High- and low-dose allergen challenges in asthmatic patients using inhaled corticosteroids

AimsThe inhaled allergen challenge model has been used previously to investigate the effects of novel anti-inflammatory drugs in inhaled corticosteroid (ICS)-naïve asthmatics. The aim of this study was to characterize high- and low-dose allergen challenges in asthmatic patients using ICS.MethodsTwenty-eight asthmatic patients taking ICS (beclomethasone equivalent <1000 μg day⁻¹) were recruited for high-dose allergen challenge, of whom 10 subsequently also had a repeat low-dose challenge comprising seven allergen challenges. Induced sputum was collected for measurements of cell counts and supernatant biomarkers.ResultsThe high-dose allergen challenge caused an early and late asthmatic response in 19 of 28 patients; the mean maximal fall in the forced expiratory volume in 1 s (FEV₁) was 29.1% (SD 6.2%) and 25.1% (SD 9.6%), respectively. There was also an increase in sputum eosinophils of 6.2% (P = 0.0004), as well as supernatant eosinophil cationic protein levels. The low-dose allergen challenge caused an acute fall in FEV₁, but had no effect on FEV₁ at 24 h after challenge or sputum measurements.ConclusionsThe high-dose allergen challenge in asthmatics using ICS induces a late asthmatic response associated with an increase in eosinophilic airway inflammation. This may be a suitable model for studying the effects of novel anti-inflammatory drugs added to maintenance ICS treatment.     

Inhibition of histamine release from basophil leucocytes of asthmatic patients treated with corticosteroids

We studied the protective effect of corticosteroids in asthmatic patients both in vivo and in vitro. Steroid treatment of patients inhibited the in vivo response to bronchial challenge with the specific allergen as shown by the substantial rise in allergen-threshold. It also produced inhibition of the in vitro elicited release of histamine and slow-reacting substance of anaphylaxis from blood leucocytes. This effect was apparent within 24 h of starting treatment with prednisolone in a daily dose of 30 mg, and reached a maximum after 48 h. In addition, in peripheral venous blood basophil count and total leucocyte histamine content were reduced, eosinophils disappeared and neutrophils increased.     

吸入性糖皮质激素对哮喘气道重塑模型平滑肌的影响

目的探讨吸入性糖皮质激素对哮喘气道重塑模型平滑肌的影响。方法雄性豚鼠108只,随机分为哮喘发作组(A组)、治疗组(B组)和对照组(C组)。每组动物分别予以卵蛋白(OVA)、布地奈德或生理盐水处理,在每个时点末次激发后24 h处死,留取肺组织,测量气道平滑肌的厚度。结果在12周时各组气道平滑肌层厚度,A组(26.56±3.39)μm,B组(18.29±4.11)μm,C组(9.85±3.59)μm,两两比较均有显著性差异(P<0.05)。在首次激发后24 h各组气道平滑肌层厚度分别为(7.66±1.86)μm、(7.81±1.61)μm和(7.79±1.55)μm,两两比较均无显著性差异(P>0.05),直到激发8周后各组平滑肌层厚度才出现显著性差异(P<0.05)。结论吸入性糖皮质激素能抑制气道平滑肌层增厚,但这种作用是不完全的。     

The place of inhaled corticosteroids in chronic obstructive pulmonary disease

SUMMARY

The role of systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD) is well established. However, despite being frequently prescribed for the treatment of COPD, the clinical utility of inhaled corticosteroids (ICS) is less clearly defined.

While individual clinical and epidemiological studies have yielded conflicting results, meta-analysis of available data suggests that ICS may reduce the frequency and severity of exacerbations, the number of hospitalisations and the mortality rate, as well as yielding improvements in lung function and health-related quality of life (HRQL) in some subgroups of COPD patients. More recently, clinical trials evaluating the effect of combination therapy with ICS and long-acting β₂-agonists (LABA) have shown significant effects on the prevention of exacerbations and HRQL. Emerging data are expected to clarify the role of ICS in the management of patients with COPD of different severities as well as the place of treatment with ICS/LABA combinations in the management of this chronic and disabling disorder.     

The place of inhaled corticosteroids in chronic obstructive pulmonary disease

The role of systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease (COPD) is well established. However, despite being frequently prescribed for the treatment of COPD, the clinical utility of inhaled corticosteroids (ICS) is less clearly defined. This review article seeks to clarify the role of ICS in the clinical management of COPD through a review of key pivotal short-, medium- and long-term studies in this field. Studies for inclusion in this review were identified by means of a computerised search of several databases (including MEDLINE, BIOSIS and EMBASE) from 1980 to 2003. While individual clinical and epidemiological studies have yielded conflicting results, meta-analysis of available data suggests that ICS may reduce the frequency and severity of exacerbations, the number of hospitalisations and the mortality rate, as well as yielding improvements in lung function and health-related quality of life (HRQL) in some subgroups of COPD patients. More recently, clinical trials evaluating the effect of combination therapy with ICS and long-acting beta2-agonists (LABA) have shown significant effects on the prevention of exacerbations and HRQL. Emerging data are expected to clarify the role of ICS in the management of patients with COPD of different severities as well as the place of treatment with ICS/LABA combinations in the management of this chronic and disabling disorder.     

吸入皮质激素治疗哮喘患者的骨密度、骨代谢变化及其危险因素

目的：探讨接受可吸入性皮质激素治疗-年以上的哮喘患者的骨质减少和骨质疏松的发病状况以及哮喘患者骨质减少和骨质疏松的危险因素。方法：自2007年8月到2011年7月,接受吸入性皮质激素治疗且治疗时间-年以上的哮喘患者为研究组,未接受吸入性皮质激素治疗的哮喘患者为对照组,哮喘患者年龄均在18岁以上。骨密度检测采用DEXA检测。骨质减少和骨质疏松采用WHOT—score评分。骨代谢指标包括血骨钙素以及碱性磷酸酶等,检测方法采用放免法进行。结果：研究对象共143名,其中研究组69例,对照组74例。研究组与对照组患者的血骨钙素水平分别为（3．8±2．4）、（2．7±1．4）μg／L,两组间无统计学差异（P=0．57）。两组患者的血碱性磷酸酶水平分别为（126±68）、（119±66）IU／L,两组间无统计学差异（P=0．37）。研究组和对照组患者的脊柱T—score评分均数分别为-0．72和-0．57（P=0．98）;股骨T—score评分均数分别为-0．60和-0．80（P=0．474）;髋骨T—score评分均数分别为0．19和0．06（P=0．275）。脊柱、股骨和髋骨T—score评分与年龄呈显著负相关,而与体重指数呈显著正相关。结论：哮喘患者骨质减少和骨质疏松危险因素是高龄和低体重指数,吸入皮质激素无累积效应。与对照组患者相比,吸入皮质激素治疗哮喘的患者没有其他的骨质减少和骨质疏松的危险因素。     

A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease

Introduction: Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β₂-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects.

Areas covered: Although the existence of asthma in patients with asthma–COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation.

Expert opinion: For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.     

A comparison of methods for assessing hypothalamic-pituitary-adrenal (HPA) axis activity in asthma patients treated with inhaled corticosteroids

Suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an accepted indicator of potential side effects from inhaled corticosteroids. Although cortisol monitoring is frequently used to detect changes in HPA axis activity, the optimal method for identifying the subset of asthma patients on inhaled steroids who experience severe cortisol suppression of potential clinical significance has not been established. The objective of this study was to compare several methods for assessing HPA axis activity in asthma patients taking inhaled corticosteroids. After screening, 153 patients with mild to moderate asthma were randomly assigned to receive inhaled fluticasone propionate (110, 220, 330, or 440 microg bid), flunisolide (500 microg or 1000 microg bid), or one of two control regimens (prednisone or placebo) for 21 days. Salivary (8 a.m.) and urinary (24-h) cortisol determinations were compared against 22-hour area under the serum cortisol concentration-time curve (AUC0-22 h) measured at baseline and on day 21. Comparisons were also made against 8 a.m. serum cortisol. A significant positive correlation was found between AUC0-22 h of serum cortisol and 8 a.m. serum cortisol level (r = 0.5140; p = 0.0001). The AUC0-22 h of serum cortisol was weakly correlated with 24-hour urinary cortisol levels, both corrected (r = 0.4388; p = 0.0001) and uncorrected (r = 0.3511; p = 0.0001) for creatinine excretion. The 8 a.m. salivary cortisol level correlated positively with the 8 a.m. serum cortisol level (r = 0.5460; p = 0.0001). Salivary cortisol was both sensitive and specific for the detection of a 50% decline in AUC0-22 h of serum cortisol. Cortisol reductions of this magnitude have been observed following repeated use of inhaled steroids. Because it is noninvasive, salivary cortisol measurement offers distinct advantages as a screening method for detecting pronounced HPA axis suppression in asthma patients receiving corticosteroid therapy.     

Treatment of chronic obstructive pulmonary disease with inhaled pharmacotherapy: role of corticosteroids

Cigarette smoke-induced airway inflammation plays a central role in the pathophysiology of chronic obstructive pulmonary disease (COPD). It causes bronchial epithelial cell injury, which in turn initiates the recruitment of inflammatory cells and increases the production of cytokines, chemokines, proteases and other proinflammatory mediators followed by oxidative stress and protease/anti-protease imbalance impairing lung parenchymal elastic structures. Inhaled corticosteroids in combination with long-acting bronchodilators are generally recommended for the treatment of COPD. However, steroid responsiveness of patients with COPD is often poor, since oxidative stress may reduce the activity and expression of histone deacetylases, and therefore interfere with the anti-inflammatory action of corticosteroids. Recently, a number of studies has indicated that presence of sputum eosinophilia and/or elevated exhaled nitric oxide (NO) level may predict a better response to corticosteroid treatment in COPD patients. While sputum processing and its profiling is a time-consuming and technically demanding method, exhaled NO measurement is a simple and completely non-invasive tool, thus, the later could be more convenient for routine clinical use in the future.     

Safety of inhaled corticosteroids for treating chronic obstructive pulmonary disease

Introduction: The frequent use of inhaled corticosteroids (ICSs), especially at higher doses, has been accompanied by concern about both systemic and local side effects. Patients suffering from chronic obstructive pulmonary disease (COPD) are more at risk from side effects, likely because of the use of higher doses of ICS in COPD to overcome corticosteroid unresponsiveness.

Areas covered: There is considerable concern about increased incidence of pneumonia, osteoporosis and hyperglycemia in diabetic patients and cataracts. The local side effects of ICSs, such as hoarseness and pharyngeal discomfort, oral and oropharyngeal candidiasis, cough during inhalation, and a sensation of thirst, are not usually serious but are of clinical importance because they may lead to patients discontinuing therapy.

Expert opinion: The possibility that ICSs induce adverse side effects should not lead us to avoid their use in patients in whom clinical evidence suggests that they may be helpful. However, clinicians should balance the potential benefits of ICSs in COPD against their potential side effects and always consider using the lowest possible dose to achieve the best possible management.     

Combination therapy of inhaled corticosteroids and long-acting beta2-adrenergics in management of patients with chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) affects over 5% of the adult population and is the only major cause of death in the United States where morbidity and mortality are increasing. Clinically, COPD is characterized by irreversible airflow obstruction and airway inflammation that eventually lead to dyspnea, cough and sputum production. Long-acting beta(2)-agonists (LABAs) are effective in reducing patient symptoms through their bronchodilatory action on airway smooth muscle. More importantly, when LABAs are given in conjunction with inhaled corticosteroids, they appear to provide added benefits for patients. While the mechanisms for this observation are not entirely clear, there is emerging evidence to indicate that LABAs and corticosteroids attenuate different but complementary components of the inflammatory cascade related to COPD. Moreover, LABAs and corticosteroids may beneficially interact to prevent downregulation of beta(2)-receptors in airway cells (and thereby preventing tachyphylaxis) and to facilitate translocation of glucocorticoid receptors into the nucleus of inflammatory cells (thereby, amplifying the anti-inflammatory activity of the corticosteroid). Regardless of the mechanism, several large, high-quality randomized controlled clinical trials indicate that combination therapy of LABA with inhaled corticosteroids improves patient symptoms, and reduces exacerbations by a third (compared to placebo). More importantly, combination therapy produces superior health outcomes than mono-therapy with inhaled corticosteroids or LABA, suggesting added clinical benefits of these two compounds in COPD. This article will present a comprehensive overview of the currently available clinical evidence for the use of combination therapy as well as the potential mechanisms of their actions in COPD.     

The risk/benefit of inhaled corticosteroids in chronic obstructive pulmonary disease

Although inhaled corticosteroids have a well defined role in asthma therapy, their use remains controversial in nonasthmatic, smoking-related chronic obstructive pulmonary disease (COPD). Some studies have shown an effect of inhaled corticosteroids on airway inflammation in COPD, but the clinical relevance of these results is unknown. Data from five long-term, large studies, provide evidence that prolonged treatment with inhaled corticosteroids does not modify the rate of decline of forced expiratory volume in one second (FEV1) in patients with COPD and no reversibility to short-acting beta(2)-agonists. FEV1 was slightly improved over the first six months of treatment and lower reactivity in response to methacholine challenge has been observed. Improvement of respiratory symptoms and health status were also reported. A reduction of exacerbations rate was observed in two studies. No survival benefit was demonstrated. Two recent reports suggest that long term use of inhaled corticosteroids in COPD patients improves quality-adjusted life expectancy and is cost-effective. Combination therapy with inhaled corticosteroids and long-acting beta(2)-agonists have proven benefit in four long term large studies compared to placebo for FEV1, exacerbation rate, symptoms and health status. However, only two studies found that combination therapy was more effective than long-acting beta(2)-agonists alone for symptoms and health status improvement. The long term safety of inhaled corticosteroids is not known in COPD patients but topical adverse effects, and systemic effects such as a decrease of bone density of lumbar spine and femur and cutaneous adverse effects, have been reported after three years of treatment. However, three recent observational studies found a slight increase in the risk of fractures (hip, upper extremities and vertebral) in association with high doses of inhaled corticotherapy.     

Underuse of inhaled corticosteroids in adults with asthma

Despite strong evidence that inhaled corticosteroids are beneficial in treating asthma, a number of small studies suggest a use rate of only 34-56%. The primary objective of this study was to determine patterns of prescribing inhaled corticosteroids for high-risk patients with asthma. Secondary objectives were to assess patterns of practice with respect to other agents prescribed before and at hospital discharge, and to determine if an emergency room asthma care map at one of the study hospitals was being followed. We retrospectively reviewed charts of 1022 patients with an acute attack of asthma treated in the emergency rooms of the Royal Alexandra Hospital and University of Alberta Hospital from January 1, 1996, to March 31, 1997. A forward stepwise logistic regression analysis was performed with the dependent variable defined as whether or not the patient was using an inhaled or oral corticosteroid during the index visit, and the independent variable being all major demographic variables. Inhaled corticosteroids were prescribed for 460 patients (52.0%) at the index visit. Overall, antiinflammatory drugs were prescribed for 548 patients (62.1%). An asthma care map was followed for 107 (16.8%) patients treated at the Royal Alexandra Hospital at the index visit. Logistic regression analysis showed that women and patients with more than one emergency room visit most likely were to be using inhaled or inhaled plus oral corticosteroids at the index visit. Documentation of drug therapy at discharge was poor for 42% of patients; therefore, analysis of practice patterns in this group was not attempted. This study shows that inhaled corticosteroids were prescribed for only about one-half of patients with an acute asthma attack. Given this low use by high-risk patients, the need for programs designed to improve asthma therapy is evident.     

Benefits and risks of inhaled corticosteroids in chronic obstructive pulmonary disease.

Inhaled corticosteroids have a proven benefit in the management of asthma, but until recently, their efficacy in non-asthmatic, smoking-related chronic obstructive pulmonary disease (COPD) was not evidence-based. Airway inflammation in COPD differs from inflammation in asthma. Some studies have shown an effect of inhaled corticosteroids on airway inflammation in COPD but the clinical relevance of these results are unknown. Short-term studies evaluating the effect of inhaled corticosteroids in patients with COPD were associated with no or modest improvements in lung function. Data from five, long-term, large studies have provided evidence that prolonged treatment with inhaled corticosteroids does not modify the rate of decline of forced expiratory volume in one second (FEV(1)) in patients with COPD and no reversibility to short-acting beta(2)-adrenoceptor agonists. FEV(1) was slightly improved over the first 6 months of treatment in two studies and lower airway reactivity in response to methacholine challenge has been observed. Improvement of respiratory symptoms and health status was also reported in three studies. A reduction in the rate of exacerbations was observed in two studies. No survival benefit was demonstrated in any study. The advantage of using inhaled, rather than oral, corticosteroids is a reduction in adverse effects for the same therapeutic effect, because inhaled corticosteroids rely more on topical action than systemic activity. The long-term safety of inhaled corticosteroids is not known in patients with COPD. However, topical adverse effects, and systemic effects such as a decrease of bone density of lumbar spine and femur and cutaneous adverse effects, have been reported in patients with COPD after 3 years of treatment with inhaled corticosteroids.     

The risk/benefit of inhaled corticosteroids in chronic obstructive pulmonary disease

Although inhaled corticosteroids have a well defined role in asthma therapy, their use remains controversial in nonasthmatic, smoking-related chronic obstructive pulmonary disease (COPD). Some studies have shown an effect of inhaled corticosteroids on airway inflammation in COPD, but the clinical relevance of these results is unknown. Data from five long-term, large studies, provide evidence that prolonged treatment with inhaled corticosteroids does not modify the rate of decline of forced expiratory volume in one second (FEV1) in patients with COPD and no reversibility to short-acting β₂-agonists. FEV1 was slightly improved over the first six months of treatment and lower reactivity in response to methacholine challenge has been observed. Improvement of respiratory symptoms and health status were also reported. A reduction of exacerbations rate was observed in two studies. No survival benefit was demonstrated. Two recent reports suggest that long term use of inhaled corticosteroids in COPD patients improves quality-adjusted life expectancy and is cost-effective. Combination therapy with inhaled corticos-teroids and long-acting β₂-agonists have proven benefit in four long term large studies compared to placebo for FEV1, exacerbation rate, symptoms and health status. However, only two studies found that combination therapy was more effective than long-acting β₂-agonists alone for symptoms and health status improvement. The long term safety of inhaled corticosteroids is not known in COPD patients but topical adverse effects, and systemic effects such as a decrease of bone density of lumbar spine and femur and cutaneous adverse effects, have been reported after three years of treatment. However, three recent observational studies found a slight increase in the risk of fractures (hip, upper extremities and vertebral) in association with high doses of inhaled corticotherapy.     

吸入型糖皮质激素用于哮喘患者的效果研究

目的借助于哮喘控制测试（ACT）,论证使用吸入型糖皮质激素作为控制哮喘患者病情的临床疗效,与未使用任何药物控制哮喘症状或疾病发作的患者进行数据比较。方法在2012年7月,总共60名哮喘患者被要求做ACT问卷,其中32名患者作为对照组（n=32）未使用任何控制药物;28名患者作为观察组（n=28）使用吸入型糖皮质激素;并对两组的ACT结果进行了比较。结果所有患者都进行了ACT,并得到了相应的ACT分值。在对照组中,所有男性（n=13）患者的哮喘病情都控制不佳,19名女性中只有2名（10.53%）患者的病情得到了轻微的控制,其余的17名女性患者（89.47%）哮喘病情都控制不佳。在观察组中,男性患者（n=13）有6名（46.15%）患者哮喘病情未得到控制,女性患者（n=15）中,只有3名（20%）患者哮喘病情未得到控制。总体来说,ACT分值高于19的情况下,11名（39.29%）患者的哮喘得到了良好控制。结论使用吸入型糖皮质激素的哮喘控制物,例如倍氯米松和去炎松在维持哮喘的良好控制方面取得较好结果 ,ACT分值结果展示了这一点。使用吸入型糖皮质激素与未使用任何控制物相比,ACT分值得到了显著改变。     

顺尔宁联合糖皮质激素吸入和单纯糖皮质激素吸入治疗儿童哮喘的效果对比

目的探讨顺尔宁联合糖皮质激素吸入和单纯糖皮质激素吸入治疗儿童哮喘的临床效果。方法将2014年2月~2016年12月在我院接受治疗的60例儿童哮喘患者作为本次研究对象,将其按照随机数字法平均分为两组,30例采用单纯糖皮质激素吸入治疗(对照组),30例给予顺尔宁联合糖皮质激素吸入治疗(研究组)。将两组患者临床疗效、湿啰音消失时间、哮鸣音消失时间、咳嗽消失时间、住院时间、FEV1、PEF、Eos指标及不良反应发生情况进行比较。结果研究组临床总有效率为86.66%,对照组临床总有效率为63.33%,研究组患者临床总有效率显著高于对照组(P<0.05)。研究组患者湿啰音消失时间、哮鸣音消失时间、咳嗽消失时间及住院时间均显著短于对照组(P<0.05)。干预前两组患者FEV1、PEF、Eos指标比较差异无统计学意义(P>0.05),干预后两组患者FEV1、PEF指标均显著升高,Eos指标均显著降低(P<0.05),且研究组较对照组改善显著(P<0.05)。研究组不良反应发生率为6.66%,对照组不良反应发生率为10.00%。两组患者不良反应发生率比较差异无统计学意义(P>0.05)。结论在儿童哮喘患者治疗中选择顺尔宁联合糖皮质激素吸入治疗可显著缩短患者临床症状消失时间及住院时间,提高治疗效果,降低患者经济负担,改善患者肺功能,且不良反应低安全有效,值得在临床上推广使用。