Corticosteroids in COPD

Appropriate situations to consider corticosteroids in COPD include (1) shortterm systemic use for acute exacerbations and (2) inhalation therapy for chronic stable COPD. 

The role of inhaled corticosteroids in COPD is controversial. Major clinical trials have failed to demonstrate any benefit from chronic treatment in modifying long-term decline in lung function. However, other important benefits have been observed in some patients, including a decrease in exacerbation frequency and improvements in overall health status. 

Table 5. Randomized placebo controlled trials on inhaled corticosteroids in COPD ...

Renkema TE, Schouten JP, Koeter GH, Postma DS. Effects of long-term treatment with corticosteroids in COPD. Chest 1996 109 1156-62. 

The anti-inflammatory mechanisms whereby corticosteroids exert their beneficial effect in COPD include (1) reduction in capillary permeability to decrease mucus, (2) inhibition of release of proteolytic enzymes from leukocytes, and (3) inhibition of prostaglandins. Unfortunately, the clinical benefits of systemic corticosteroid therapy in the chronic management of COPD are often not evident, and the risk of toxicity is extensive and far-reaching. Currently, the appropriate situations to consider corticosteroids in COPD include (1) short-term systemic use for acute exacerbations and (2) inhalation therapy for chronic stable COPD. 

Welte T. Inhaled corticosteroids in COPD and risk of pneumonia. Lancet 2009 374 (9691) 668-70. 

Inhaled steroids (commonly used are beclomethasone, budesonide, triamcinolone, fluticasone, flunisolide) appear to attenuate the inflammatory response, to reduce bronchial hyperreactivity, to decrease exacerbations and to improve health status they may also reduce the risk of myocar dial infar ction, but they do not modify the longterm decline in lung function. Whether- steroids affect mortality remains unclear. Many patients appear to be resistant to steroids and large, long-term trials have shown only limited effectiveness of inhaled corticosteroid ther apy. Certainly, the benefit from steroids is smaller in COPD than in asthma. Topical side-effects of inhaled steroids are oropharyngeal candidiasis and hoarse voice. At the normal doses systemic side-effects of inhaled steroids have not been firmly established. The current recommendation is that the addition of inhaled gluco-coiticosteroids to bronchodilator treatment is appropriate for patients with severe to veiy sever e COPD. 

Corticosteroids have been evaluated in several types of cerebral injury, including cerebral infarction. Corticosteroids reduce vasogenic edema, such as that associated with neoplasms, but not cytotoxic edema, the type associated with ischemic stroke. A large meta-analysis found no benefit to the use of corticosteroids in ischemic stroke (or intracerebral hemorrhage), and their use is not recommended, except to treat concomitant conditions that mandate it (e.g., COPD flare). 

The antiinflammatory mechanisms whereby corticosteroids exert their beneficial effect in COPD include reduction in capillary permeability to decrease mucus, inhibition of release of proteolytic enzymes from leukocytes, and inhibition of prostaglandins. 

Presently, inhaled steroids (up to the equivalent of BDP 1000 pg/d, budesonide 800 pg/d, fluticasone 500 pg/d) should be given to patients who show an objective response to either oral or inhaled steroids (s. corticosteroid reversibility testing). For those patients who experience no symptomatic relief, the currently available evidence does not support the use of ICS for alteration of the natural history of the disease. Nevertheless, corticosteroids are effective in treating acute exacerbations in COPD and taking patients of off their ICS regimen may lead to deterioration. Oral corticosteroids (e.g. 40 mg prednisolone for ten days) are recommended for exacerbations, if... 

Inhaled corticosteroids do have a role in COPD. They should be prescribed for patients with an FEV, <50% predicted, with two or more exacerbations in 12 months that require antibiotics or oral corticosteroids. These patients are still breathless despite monotherapy with a long-acting beta2-agonist. Maintenance use of oral corticosteroids is not recommended, but some patients with advanced COPD may require them. Oral corticosteroids should be used in all patients admitted to hospital with an exacerbation of COPD. There is insufficient evidence to establish the minimum dose of inhaled corticosteroids to obtain benefit (NICE, 2004). 

Inhaled corticosteroids should be prescribed for patients with an FEVi of 50% predicted or less, who have two or more exacerbations needing treatment with antibiotics or oral corticosteroids a year. Warn patients about the possible risk of osteoporosis and other side effects of high-dose inhaled corticosteroids. None of the inhaled corticosteroids currently available is licensed alone for use in COPD. 

In addition to the above measures, systemic corticosteroids are used to improve pulmonary function and provide symptomatic relief. Treatment durations in excess of 2 weeks are associated with increased corticosteroid-related adverse effects. The use of topical, inhaled corticosteroids in the acute management of COPD exacerbation is not appropriate. 

The role of inhaled corticosteroid therapy in COPD is not well established. Patients with severe COPD and frequent exacerbations may benefit from inhaled corticosteroids. 

Corticosteroid therapy has been studied and debated in COPD therapy for half a century however, owing to the poor risk-benefit ratio, chronic systemic corticosteroid therapy should be avoided if possible. Because of the potential role of inflammation in the pathogenesis of the disease, clinicians hoped that corticosteroids would be promising agents in COPD management. However, their use continues to be debated, especially in the management of stable COPD. 

Although a dose-response relationship for inhaled corticosteroids has not been demonstrated in COPD, the major clinical trials employed moderate to high doses for treatment. Side effects of inhaled corticosteroids are relatively mild compared with the toxicity from systemic therapy. Hoarseness, sore throat, oral candidiasis, and skin bruising have been reported in the clinical trials. Severe side effects, such as adrenal suppression, osteoporosis, and cataract formation, have been reported less frequently than with systemic corticosteroids, but clinicians should monitor patients who are receiving high-dose chronic therapy. ... 

Davies and colleagues evaluated the oral use of corticosteroids in hospitalized patients with acute exacerbations of COPD. Patients received either 30 mg/day oral prednisolone or placebo for 14 days. Patients who were treated with corticosteroids had a significantly more rapid improvement in FEVi and a shorter hospital stay than did patients who received placebo. There was no significant difference between groups at 6-week follow-up. 

Singanayagam A, Chalmers JD, Akram AR, Hill AT. Impact of inhaled corticosteroid use on outcome in COPD patients admitted with pneumonia. Eur Respir J 2011 38(1) 36-41. 

Crim C, Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Willits LR, Yates JC, Vestbo J. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination TORCH study results. Eur Respir J 2009 34(3) 641-7. 

Hanania, N. A. (2008). The impact of inhaled corticosteroid and long-acting beta-agonist combination therapy on outcomes in COPD. Pulmonary Pharmacology Therapeutics, 21(2), 540-550. 

In symptomatic patients with severe COPD and frequent exacerbations, regular treatment with inhaled corticosteroids decreases the number of exacerbations per year and improves health status however, corticosteroids do not slow the longterm decline in pulmonary function. 

Upon discontinuation of inhaled corticosteroids some patients may experience deterioration in lung function and an increase in dyspnea and mild exacerbations it is reasonable to reinstitute the medication in these patients.25 Completion of ongoing clinical trials assessing mortality should help to clarify the role of corticosteroid treatment of COPD. 

The clinical benefits of systemic corticosteroid therapy in the chronic management of COPD are often not evident, and there is a high risk of toxicity. Consequently, chronic, systemic corticosteroids should be avoided if possible. 

The first commercially available DPI system appeared on the market in 1949, developed and marketed by Abbott under the name Aerohaler. Like all early pulmonary drug-delivery devices, it delivered small-molecule compoimds (bronchodilators or inhaled corticosteroids) to the airways (not necessarily the deep limg) for the treatment of asthma or chronic obstructive pulmonary disease. Table 6 lists some of the early DPI systems used for asthma and COPD the energy somces in these devices were mechanical and patient inspiration. 

Reversibility tests to bronchodilators are recommended at all stages of obstructive airways diseases. They are helpful in differentiating patients with COPD with those of asthma. Many patients with COPD and even those with severe airflow obstruction can demonstrate (partial) reversibility. Patients with a positive bronchodilator response i.e. reversibility are more likely to respond to a trial of oral or inhaled corticosteroids. 

Although a variety of interpretations have been issued, reversibility to bronchodilators is considered to be present when the FEV i increases by 200 ml and 12% of the pre-bronchodilator value. Although in the latest GINA guidelines this issue is no longer addressed, the same criteria have been used for evaluation of the response to corticosteroids. A corticosteroid trial compared spirometric tests before and at the end of oral prednisolone (e.g. 30 mg/d) taken for two weeks or a course of inhaled steroid (e.g. beclomethasone 500 pg twice daily or equivalent) taken for six weeks. A positive response to corticosteroids justified prescription of regular inhaled steroid. Subjective improvement as a single efficacy parameter is not considered to be a satisfactory end point. Objective improvement is seen in 10-20% of patients with COPD. 

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