Corticosteroids in chronic obstructive pulmonary disease. Clinical benefits and risks

The use of systemic and inhaled corticosteroids for COPD has increased appreciably over the past 20 years. Clearer indications for corticosteroid therapy in COPD are beginning to emerge as the results from large clinical trials become available. Systemic corticosteroids are only modestly effective for acute COPD exacerbations, increase the risk for hyperglycemia, and should be given for no more than 2 weeks. The efficacy of long-term systemic corticosteroid therapy has not been adequately evaluated in this patient population. If longer term use of systemic steroids in COPD should be found to be useful, this conclusion would have to be weighed against the risk for serious adverse effects. High doses of inhaled corticosteroids cause a small sustained increase of the FEV1 in patients with mild and moderately severe COPD, but they do not slow the rate of FEV1 decline. Based on analyses of secondary outcome, inhaled corticosteroids may improve the respiratory symptoms and decrease the number and severity of COPD exacerbations in patients with more advanced disease. Low doses of inhaled corticosteroids appear to be safe, but there is growing awareness that higher doses may not be so benign.     

Similarities and differences in asthma and chronic obstructive pulmonary disease exacerbations

There is no generally accepted definition of an exacerbation either for asthma or for chronic obstructive pulmonary disease. There is little consistency among the symptomatic or functional criteria used in different studies. The most consistent criterion is the introduction of systemic corticosteroids for the acute worsening of the disease. The time course of an exacerbation does not seem to differ very much between asthma and chronic obstructive pulmonary disease (COPD). The decrease in peak flow rate is more pronounced in asthma than in COPD. The frequency of exacerbations is linked to disease severity both in asthma and COPD. Common causes are viral infections and increased environmental air pollution, whereas allergen exposure and bacterial infections are more specific for asthma and COPD exacerbations, respectively. Few data are available about the airway pathology of asthma or COPD exacerbations. Eosinophilia and/or neutrophilia have been associated with exacerbations in both diseases. Avoidance of the causal factors decreases exacerbation rate in both diseases. Pharmacologic prevention of exacerbations in asthma has been shown for inhaled corticosteroids, combination therapy with long-acting inhaled beta(2)-agonists and inhaled corticosteroids, and monoclonal anti-IgE. Inhaled corticosteroids, long-acting inhaled beta(2)-agonists, combination therapy with both, and the long-acting inhaled anticholinergic tiotropium decrease the exacerbation rate in COPD.     

Inhaled corticosteroids in chronic obstructive pulmonary disease and risk of death and hospitalization: time-dependent analysis

Observational studies of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD) have shown improved survival whereas randomized trials have not. It has been suggested that this difference may be due to immortal time bias. To investigate this further, we performed a prospective cohort study of patients with COPD, using time-dependent methods to determine whether use of inhaled corticosteroids more than 80% of the time reduced the risk of all-cause mortality and COPD exacerbations. Of 8,033 patients, 2,686 (33%) received inhaled corticosteroids. We did not find a significant reduction in mortality for average inhaled steroid use at either low (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.69-1.33) or medium/high dose (HR, 0.86; 95% CI, 0.67-1.10). Similarly, recent inhaled corticosteroid use was not associated with a reduction in mortality at low (HR, 0.80; 95% CI, 0.60-1.07) or medium/high doses (HR, 0.88; 95% CI, 0.71-1.09). There was no association between inhaled corticosteroid use and hospitalizations or exacerbations due to COPD. Patients using medium/high-dose inhaled corticosteroids did not have a significantly lower risk of COPD hospitalizations (HR, 0.85; 95% CI, 0.64-1.13) or COPD exacerbations (HR, 1.13; 95% CI, 0.94-1.36). In a time-dependent study of outpatients with COPD, adherence to inhaled corticosteroid use was not associated with a decreased risk of mortality or exacerbations.     

Inhaled corticosteroids and hospitalisation due to exacerbation of COPD.

Previous studies have provided conflicting evidence as to the possible benefits of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease (COPD). Using the Saskatchewan healthcare databases subjects were identified who were aged > or = 55 yrs, initiating regular treatment for COPD but without any prior treatment for asthma. In the current nested case-control analysis, the authors concentrated on 1,742 subjects with a first hospitalisation for COPD after January 1, 1990 and examined whether the use of inhaled corticosteroids was associated with a change in the risk of a subsequent hospitalisation for COPD. The cases consisted of 846 patients with a subsequent hospitalisation for COPD. These were matched on age, time since the prior hospitalisation and use of other respiratory therapy to all possible person moments in the cohort without rehospitalisation. After further adjustment for comorbidity, sex, calendar year and intensity of other drug therapy, inhaled corticosteroids were not significantly associated with risk of a subsequent COPD hospitalisation. Even relatively high doses of inhaled corticosteroids, >800 microg of beclomethasone or the equivalent per day, were not associated with the risk of COPD hospitalisation. No reduction in chronic obstructive pulmonary disease exacerbations requiring hospitalisation, in relation to the use of inhaled corticosteroids, were observed.     

Initial corticosteroid therapy for asthma

PURPOSE OF REVIEW: This review examines the commencement of maintenance pharmacotherapy for asthma: inhaled corticosteroids alone or in combination with long-acting beta2 agonists. RECENT FINDINGS: A systematic review of randomized controlled trials has examined the starting dose of inhaled corticosteroids (high, moderate, low) and the dose regimen (step down versus constant) in asthma. There was no significant difference in key asthma outcomes for step down compared with a constant inhaled corticosteroid dose. There was no significant difference between high or moderate dose inhaled corticosteroid groups (n=11) for morning peak expiratory flow, symptoms and rescue medication use. There may be a benefit from high-dose inhaled corticosteroids for airway hyperresponsiveness. There was a significant improvement in peak expiratory flow and nocturnal symptoms in favour of a moderate inhaled corticosteroid dose compared with low-dose treatment. Long-acting beta2 agonists combined with inhaled corticosteroids as initial asthma therapy has been examined in a systematic review of nine randomized controlled trials. Inhaled corticosteroids combined with long-acting beta2 agonists led to significant improvements in forced expiratory volume in 1 s, morning peak expiratory flow, symptom score and symptom-free days but no difference in exacerbations requiring oral corticosteroids. A randomized controlled trial of patients with uncontrolled asthma found a benefit of escalating doses of salmeterol/fluticasone compared with fluticasone on asthma control. SUMMARY: Initial inhaled corticosteroid therapy should begin with a constant, moderate dose. Initial therapy with long-acting beta2 agonist and inhaled corticosteroids achieves superior improvement in symptoms and lung function, and at a quicker rate than inhaled corticosteroids alone. There is no benefit in terms of reduced exacerbations unless an escalating inhaled corticosteroid dose strategy is used.     

The role of corticosteroids in chronic obstructive pulmonary disease

Oral corticosteroids are powerful relatively nonspecific antiinflammatory agents with a range of well-characterized side effects. There is good evidence to show that they accelerate the rate of resolution of exacerbations of COPD and relapse is less likely if patients receive these drugs. Maintenance therapy with oral preparations is associated with worse mortality and skeletal muscle myopathy is a particular problem. Corticosteroids have little effect on biopsy proven inflammation or its surrogates in COPD and did not change the rate of decline of FEV (1) over a range of spirometric disease severity in a number of trials each lasting 3 years. However, meta-analysis of the data suggests that a small effect (up to 10 ml /year) might be present. There is more consistent evidence for an effect on postbronchodilator FEV (1) with both fluticasone propionate and budesonide. In patients with a postbronchodilator FEV (1) < 50% predicted where self-reported exacerbations become more common, inhaled corticosteroids can reduce the number of attacks. This effect is the major factor accounting for the reduction in deterioration in health status seen in patients who receive inhaled corticosteroids. Inhaled corticosteroids are much safer than oral therapy, although they do have a predictably higher incidence of candidiasis and hoarseness of the voice. Skin bruising is seen in patients with better lung function who use these drugs. Triamcinolone use is associated with reduction in bone density but this was not seen with budesonide. Combining an inhaled corticosteroid and a long-acting beta-agonist in the same inhaler increases the efficacy of the latte drug in COPD patients, with a significantly larger improvement in FEV (1), a larger reduction in reported breathlessness, and a reduction in exacerbation numbers in those with severe disease where beta-agonists appear to be less effective. Inhaled corticosteroids are not suitable for monotherapy in COPD but can be helpfully combined with an inhaled bronchodilator in patients with symptomatic disease.     

Modifying the Course of Chronic Obstructive Pulmonary Disease: Looking Beyond the FEV1

Abstract

COPD is defined by airflow limitation that is not fully reversible and is usually progressive. Thus, airflow obstruction (measured as FEV₁) has traditionally been used as the benchmark defining disease modification with therapy. However, COPD exacerbations and extrapulmonary effects are common and burdensome and generally become more prominent as the disease progresses. Therefore, disease progression should be broader than FEV₁ alone. Interventions that reduce the frequency or severity of exacerbations or ameliorate extrapulmonary effects should also be considered disease modifiers. A narrow focus on FEV₁ will fail to capture all the beneficial effects of therapy on disease modification. Although smoking cessation has been unequivocally demonstrated to slow the rate of FEV₁ decline, inhaled corticosteroid–long-acting bronchodilator therapy may also have modest effects according to post hoc analysis. Maintenance pharmacotherapy with inhaled long-acting anti-muscarinic or ®-adrenergic agents or combined ®-adrenergic—inhaled corticosteroid reduces symptoms, improves lung function, reduces the frequency of exacerbations, and improves exercise capacity and HRQL. Pulmonary rehabilitation reduces symptom burden, increases exercise capacity, improves HRQL, and reduces health care utilization, probably through reducing the severity of exacerbations. Smoking cessation, lung volume reduction surgery, inhaled maintenance pharmacotherapy, and pulmonary rehabilitation administered in the post-exacerbation period may reduce mortality in COPD. These improvements over multiple outcome areas and over relatively long durations suggest that disease modification is indeed possible with existing therapies for COPD. Therefore, therapeutic nihilism in COPD is no longer warranted.     

Inhaled corticosteroids and survival in chronic obstructive pulmonary disease: does the dose matter?

Recent data suggest that inhaled corticosteroids reduce the number of clinical exacerbations in chronic obstructive pulmonary disease (COPD). It remains unknown whether a dose/response relationship exists. The present study was conducted to evaluate the long-term impact of varying doses of inhaled corticosteroids on COPD mortality. Hospital discharge data were used to identify all patients aged > or = 65 yrs recently hospitalised due to COPD in Alberta, Canada (n = 6,740). The relative risk (RR) for all-cause mortality was compared across different dose categories of inhaled corticosteroids (none and low, medium and high doses) following hospital discharge. Inhaled corticosteroid therapy after discharge was associated with a 25% relative reduction in risk for all-cause mortality (RR 0.75, 95% confidence interval (CI) 0.68-0.82). Patients on medium- or high-dose therapy showed lower risks for mortality than those on low doses (RR 0.77, 95% CI 0.69-0.86 for low dose; RR 0.48, 95% CI 0.37-0.63 for medium dose; and RR 0.55, 95% CI 0.44-0.69 for high dose). Use of inhaled corticosteroids following hospital discharge for chronic obstructive pulmonary disease was associated with a significant reduction in the overall mortality rate. Low- was inferior to medium- or high-dose therapy in protecting against mortality in chronic obstructive pulmonary disease.     

The Risk of Sepsis with Inhaled and Oral Corticosteroids in Patients with COPD

The use of oral and inhaled corticosteroids is associated with increases in the risk of infection, especially pneumonia. The risk of sepsis with corticosteroid treatment in patients with chronic obstructive pulmonary disease (COPD) has been little studied, however. We assessed whether the use of inhaled and oral corticosteroids in COPD is associated with an increase in the risk of sepsis. We carried out a retrospective cohort study using the administrative health databases of the province of Quebec, Canada, over the period 1990–2007. The cohort of patients with COPD included patients aged 55 years or older who used respiratory medications. A quasi-cohort analysis was used to estimate the rate ratio (RR) of sepsis in current users of inhaled corticosteroids and oral corticosteroids separately, after adjusting for differences in COPD disease severity and co-morbid conditions. The cohort included 163,514 patients treated for COPD, including 1,704 who were hospitalized for or died with sepsis during follow-up (incidence rate 1.94 per 1000 per year). The RR of sepsis associated with current use of inhaled corticosteroids was 0.98 (95%confidence interval [CI] 0.84–1.14). Current oral corticosteroid use was associated with a 66% increase in the risk of sepsis (RR 1.66; 95% CI: 1.35–2.05). The increase in risk remains for around 5 months after the oral corticosteroid exposure. Among patients treated for COPD, the risk of sepsis is not increased with inhaled corticosteroids, even at high doses, while the risk is increased with oral corticosteroids. This risk should be considered when treating exacerbations of COPD.     

Pulmonale Erkrankungen im Alter

In asthma, inhaled corticosteroids (ICS) can be regarded as disease-modifying drugs. They represent the mainstay of pharmacotherapy of asthma. In elderly, ICS are currently underused. In chronic obstructive pulmonary disease (COPD), there is recent evidence to suggest that ICS may reduce the rate and severity of COPD exacerbations and may improve health-related quality of life. Particularly patients with moderate-to-severe COPD appear to benefit from ICS therapy. In both asthma and COPD, fixed combinations of ICS and long-acting beta 2-agonists may provide clinically meaningful benefits to patients and may represent a further therapeutic advantage.     

The relationship between inflammation and symptoms in asthma

In asthma, symptoms are the main reason for recourse to healthcare and are a fundamental parameter for the evaluation of asthma control. Currently, asthma is defined as a chronic inflammatory disease. Uncontrolled asthmatics have an increased number of eosinophils in induced sputum and an increased production of exhaled NO. Control by anti-inflammatory treatment is accompanied by a reduction in bronchial eosinophilia and exhaled NO. Asthma symptoms are the result of complex mechanisms and many factors modify their perception. Experimental data suggests that there is a relationship between the perception of symptoms and eosinophilic inflammation, and that inhaled corticoid therapy improves this perception. Although they are still not applicable in routine practice, follow-up strategies based on the evaluation of inflammation are thought to be more effective in reducing exacerbations than those usually recommended based on retrospective evaluation of symptoms and sequential analysis of respiratory function. Inhaled corticosteroid therapy is the reference maintenance therapy for persistent asthma and adjustment of anti-inflammatory treatment based on symptoms is an effective strategy to prevent exacerbations and reduce the total dose of inhaled corticosteroids. A French expert group has undertaken a study of the association between inflammation and asthma symptoms by carrying out a critical review of the international literature.     

The role of combination therapy with corticosteroids and long-acting ��2-agonists in the prevention of exacerbations in COPD

Acute exacerbations of COPD can complicate the course of the disease in patients with severe airway obstruction. Reduction of exacerbations is an important clinical outcome in evaluating new therapies in COPD. Combination therapies with long-acting β-agonists and inhaled corticosteroids have now been approved for use. Three 1-year randomized clinical trials, which studied the effect of combining a long-acting β₂-agonist with an inhaled corticosteroid in COPD, documented that exacerbation frequency was lower with therapy than placebo. Combination therapy had a similar effect to its monocomponents in the trial evaluating salmeterol/fluticasone combination. However, when patients with more severe COPD were studied using a combination of budesonide and formoterol, a clear improvement was seen in the overall exacerbation rates compared with the use of a long-acting β₂-agonist alone.     

Bronchial hyper-responsiveness and exhaled nitric oxide in chronic obstructive pulmonary disease

Several lung diseases including asthma and chronic obstructive pulmonary disease (COPD) involve chronic inflammation of the airways. Therefore, there is great interest in non-invasive methods assessing airway inflammation. Measurement of bronchial hyper-responsiveness (BHR) and exhaled nitric oxide (NO) are such indirect markers of airway inflammation. Additional information about severity of disease, prognosis and possible response to anti-inflammatory treatment with inhaled corticosteroids can be gained by these methods. However, they are not yet established in assessing patients with COPD in clinical routine. BHR has long been recognised as a hallmark of asthma. Less is known about prevalence and clinical relevance of BHR in the general population and in COPD patients. Longitudinal studies have shown that BHR in healthy persons is a risk factor for development of respiratory symptoms, asthma and COPD. BHR has also been shown to increase the detrimental effect of cigarette smoke and is associated with a decline in lung function. Furthermore, studies indicate that the presence of BHR is a prognostic factor in COPD. Increased BHR to histamine has been shown to be a predictor for mortality in COPD patients. Based on current guidelines, treatment of patients with severe COPD (GOLD stage III and IV) and regular exacerbations includes therapy with inhaled corticosteroids. Inhaled corticosteroids have been shown to reduce frequency of exacerbations but they have not been shown to modify long-term decline in FEV1. However, one small study found that BHR to inhaled mannitol could possibly predict responsiveness to inhaled corticosteroids in patients with moderately severe COPD and identify a subgroup of patients that is likely to benefit from this treatment. Exhaled NO has been shown to correlate with other inflammatory markers and to be elevated in asthma. In COPD patients, data is inconsistent. However, measuring exhaled NO may have a role in the identification of patients with severe, unstable COPD who were shown to have higher NO levels compared to patients with stable COPD. This suggests that exhaled NO might be a method to assess and monitor disease activity in COPD. Possible explanations for the contradictory results are different measurement techniques of exhaled NO and different smoking histories of patients in various studies. Smoking has been found to be a confounding factor by reducing NO levels significantly, an effect which might counteract the potentially increased exhaled NO due to airway inflammation. In conclusion, measuring BHR and exhaled NO in patients with COPD might provide additional information about disease severity, prognosis and possible response to anti-inflammatory medical treatment. However, to establish these methods in clinical routine in COPD patients, more data is clearly needed.     

Limitations of drug prescriptions in patients with chronic obstructive pulmonary disease

National and international guidelines have described in detail the role of bronchodilators and inhaled corticosteroids for the management of patients with chronic obstructive lung disease (COPD). Such guidelines are identical to marketing approval documents in France. The French marketing approval, which limits use of bronchodilators to reversible COPD, is no longer coherent with recent evidence demonstrating the poor reproducibility of reversibility tests and the absence of correlation between reversibility and dyspnea relief. France has not delivered marketing authorization for any inhaled corticosteroid for the treatment of COPD. Clinical trials versus placebo have demonstrated that inhaled corticosteroids do not slow down the decline in ventilatory function but that they do diminish the risk of exacerbation. Decreased risk of exacerbation could be clinically pertinent in patients with severe COPD who often experience exacerbations requiring to specialist management. Inquiries concerning precriptions for COPD show that the majority of patients are treated by inhaled corticosteroids, demonstrating the gap between medical practice and national and international recommendations and marketing approval documents.     

Exacerbation-free COPD: a goal too far?

The seventh Lund COPD workshop focused on exacerbations. As chronic obstructive pulmonary disease (COPD) progresses, exacerbations, events characterized by acute worsening of symptoms, increase in frequency and severity. Patients fear their occurrence, as they compromise function and quality of life, may require admission to the hospital, and can be fatal. There are therapies that improve outcome of exacerbations, such as antibiotics and corticosteroids. More importantly, some treatments, such as regular inhaled bronchodilator therapy (particularly with long-acting agents), inhaled corticosteroids, and vaccination against influenza virus, can partially prevent attacks. However, exacerbations remain a challenge, as no therapy effectively banishes them. The current symposium, "Exacerbation-free COPD, a goal too far?", was designed to address this problem. The challenge addressed by the participants was whether more effective treatments could be developed that could further eliminate COPD exacerbations.     

The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics.

The clinical benefit and steroid-sparing effect of treatment with the anti-immunoglobulin-E (IgE) antibody, omalizumab, was assessed in patients with moderate-to-severe allergic asthma. After a run-in period, 546 allergic asthmatics (aged 12-76 yrs), symptomatic despite inhaled corticosteroids (500-1,200 microg daily of beclomethasone dipropionate), were randomized to receive double-blind either placebo or omalizumab every 2 or 4 weeks (depending on body weight and serum total IgE) subcutaneously for 7 months. A constant beclomethasone dose was maintained during a 16-week stable-steroid phase and progressively reduced to the lowest dose required for asthma control over the following 8 weeks. The latter dose was maintained for the next 4 weeks. Asthma exacerbations represented the primary variable. Compared to the placebo group, the omalizumab group showed 58% fewer exacerbations per patient during the stable-steroid phase (p<0.001). During the steroid-reduction phase, there were 52% fewer exacerbations in the omalizumab group versus the placebo group (p<0.001) despite the greater reduction of the beclomethasone dosage on omalizumab (p<0.001). Treatment with omalizumab was well tolerated. The incidence of adverse events was similar in both groups. These results indicate that omalizumab therapy safely improves asthma control in allergic asthmatics who remain symptomatic despite regular use of inhaled corticosteroids and simultaneous reduction in corticosteroid requirement.     

The importance of control in asthma management: do leukotriene receptor antagonists meet patient and physician needs?

Achieving control of asthma is a major goal of asthma management. Overreliance on high doses of a beta-agonist or a recent increase in beta-agonist requirement, increasing or wide variability in peak expiratory flow (PEF), and increased frequency of nocturnal symptoms are indicators of poor or declining asthma control, which should highlight the need to take action to avoid the risk of severe and potentially life-threatening asthma exacerbations. The prevention of exacerbations is important because these often require unscheduled physician visits and involve costly medical care. If control is not achieved, diagnosis, treatment, and compliance with therapy should be reviewed, stepping up to a more powerful treatment only if necessary to control symptoms. Many patients often receive inadequate treatment despite the best intentions of their physician. Incorrect inhaler technique and non-compliance with prescribed inhaled asthma therapy may contribute to treatment failure in 50% of patients and are recognized increasingly as reasons for poor response to treatment. Growing evidence indicates that leukotriene receptor antagonists (LTRAs) are useful as controller agents. As a simple tablet therapy, LTRAs should be considered as an alternative treatment option to inhaled corticosteroids in specific patient groups who are poorly compliant or reluctant to use inhaled corticosteroids. These agents reduce the risk of asthma exacerbations and are associated generally with improved compliance compared with inhaled corticosteroids or cromolyn sodium. Moreover, add-on therapy with LTRAs can provide additional benefits to patients whose asthma is not controlled adequately with existing doses of inhaled corticosteroids, and the complementary benefits obtained with these drugs facilitate the achievement of long-term control without the need for increasing the dose of corticosteroids.     

Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations.

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients showed greatest benefit. In this study the patients were stratified into mild and moderate-to-severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined. There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate-to-severe disease. The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate-to-severe disease. FP reduced the overall exacerbation rate in moderate-to-severe disease (FP median rate 1.47 yr(-1), placebo 1.75 yr(-1)), but not in mild disease (FP 0.67 yr(-1), placebo 0.92 yr(-1)). FP use was associated with fewer patients with > or = 1 exacerbation x yr(-1) being treated with oral corticosteroids (mild: FP 8%, placebo 16%; moderate-to-severe: FP 17%, placebo 30%). Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second <50% predicted. These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate-to-severe chronic obstructive pulmonary disease who experience recurrent exacerbations.