. There was a significant relationship between the risk of cataracts and ICS dose, with a random effects pooled odds ratio for risk of cataracts per 1000 µg increase in daily beclomethasone dipropionate dose of 1.25 (95% CI: 1.14–1.37).
Conclusions:   The risk of cataracts was increased by approximately 25% for each 1000 µg per day increase in the dose of beclomethasone dipropionate or equivalent. These findings reinforce the importance of prescribing within the therapeutic dose–response range for ICS in asthma and the need to determine the dose–response relationship for the efficacy of ICS in COPD. Screening for the presence of cataracts could usefully be undertaken in older subjects with asthma and COPD, particularly current or ex-smokers.     

Inhaled corticosteroids (ICS) and risk of mycobacterium in patients with chronic respiratory diseases: a meta-analysis

Background

Studies have indicated that therapy with inhaled corticosteroids (ICS) can be associated with a higher risk of pneumonia. However, it is not known whether ICS increases the risk of mycobacterium. Most of these published studies were small, and the conclusions were inconsistent.

Methods

A meta-analysis was conducted into whether ICS increases the risk of mycobacterium in patients with chronic respiratory diseases. PubMed, OVID, EMBASE and Cochrane Library databases were searched.

Results

Five studies involving 4,851 cases and 28,477 controls were considered in the meta-analysis. From the pooled analyses, there was significant association between ICS and risk of mycobacterium in all patients with chronic respiratory diseases [risk ratio (RR) =1.81; 95% confidence interval (CI), 1.23-2.68; P=0.003]. Among patients with chronic respiratory diseases, the relationship between ICS and risk of tuberculosis (TB) was also significant (RR =1.34; 95% CI, 1.15-1.55; P=0.0001). And meta-analysis of four studies in patients with chronic obstructive pulmonary disease (COPD) (RR =1.42; 95% CI, 1.18-1.72; P=0.0003) or two studies in patients who have prior pulmonary TB (RR =1.61; 95% CI, 1.35-1.92; P<0.00001) or three studies in patients with high-dose ICS (RR =1.60; 95% CI, 1.28-1.99; P<0.0001) showed a relationship between ICS and risk of mycobacterium.

Conclusions

Significant relationship has been shown between ICS use and risk of mycobacterium in all patients with chronic respiratory diseases. ICS use also increases the risk of TB among the patients with chronic respiratory diseases. Use of ICS increases the risk of mycobacterium in patients with COPD or patients with prior pulmonary TB or patients inhaling high-dose corticosteroids. Further research is required to establish the potential adverse effect of ICS as a therapy for chronic respiratory diseases.     

Association between APE1 rs1760944 and rs1130409 polymorphism with prostate cancer risk: A systematic review and meta-analysis

Background:Recently, some studies have suggested that the association of apurinic/apyrimidinic endonuclease 1 (APE1) gene polymorphism with prostate cancer (PCa) risk, but there are still some controversies. Hence, we elaborated the relationship between APE1 rs1760944 and rs1130409 gene and PCa risk through systematic literature review and meta-analysis.Methods:As of March 2020, EMBASE, PubMed, the Cochrane Library, Science Direct/Elsevier, MEDLINE and CNKI were used for systematic literature retrieval to investigate the correlation between APE1 rs1760944 and rs1130409 gene polymorphism with PCa risk. Meta-analysis was performed using Review Manager and Stata software.Results:Seven studies were distinguished, consists of 1769 cases of PCa patients and 2237 normal controls. Our results illustrated that there are significant correlation between the APE1 rs1760944 gene polymorphism and PCa in all genetic models (P < .05). The combined odds ratios and 95% confidence intervals were as follows: Additive model (ORs 0.62, 95%, CI [0.39, 0.97]); Codominant model (ORs 0.74, 95% CI [0.58, 0.95]); Dominant model (ORs 0.75, 95%, CI [0.59, 0.95]); Recessive model (ORs 0.63, 95% CI [0.41, 0.96]); Allele model (ORs 0.78, 95% CI [0.65, 0.94]). There also have significant associations between APE1 rs1130409 polymorphisms and PCa in all genetic models (P < .05). The combined odds ratios and 95% confidence intervals were as follows: Additive model (ORs 1.37, 95%, CI [1.01, 1.85]); Codominant model (ORs 1.21, 95% CI [1.01, 1.44]); Dominant model (ORs 1.33, 95%, CI [1.02, 1.73]); Recessive model (ORs 1.74, 95% CI [1.06, 2.85]); Allele model (ORs 1.14, 95% CI [1.00, 1.29]).Conclusion:This study suggests that APE1 rs1760944 polymorphisms might be a protective factor of PCa, and APE1 rs1130409 is suggested to be a risk factor of PCa. APE1 rs1760944 and rs1130409 polymorphisms may be used in the risk assessment of PCa.     

Review of the effect of the dosing interval for inhaled corticosteroids in asthma control

Abstract
Background : Asthma is recognized as an inflammatory disease of the airways and treatment includes anti-inflammatory agents such as corticosteroids. Inhaled corticosteroids (ICS) are widely prescribed for long-term prophylaxis, yet their optimal dosing interval is not clear.
Aims : To determine whether the dosing interval of ICS affects asthma control.
Methods : We performed an electronic search of the literature to identify studies on the dosing interval of ICS in asthmatic subjects. Data were extracted from suitable studies by two independent researchers and, where possible, a meta-analysis performed.
Results : A total of 4267 titles were retrieved, of which 13 met inclusion and exclusion criteria and 11 had extractable data. There were no significant differences between outcomes for: (i) once daily vs twice daily administration (7 trials, 810 subjects), (ii) once daily vs four times daily administration (2 trials, 68 subjects) and (iii) twice daily vs four times daily administration (4 studies, 111 subjects). There was a variety of outcomes used to assess differences between dosing intervals. These included symptom scores, lung function, use of rescue medication and adverse drug effects. The number of subjects that could be included in the statistical analysis of any of such outcomes was small, much smaller than the total sample size.
Conclusions : There was no significant difference in measures of asthma control between the assessed dosing intervals of ICS. Current evidence indicates that single daily administration of ICS produces equivalent asthma control to multiple daily administration. (Intern Med J 2002; 32: 72–78)