Oral corticosteroids for stable chronic obstructive pulmonary disease

Julia AE Walters; E Haydn Walters; Richard Wood‐Baker

doi:10.1002/14651858.CD005374

. 2005 Jul 20;2005(3):CD005374. doi: 10.1002/14651858.CD005374

Oral corticosteroids for stable chronic obstructive pulmonary disease

Julia AE Walters ^1,^✉, E Haydn Walters ², Richard Wood‐Baker ¹

Editor: Cochrane Airways Group

PMCID: PMC13634668 PMID: 16034972

Abstract

Background

Chronic obstructive pulmonary disease (COPD) is a common chronic lung disorder, usually related to cigarette smoking, representing a major and increasing cause of morbidity and mortality. It is defined "as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases". The use of corticosteroids for their anti‐inflammatory effects has been suggested.

Objectives

To assess the effects of oral corticosteroids on the health status of patients with stable COPD.

Search methods

Searches of the Cochrane Airways Group Specialised Register and MEDLINE were carried out in December 2003 and 2004. Review articles and bibliographies were searched.

Selection criteria

Randomised controlled prospective studies in adults with stable COPD ( post‐bronchodilator FEV1 <80% of predicted, FEV1/FVC <70%) and a history of smoking, excluding known asthmatics, in which oral steroid use was compared with placebo and use of co‐interventions was matched in both groups.

Data collection and analysis

Data was extracted independently by two reviewers. All trials were combined using Review Manager.

Main results

From 459 titles 24 studies met the inclusion criteria. Treatment lasted three weeks or less in 19 studies, high dose oral steroid was used in 21 studies and subjects had moderate or severe COPD in 15 studies. There was a significant difference in FEV1 after two weeks treatment, WMD 53.30 ml; 95% confidence interval 22.21 to 84.39 favouring oral steroid use compared to placebo when 14 studies with available data (n=396) were combined, with no significant heterogeneity. There was a significant increase in odds for individual patient FEV1 response greater than 20% from baseline with high dose oral steroid treatment compared to placebo, OR 2.71; 95% CI 1.84 to 4.01 (9 studies) . It would be necessary to treat 7 patients (95% CI 5 to 12) with oral corticosteroids to achieve one extra case of increasing FEV1 by more than 20%, with a placebo group risk of 0.13. All differences in health‐related quality of life were less than the minimum clinically important difference.

There were small statistically significant advantages for functional capacity and respiratory symptom of wheeze with oral steroid treatment but no significant difference in risk of withdrawal from study due to an exacerbation or rate of serious exacerbations over 2 years with low dose oral steroid treatment. There was an increased risk of adverse effects, including increased blood glucose, adrenal suppression and reduced serum osteocalcin.

Authors' conclusions

There is no evidence to support the long‐term use of oral steroids at doses less than 10‐15 mg prednisolone though some evidence that higher doses (≥ 30 mg prednisolone) improve lung function over a short period. Potentially harmful adverse effects e.g.. diabetes, hypertension, osteoporosis would prevent recommending long‐term use at these high doses in most patients.

Keywords: Humans; Administration, Oral; Adrenal Cortex Hormones; Adrenal Cortex Hormones/administration & dosage; Pulmonary Disease, Chronic Obstructive; Pulmonary Disease, Chronic Obstructive/drug therapy; Randomized Controlled Trials as Topic

Plain language summary

Oral corticosteroids for stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a common, progressive lung disorder with mainly non‐reversible limitation of airflow. Corticosteroids improve airflow limitation in asthma and have been tried in COPD. This review found treatment with oral steroids improved lung function and symptoms more than placebo, but not all people benefited equally. Long‐term use did not slow the decline in lung function and there was an increased risk of side‐effects such as diabetes and osteoporosis.

Background

Chronic obstructive pulmonary disease (COPD) is a common chronic lung disorder, usually caused by cigarette smoking, representing a major and increasing cause of morbidity and mortality (NHLBI 1998). The World Health Organization (WHO) estimates that COPD is currently the seventh leading cause of death and disability worldwide, but will rise to the fifth position by 2020 (Murray 1997). The estimated prevalence of COPD worldwide in 2001 was 1013 per 100,000 population; it was highest in the Western Pacific Region and lowest in Africa.

The diagnosis and management of Chronic Obstructive Pulmonary Disease (COPD) has been hindered over many years by lack of agreement on definition and classification. The definition of COPD has varied historically but generally included the presence of airflow obstruction, which was described as mostly irreversible and was progressive. (ATS 1995, BTS 1997, Siafakas 1995). These definitions attempted to link the clinical syndrome of chronic bronchitis, i.e. cough and sputum production on most days for three consecutive months in each of two consecutive years with the pathological processes leading to pulmonary emphysema (destruction of the lung parenchyma with widening and loss of the terminal air spaces). In the late 1990s the need to raise awareness of COPD and decrease morbidity and mortality from the disease led to the establishment of an international initiative between the World Health Organization (WHO) and National Heart, Lung and Blood Institute (NHLBI) to form the Global Initiative for Obstructive Lung Disease (GOLD). GOLD defines COPD "as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases" (Pauwels 2001). This definition includes a recognition that COPD is characterised by chronic airway inflammation. It was based on well documented pathologic changes found in central airways (trachea, bronchi and bronchioles >2 mm diameter) of inflammatory cell infiltrates (Saetta 1993) , in peripheral airways (small bronchi and bronchioles with a diameter < 2 mm ) of injury and repair cycles (Saetta 1998) and enlargement of mucus‐secreting glands (Mullen 1985). Macrophages, T lymphocytes (predominantly CD8+ suppressor/killer cells) and neutrophils were found to be increased in various parts of the airways and lung.

Inflammation as the basis for the pathogenesis of COPD is now incorporated into clinical guidelines for the management of COPD (GOLD, COPDX, NICE) (Pauwels 2001, McKenzie 2003, NICE 2004). Corticosteroids have historically been used empirically in patients with COPD. However, in a 1978 a review of studies apparently showing a positive effect of systemic therapy in COPD, included only one non‐blinded controlled trial (Sahn 1978). Hudson 1990 suggested that one rationale for corticosteroid use in COPD was their anti‐inflammatory action. In 1991 a review and meta‐analysis including ten studies of oral corticosteroid therapy for patients with stable COPD concluded that patients receiving oral steroids had a 20% or greater improvement in baseline FEV1 in 10% more cases that those on placebo (reported as an absolute increase), (Callahan 1991).

The natural history of COPD has been classically portrayed as one of chronic progressive decline in lung function with time (Fletcher 1977) with the decrease being accelerated in continuing smokers. It has been shown that smoking cessation slows progression of COPD (Anthonisen 1994) but there is evidence that the structural and inflammatory changes initiated by smoking persist even after smoking cessation has been achieved (Sutherland 2003). The clinical course is punctuated by acute respiratory exacerbations, often triggered by upper respiratory tract infections (ATS 1995), which further decrease lung function.

A recent Cochrane Review has concluded that systemic steroids are of benefit in acute exacerbations of COPD (Wood‐Baker 2003). Four randomised studies of inhaled corticosteroid use in COPD are inconclusive (Burge 2000; LungHealth Stdy 2000; Pauwels 1999; Vestbo 1999) and a protocol for a comprehensive review and meta‐analysis of their use in stable COPD is currently on the Cochrane Library (Yang 2001).

In developed countries with adequate availability of health care, more costly inhaled corticosteroids have replaced the use of readily available and easy to administer oral corticosteroids for long‐term use in respiratory diseases such as asthma and COPD. However, the rise in morbidity and mortality from COPD will be most dramatic in Asian and African countries over the next two decades, mostly due to progressive increase in the prevalence of smoking (Chan‐Yeung 2004). As these regions include many poor developing countries, if the use of oral steroids in COPD can be justified, they may be able to make considerable financial savings.

However, there are well known adverse effects to the use of systemic corticosteroids. These include increased risk of infections, glucose intolerance, hypertension, osteoporosis, adrenal suppression and posterior subcapsular cataract formation.   This review examines whether oral corticosteroids have any benefit in stable COPD and what long term adverse consequences their use may have.

Objectives

The objectives of this review are to determine whether systemic oral corticosteroids improve the health status of patients with stable COPD in terms of lung function, quality of life, functional capacity, rate of exacerbations requiring treatment and to examine the negative effects of treatment.

Methods

Criteria for considering studies for this review

Types of studies

Randomised, placebo controlled prospective studies, single or double blind, parallel group or crossover.

Types of participants

Adults with a diagnosis of COPD based on objective criteria such as those of GOLD. We looked for evidence of incomplete reversibility of airflow obstruction (a post‐bronchodilator FEV1 <80% of the predicted value, the ratio of FEV1 to FVC <70%) and a history of smoking. We assessed stability of disease at the time of entry, with a minimum of one month without an acute exacerbation or use of systemic steroids. We assessed criteria used to identify and exclude patients with asthma.

Types of interventions

Corticosteroid administered orally on a daily or alternate‐day regimen for a minimum duration of one week. A comparison group treated ideally with matching placebo. Co‐interventions such as a beta‐agonist agent, theophylline and inhaled corticosteroid were permitted, provided their use was matched in both groups.

Types of outcome measures

Primary outcomes

The primary outcomes were (1) changes in FEV1 and (2) health‐related quality of life.

Secondary outcomes

Secondary outcomes were the proportion of patients who are "responders" to therapy, acute exacerbations of COPD, symptom severity, functional capacity and adverse effects of medications. Outcome analysis was stratified into short‐term use (steroids for less than six weeks) and long‐term use (steroids for six weeks or more), low dose or high dose oral steroid use, concomitant inhaled corticosteroid use and severity of disease.

Search methods for identification of studies

Electronic searches

A search of the Cochrane Airways Group Specialised Register of COPD trials was carried out using the terms:   glucocorticoid* or hydroxycorticosteroid* or hydroxysteroid* or anti‐inflammator* or "anti inflammator*"or steroid* or corticosteroid* or prednisone or prednisolone or methylprednisolone or dexamethasone or cortisone or hydrocortisone* or medrol or solumedrol or solu‐medrol

A additonal search of MEDLINE was carried out using the terms: (COPD OR emphysema OR COAD OR chronic obstructive pulmonary disease OR chronic obstructive airways disease OR chronic bronchitis) AND ("adrenal cortex hormone*" OR steroid* OR glucocorticoid* OR corticosteroid* OR betamethasone OR cortisone OR dexamethasone OR hydrocortisone OR prednisolone OR prednisone OR methylprednisolone OR methylprednisone OR triamcinolone OR hydroxycorticosteroid* OR anti‐inflammator* OR "anti inflammator*").

Searching other resources

Review articles and the bibliographies of studies located for inclusion were searched for relevant references. The most recent searches were carried out in December 2004.

Data collection and analysis

Selection of studies

Titles, abstracts and citations were reviewed by one reviewer (JAEW) to assess potential relevance for full review. The full text of articles on studies which clearly did not fall outside the entry criteria were assessed independently for inclusion by one reviewer with technical assistance from the Cochrane Airways Reviewer Support (CARS) project. The reviewer and CARS personnel independently specified the reason for exclusion for studies not selected. They assessed the included studies independently for quality using two methods.

Data extraction and management

Data was extracted from published selected studies and entered into the Cochrane Collaboration software program Review Manager independently by one reviewer with technical assistance from the CARS project. Any disagreements were resolved by consensus and discussion with a second reviewer (RWB). Authors were requested to clarify and provide additional information when data extracted from texts, tables or graphics were not clear to the reviewers.

Where actual P‐values obtained from t‐tests were quoted, we extracted standard deviations by first obtaining the corresponding t‐value from a table of the t‐distribution (using the appropriate degrees of freedom NE + NC‐ 2), and then transforming the t‐value into a standard deviation. The standard error of the difference in means is obtained by dividing the difference in means (MD) by the t‐value: SE MD = MD/t‐statistic

The average standard deviation for both groups was calculated using the formula: SD=(SE of MD)/ √(1/Ne + 1/Ni)

Assessment of risk of bias in included studies

First, using the method described in the Cochrane Handbook which involves assessing the quality of the random allocation (i.e. control of selection bias at entry). This uses a three point scale :   Grade A: Adequate concealment   Grade B: Unclear concealment   Grade C: Obviously not adequate concealment

Second, each study was also assessed for validity on a standardized 0‐5 scale (Jadad 1996) as follows:

Study described as randomised? (1=yes, 0=no)
Study described as double‐blind? (1=yes, 0=no)
Description of withdrawals and drop outs? (1=yes, 0=no)
Method of randomizations well described and appropriate? (1=yes, 0=no)
Method of double‐blinding well described and appropriate? (1=yes, 0=no)
1 point deducted if methods of randomizations or blinding were inappropriate.

Any disagreements were resolved by consensus or by discussion with a second reviewer (RWB). The impact of quality score was evaluated via sensitivity analysis (score 1‐3 versus score 4 or 5). Kappa statistics were used to assess reviewer agreement.

Unit of analysis issues

Data from crossover studies was extracted according to published results. If the data from the first period was available separately this was used as a parallel group comparison. Where this was not available, the effect estimate for continuous variables calculated using methods for paired data were sought . For dichotomous variables, the marginal method of Becker‐Balgatas was used to calculate the crossover OR and variance (Curtin 2002). For analyses involving crossover studies the effect estimates were pooled using the generic inverse variance method in which the weight for each study is taken to be the inverse variance of the effect estimate (Deeks 2004). In order to allow dichotomous and continuous data to be pooled together for outcomes not presented in the same manner the method of Chinn 2000 was used, a statistical approach which re‐expresses odds ratios as standardised mean differences (and vice versa) subject to particular distributional assumptions.

Data synthesis

For continuous variables, the results of individual studies were calculated as the effect estimate and 95% confidence interval (CI). For parallel group studies alone, the pooled fixed effect weighted mean difference (WMD) or standardised mean difference (SMD) and 95% CI were calculated using the Mantel‐Haenszel method. For pooled effects, a Breslow‐Day test of heterogeneity was carried out, and a P value <0.05 was considered significant. The I² statistic was calculated for pooled effects, using the formula [(Q‐df)/Q] x 100%, where Q is the chi squared statistic and df is the degrees of freedom, to describe the percentage of total variation across studies due to heterogeneity rather than chance (Higgins 2003).

For dichotomous outcomes the odds ratio (OR) with 95% confidence interval was calculated and compared with the risk ratio (RR) and risk difference (RD). For outcomes with very low events or none in groups the Peto odds ratio was used.

Subgroup analysis and investigation of heterogeneity

Planned subgroup comparisons planned were:

Use of inhaled steroids
Steroid dose used
Severity of COPD at study entry (based on FEV1 as a percentage of predicted normal for age and sex)
Length of intervention‐ short term < 3 months, long term > 3 months

Subgroup analyses were actually carried out using the following criteria (some studies reported results for sub‐groups not specified in the protocol):   1. Steroid dose‐ high dose (equivalent to at least 30 mg prednisolone for most of the treatment period) or intermediate dose to low dose (equivalent to < 20 mg prednisolone)   2. Length of intervention‐ [short term 1‐3 weeks versus long term ≥ 6 weeks]   3. Severity of COPD at study entry‐ mild to moderate versus moderate to severe, using guideline specified criteria   4. Bronchodilator reversibility status (subjects showing > 20% increase in baseline FEV1 following inhalation of salbutamol)   5. Use of inhaled corticosteroids   6. Sputum eosinophil count

Results

Description of studies

Results of the search

A search of the Airways Review Group trials register in December 2003 yielded 459 results. Sixty were assessed for possible inclusion. Twelve were not relevant, 10 provided background information and 38 were obtained for full assessment. Reference lists and bibliographies were searched for studies not already identified. A repeat search in December 2004 did not yield any additional completed studies meeting the inclusion criteria. One study was on‐going (Mortimer).

14 studies assessed for inclusion in 2003 were then excluded and two in 2004. The reasons for exclusion were: lack of randomisation (14), lack of placebo group (1) and COPD not stable (1) as detailed in Characteristics of excluded studies.

Included studies

24 studies (two with double citation) meeting the inclusion criteria were included in the review. Three studies were published prior to 1970, 11 between 1970 and 1989, 8 between 1990 and 1999 and two studies since 2000.

One was published only in abstract form (Davies 2000). A request was sent to the authors of this study and also to Goel 1992 for further details of study design and missing results. A copy of the unpublished paper was supplied for Davies 2000.

A full description of all studies can be found in Characteristics of included studies.

Participants

The subjects in all included studies (with full publication) had chronic airflow limitation, the basis for which was specified . Apart from two early studies (Moyes 1957; O'Reilly 1982) all studies also specified that most subjects included had a long history of smoking.

Twelve studies included subjects with moderate or severe COPD (Blair 1984; Davies 2000; Eliasson 1986; Lam 1983; Mendella 1982; Mitchell 1984; Mitchell 1986; Morgan 1964; Moyes 1957; Nishimura 2000; Syed 1991; Weir 1990). Subjects in Wempe 1992 had COPD varying from mild to severe while it was uniformly severe in Beerel 1963, Corden 1998; Robertson 1986 and Weir 1993. Severity of COPD was not specified in Brightling 2000, Evans 1974, Goel 1992, O'Reilly 1982, Renkema 1996, Strain 1985 and Weiner 1999.

Thirteen studies stated that subjects had stable COPD and specified a period of at least four weeks pre‐trial during which they had been free of exacerbations (Blair 1984; Brightling 2000; Davies 2000; Eliasson 1986; Goel 1992; Lam 1983; Mendella 1982; Mitchell 1986; Nishimura 2000; Strain 1985; Syed 1991; Weir 1993; Wempe 1992). In eight studies the subjects were stated to have stable disease but the basis for this was not made clear (Beerel 1963; Corden 1998; Evans 1974; Mitchell 1984; Renkema 1996; Robertson 1986; Weiner 1999; Weir 1990). There was no reference to criteria defining stability of COPD for subjects in three fully published studies (Morgan 1964; Moyes 1957; O'Reilly 1982) however the settings of these studies and description of subjects does not indicate they were experiencing an acute exacerbation of their disease at recruitment.

The exclusion of subjects with asthma was deemed to be adequate in 19 studies, usually on the basis of clinical diagnosis with or without other confirming features of atopy or bronchial hyperreactivity. There was not enough information published in Swinburn 1986 to make a determination and in four studies ( Beerel 1963; Lam 1983; Mitchell 1984; O'Reilly 1982) we could not be sure they had all been effectively excluded. Sensitivity analyses were conducted to examine the effect of these studies.

Study design

Five studies were of parallel group design (Blair 1984; Davies 2000; Moyes 1957; Renkema 1996; Weir 1993). Nineteen studies were of crossover design of which eight did not use a washout period at crossover to alternative treatment or restrict analysis of outcome data to that measured after a period equivalent to a washout period. Ten studies has at least two weeks to allow washout at crossover and one analysed results measured after 14 days on treatment.

Intervention

The intervention group received prednisolone in all studies except Morgan 1964 in which betamethasone was used. Betamethasone is about ten times more active as an anti‐inflammatory than prednisolone.

High dose oral steroid (equivalent to prednisolone 30‐40 mg daily) was used in 20 studies, in 13 for a period of two weeks and in 3 for three weeks. Only Weiner 1999 and Goel 1992 continued treatment for six weeks. Moyes 1957 used an intermediate dose of 15 mg prednisolone for 16 weeks. Morgan 1964 used high dose betamethasone for three days followed by intermediate dose for the remaining four weeks. Evans 1974 and Renkema 1996 used a lower dose of 5 mg prednisolone but subjects in Evans 1974 were treated for only one week while Renkema 1996 gave treatment for the longest period of two years.

Five studies permitted the concurrent use of inhaled corticosteroids. All subjects were on either beclomethasone or budesonide (at an equivalent dose of 1600 mcg) in addition to study treatment in Renkema 1996 and Nishimura 2000 while in Weir 1993 subjects used 750 or 1500 mcg of beclomethasone. In Corden 1998 and Syed 1991 only a proportion of subjects used inhaled corticosteroids. Sixteen studies specifically excluded the use of inhaled corticosteroid and in four studies their use was not specified. Three of these studies included an inhaled corticosteroid comparison arm which did not form part of the analysis (Robertson 1986; Weir 1990; Wempe 1992).

Outcomes

For the two the primary outcomes specified in the protocol, only one study was of a sufficiently long duration ( 2 years) to assess the rate of decline in lung function (Renkema 1996). Lung function as FEV 1 was an outcome measured in 23 studies. For health‐related quality of life, this was assessed using a formal instrument in three studies (Brightling 2000; Nishimura 2000; Weir 1993). For secondary outcomes, some measure of symptoms was used in 13 studies (Brightling 2000; Eliasson 1986; Goel 1992; Lam 1983; Mitchell 1984; Mitchell 1986; Moyes 1957; Nishimura 2000; O'Reilly 1982; Renkema 1996; Strain 1985; Syed 1991; Weir 1993); functional exercise capacity in six studies (Brightling 2000; Goel 1992; Lam 1983; Mitchell 1984; Mitchell 1986; O'Reilly 1982); oxygen uptake in exercise in one study (Strain 1985); occurrence of exacerbations in four studies (Brightling 2000; Eliasson 1986; Moyes 1957; Renkema 1996); adverse effects in six studies (Blair 1984; Goel 1992; Moyes 1957; Nishimura 2000; Renkema 1996; Syed 1991); and airway reactivity in one study (Wempe 1992).

Risk of bias in included studies

After initial scoring, for Cochrane concealment grade the Kappa score was 0.327, with discussion resulting in re‐scoring three studies and full agreement. After initial scoring on the method of Jadad, kappa score was 0.573 with discussion resulting in eight studies being re scored and full agreement. The third reviewer independently agreed with all final scores.

Concealment of allocation to treatment could be confirmed as adequate in three studies, while it was unclear from the paper in 21 studies. None was assessed as inadequate. A grade of 5 on the Jadad scoring method was given to three studies (Brightling 2000; Moyes 1957; Renkema 1996); grade 4 to five studies (Blair 1984; Eliasson 1986; Mendella 1982; Strain 1985; Syed 1991; grade 3 to ten studies; and grade 2 to six studies.

Effects of interventions

Primary outcomes: FEV1

The most frequent measure of lung function assessed in studies was FEV1. There was a significant difference WMD 53.30 ml; 95% CI 22.21 to 84.39 favouring oral steroid use compared to placebo when 14 studies of up to three weeks treatment (n=396) were combined, Figure. There was no significant heterogeneity , chi ² 13.38, df 13, P=0.42 and I² 2.8%. In sensitivity analysis, when analysis was restricted to those with known moderately severe or severe disease, the WMD was 55.04 ml; 95% CI 16.10 to 93.99 with no significant heterogeneity, Chi2 11.11 df 7, P= 0.13, I² 37.0%. A similar result was found in studies of high quality grade: WMD 7 65.87 ml; 95% CI 22.73 to 109.00 without significant heterogeneity Chi2 3.343, df 6, P=0.76, I² 0%. When the analysis was restricted to studies that specified the exclusion of known asthmatics the WMD was 40.51 ml; 95% CI 7.05 to 73.97, without significant heterogeneity; Chi2 7.41 df 10, P =0.69, I² 0%.

Forest plot of comparison: 1 Oral steroid versus placebo‐ short term <= 3 weeks, outcome: 1.1 FEV1 (ml) all studies.

High dose studies

In the 13 short term studies (n=386) using high dose of oral steroids (≥ 30 mg prednisolone) the WMD was 61.29 ml; 95% CI 37.07 to 85.5.

Results in Brightling 2000 were reported by subgroups based on stratification of patients into tertiles by baseline sputum eosinophil count. The lowest eosinophil tertile count at baseline was <1.3%, the middle tertile 1.3‐4.5% and highest tertile > 4.5%. The mean difference between oral steroid and placebo increased progressively for FEV1 from the lowest to highest eosinophilic tertile: ‐5 ml; 95%CI ‐83.40 to 73.40 for the lowest tertile, 55 ml; 95%CI ‐23.40 to 33.40 for the middle tertile and 190 ml; 95%CI 60.0 to 230.0 for the highest tertile, which was the only group to demonstrate a statistically significant difference to placebo [ P=0.03]. Formal subgroup testing indicated significant heterogeneity of response between the three tertiles of eosinophilia (Chi² 6.36, df = 2, P = 0.04). This study excluded any subject with a clinical diagnosis of asthma, a history of acute wheeze, breathlessness or deterioration associated with allergens, or any subjects with significant bronchodilator reversibility after 2.5 mg nebulised salbutamol (<15% FEV1 or if FEV1 <1.2 L, <200 ml improvement) .

Low dose studies: short term

One study used a low dose oral steroid (5 mg prednisolone) for one week (Evans 1974, n=10) and did not show any advantage to oral steroid treatment.

Low dose studies: long term

Only one parallel group study continued treatment over a period of two years using an oral steroid dose of 5 mg prednisolone, allowing follow‐up of the change in lung function during treatment (Renkema 1996). All subjects (n=19) in the oral steroid group also used inhaled corticosteroids (Budesonide 1600 mcg). When the change in FEV1 with time was compared, the median slope was ‐60 ml/year; range ‐570 to 140 on placebo while in the actively treated groups on inhaled corticosteroids or oral steroid plus inhaled corticosteroids the slopes were ‐30 ml/year; range ‐180 to 870 and ‐40 ml/year; range ‐340 to 60 respectively. There was no significant difference in the observed median decreases between the three groups.

Proportion of patients who show response to therapy on FEV1

Ten studies (n=259) all using high dose oral steroids (≥ 30 mg prednisolone) assessed whether the individual patient FEV1 response to treatment was greater than 20% from baseline. There were significantly greater odds for response to treatment with oral steroid treatment compared to placebo, OR 2.71; 95% CI 1.84 to 4.01, with no significant heterogeneity (Analysis 1.3. One study (Weir 1990) assessed response status using either FEV1, FVC or mean PEF over the last seven days of treatment, but omitting this study altered the result only slightly: OR 2.46; 95% CI 1.64 to 3.71. All studies contributing to this outcome had a treatment period of three weeks or less. Using the odds ratio from all studies combined with a baseline risk in the placebo group of 0.13, it would be necessary to treat 7 patients (95% CI 5 to 12) with oral corticosteroids to achieve one extra case of increasing FEV1 by more than twenty percent. The NNT when using the more conservative odds ratio obtained by omitting Weir 1990, is 8 (95% CI 5 to 15).

1.3 — Comparison 1 Oral steroid versus placebo‐ short term <= 3 weeks, Outcome 3 > 20% response to treatment in FEV1.

Health‐related quality of life.

Short term studies

Quality of life was measured by the Chronic Respiratory Questionnaire (CRQ) in three studies Brightling 2000; Nishimura 2000 and Weir 1993 . The overall score was only reported in one study (Brightling 2000), MD 0.32; 95% CI 0.17 to 0.47. The difference was statistically significant but below the minimum clinically important difference.

The minimum accepted clinically relevant difference on the CRQ scale is around 0.5. The benefits found in some individual domains were small. There was a statistically significant advantage to oral steroid treatment compared to placebo (Nishimura 2000; Weir 1993; n=180) for the CRQ domain of fatigue: WMD 0.33; 95% CI 0.12 to 0.54 without significant heterogeneity (P=0.40). There was significant heterogeneity in the result for emotional function: WMD 0.21; 95% CI 0.06 to 0.37 (Chi2 24.52, df=2, P< 0.0001 I2 91.8%). The results in the domains of dyspnoea and mastery failed to reach statistical significance and showed significant heterogeneity. although the upper limit of the confidence interval for difference in fatigue score overlapped. CRQ scores in Brightling 2000 were presented by eosinophilic tertile sub‐groups with the differences increasing with increasing eosinophil count tertiles. The Chi2 for between group differences was statistically significant for dyspnoea (Chi2 10.76, P= 0.005, I² 81.4%) and mastery (Chi2 8.97, P=0.01, I² 77.7%) but not emotional function or fatigue.

Long term studies

No long term studies reported data on health related quality of life.

Secondary outcomes: Symptoms

Short term studies

Symptom scores for breathlessness were reported in three studies (Brightling 2000; Nishimura 2000; Weir 1993). There was no significant difference found in either Nishimura 2000 or Weir 1993, but no pooling was possible owing to differences in study design and scale used. Nishimura 2000 also reported results for cough MD ‐0.30; 95% CI ‐0.82 to 0.22, wheeze MD ‐0.30; 95% CI ‐1.21 to 0.61, sputum MD ‐0.20; 95% CI ‐0.75 to 0.35 and impairment of activities of daily living MD ‐0.40; 95% CI ‐1.22 to 0.42, with none being statistically significant.

Brightling 2000 reported the mean difference between treatment groups as percentage change in the VAS score. When combined there was a significant decrease with oral steroid treatment only for wheeze: WMD 16.71%; 95% CI 4.04 to 29.38. The results were available for three sub‐groups by sputum eosinophil count tertiles: these showed an increasing effect from the lowest to highest tertiles for dyspnoea, cough, wheeze and sputum scores but formal testing between the three sub‐groups did not indicate any significant heterogeneity of response.

Mitchell 1986 used a VAS to assess subjective improvement in well‐being among patients on oral steroids or placebo. There was no statistically significant difference in odds of experiencing >20% improvement in well‐being: OR 1.67; 95% CI 0.71 to 3.93.

Long term studies

A subjective assessment of overall effect of treatment was made in a 16 week study by Moyes 1957 and found no significant difference, OR 1.06; 95% CI 0.36 to 3.13.

Functional and Exercise Capacity

Short term studies

Brightling 2000 used the incremental shuttle walk test while Lam 1983, Mitchell 1984 and Mitchell 1986 used the 12 minute walk distance. Because of differences in the way results were reported we were only able to pool those from the last three studies (n=92) and obtain a standardised result. Analysis found a significant improvement in functional capacity of participants treated with oral corticosteroids compared to placebo, SMD 0.44; 95% confidence interval 0.14 to 0.74. This would be consistent with a difference between groups on the 12 minute walk test of 29 metres; 95% CI 9.1 to 48.2. Brightling 2000 found an overall difference between treatment groups in the shuttle walk test, MD 12.67 metres; 95% CI 3.82 to 21.52. They did not find a progressive increase across the lowest to highest sputum eosinophilic tertile and there was no significant heterogeneity between eosinophil sub‐groups. A significant difference in the proportion of participants whose 12 minute walk distance improved by more than 20% on prednisolone compared to placebo was found in two short term studies (Mitchell 1984; Mitchell 1986) , OR 1.80; 95% CI 1.22 to 2.65.

Exercise capacity assessed as oxygen consumption during exercise was reported in one study, Strain 1985 (n=13). Resting oxygen consumption was 4 ml/kg/min (SE 0.2). There was an increase in mean consumption for both groups but the difference was not significant: WMD 0.90 ml/kg/min; 95% CI ‐2.15 to 3.95. In only three participants was there an increase greater than 2 ml/kg/min.

Acute exacerbations of COPD

Short term studies

In three studies using high dose oral steroids ( ≥ 30 mg prednisolone) for three weeks or less (Brightling 2000; Eliasson 1986; Nishimura 2000) there was no significant reduction in the risk of withdrawal from study due to exacerbation of COPD with oral steroid compared to placebo: OR 0.44; 95% CI 0.17 to 1.18.

Long term studies

In the two year study by Renkema 1996 there was a non significant reduction in risk of withdrawing due to exacerbations when low dose OS plus ICS treatment was compared to placebo use only: Peto OR 0.33; (95% CI 0.07 to 1.70) and a non significant increased risk for OS plus ICS compared to ICS use only: Peto OR 6.68; 95% CI 0.52 to 144.35.

Renkema 1996 assessed the frequency and duration of exacerbations over a two year treatment period in three groups: 5 mg prednisolone plus 1600 mcg ICS, or 1600 mcg ICS only or placebo only. An exacerbation was defined as a "condition with increased dyspnoea and/or cough and/or sputum production, treated with standard therapy (prednisolone 35 mg/day decreasing over 7 days and an antibiotic)". Prior to the study, the range of frequency of exacerbations for all subjects was 0‐6 per year. The median frequency of exacerbations in the first year was 1.5 in the oral steroid plus ICS group (range 0 to 4), 2 in the ICS only group (range 0‐7) and 2 in the placebo group (range 0‐5). In the second year of treatment, the median frequency of exacerbations was 1.5 (0‐4) on oral steroid plus ICS , 1(0‐4) on ICS alone and 2.5(0‐5) on placebo. None of the changes from pre‐treatment levels was significant. Similarly there were no significant differences in the median number of exacerbation days per year on treatment with either oral steroid plus ICS or ICS alone.

Moyes 1957 assessed episodes of symptomatic deterioration during a 16 week study in which the active treatment group (C) received 15 mg prednisolone plus tetracycline 200 mg tds compared to a group (B) receiving tetracycline 200 mg tds and a group receiving placebo (A). They defined a severe exacerbation "as an acute chest illness associated with febrile symptoms, retiring to bed and at least 5 days total incapacity". The number of severe exacerbations was not significantly different between groups C and B: Peto OR 1.16; 95% CI 0.34 to 3.99. There was a significant reduction in the number of exacerbations when comparing groups C and A: Peto OR 0.33; 95% CI 0.11 to 0.95.

Adverse effects of medications

Many of the studies included which were of short duration did not measure or describe adverse effects of treatment. Pooling data from three short‐term studies with 111 participants (Goel 1992; Nishimura 2000; Syed 1991) gave the odds ratio for the occurrence of a major adverse event as 7.76; 95% confidence interval 2.34 to 25.70 and overall using a control event rate of 2% one extra major adverse effect occurred for every 9 people treated (95% CI 95 4 to 40). Nishimura 2000 investigated the effect of three weeks treatment with oral corticosteroids on bone metabolism. The serum osteocalcin level was significantly reduced on active treatment: MD 2.70 ng/ml; 95% CI 1.48 to 3.92. The same study found a significant increase in blood glucose levels on active treatment: WMD 1.72 mmol/L; 95% CI 0.51 to 2.93.

Goel 1992, over a six week treatment period found a non significant increase both in the risk of developing glucose intolerance (recovering after withdrawal of steroids) on active treatment: OR 4.18; 95% confidence interval 0.57 to 30.83 and the risk of mild hypertension responsive to low‐dose thiazides: OR 4.18; 95% confidence interval 0.57 to 30.83.

Renkema 1996 investigated the effects of oral steroid treatment over two years on adrenal function and found significantly greater decreases in fasting morning levels of plasma cortisol when the oral corticosteroid group was compared to inhaled corticosteroid treatment: WMD ‐136 nmol/L; 95% CI ‐221.46 to ‐50.54, or placebo treatment: WMD ‐182.00 nmol/L; 95% CI ‐274.95 to ‐89.05. The authors stated that despite the difference, the mean cortisol level in the oral steroid group at the end of the study was still within the normal reference range for their laboratory.

Other outcomes

There was a significant difference found between treatment groups for FVC in seven studies with 214 participants: WMD 128.01 ml; 95% CI 23.79 to 232.22 favouring oral steroid treatment. There was no difference seen in the one study using a low dose of oral steroids.

Peak expiratory flow was available in three studies (n=97) and the pooled result found a significant benefit for oral steroid compared to placebo: WMD 26.12 L/min ; 95% CI 7.05 to 45.19.

Airway hyper responsiveness was measured in Wempe 1992 (n= 10) by histamine challenge and no significant difference in responsiveness was found between treatment groups: MD for PC 20 histamine ‐0.22 mg/ml; 95% CI ‐2.26 to 1.82

Discussion

Overall this review found a significant increase in FEV1 on treatment with short term oral corticosteroids at reasonably high dose (≥ 30 mg prednisolone) compared to placebo. However, it was not a uniform effect with marked individual variation in response. Sub‐group analyses suggested that the variation in response might be related to increased sputum eosinophil counts but this hypothesis requires further investigation. The improvement in FEV1 was mirrored by a significant increase in peak expiratory flow, although this was measured in only three studies. There were few studies of long duration, which limited our ability to reach conclusions about any long‐term benefit on lung function, though results from Renkema 1996 also indicated marked individual variation in response when FEV1 changes were monitored over two years.     The improvement in overall quality of life measures was not significant, and any differences in the domains of health‐related quality of life were too small to be clinically meaningful, except in the sub‐group with the highest level of sputum eosinophilia with formal subgroup testing indicating significant heterogeneity of response between the three tertiles of eosinophilia (Chi² 6.36, df = 2, P = 0.04). Differences in symptom scores were not significant except for that of wheeze, though there was a trend for all scores in the subgroups to increase with increasing sputum eosinophil counts.

There was a significant effect of oral steroid treatment on functional capacity, with individual variation in response. However, the clinical importance of the differences found in 12 minute walk distance and shuttle walk distance is uncertain and it probably depends on the severity of COPD (Solway 2001). No difference in withdrawal due to exacerbations of COPD, frequency or duration of exacerbations was found.

Individual studies found increased risks of adverse effects on blood pressure, blood glucose, plasma cortisol and serum osteocalcin. These changes would be likely to have long term consequences for the development of diabetes, hypertension, osteoporosis and adrenal suppression if treatment were continued over long periods in a chronic disease such as COPD, especially with the high dose of oral corticosteroids that seems to be needed.

The absence of a washout period in many of the trials with a crossover design is of concern, particularly as the duration of improvement in outcomes detailed above is not clear. Fortunately, from the perspective of meta‐analysis, this is likely to minimise rather than exaggerate the difference between active intervention and control.

Most studies used high doses of oral corticosteroids over relatively short periods and there was no evidence to support clinical benefit to the use of lower doses (< 15 mg prednisolone daily) over a long term period. The requirement for high doses of corticosteroids to be administered in order to achieve benefits in lung function, symptoms and exercise capacity means the adverse effects would likely outweigh any general positive benefit for all COPD patients. This may not apply to a subgroup of COPD patients with larger positive effects, providing the risk of adverse events is not also increased. The existence of a subgroup or groups of COPD patients who may benefit significantly more than others from oral corticosteroid has been investigated in other studies not included in thus review. Two non‐randomised studies, Pizzichini 1998 and Shim 1978 also found sputum eosinophilia to be a predictor of positive response in FEV1 to treatment with oral corticosteroids. This would need to be tested before treatment recommendations could be based on the level of sputum eosinophils. In addition, it is not clear what occurs to subjects after cessation of corticosteroids. If the benefits are lost over time, there seems little point to a short term intervention in what is a chronic disease. On the other hand, if high doses need to be continued over long periods to maintain any benefit, the cumulative risk of adverse effects, particularly osteoporosis, is likely to increase. In addition, there is evidence from observational studies that people with COPD taking long term oral corticosteroids have a higher mortality than those not using them (Sin 2001; Schols 2001) although this could be a reflection of disease severity. Even so, this possibility is an additional disincentive to long‐term use.

Authors' conclusions

Implications for practice.

Short‐term oral corticosteroid in stable COPD produces statistically significant benefits in lung function, symptoms and exercise capacity, but at the cost of increased adverse events, and at doses which are unlikely to be acceptable in the long‐term. The benefit of these short term gains to people living with COPD is unclear.

Implications for research.

Whether there are long term benefits to be gained from the short term use of high dose oral corticosteroids needs to be established for them to become useful in the management of COPD. While this review did not set out to investigate whether responsiveness to oral steroids is a predictor of long term response to other interventions with a lower adverse event profile, such as low dose oral corticosteroid or inhaled corticosteroid, this needs to be established. A clearer definition of "responders", for example in terms of bronchodilator responsiveness or eosinophil sputum counts may allow subsequent studies of long term oral corticosteroids in subjects with a potentially better risk‐benefit profile to be performed. Unfortunately, at present the number of studies of oral corticosteroids with data available is very small, although they are widely prescribed COPD, a disease with a high prevalence. Further studies in well defined populations are needed to establish their role, if any, in the long term management of the disease.

What's new

Date	Event	Description
15 August 2008	Amended	Converted to new review format.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 FEV1 (ml) all studies	14	687	WMD (Fixed, 95% CI)	53.30 [22.21, 84.39]
1.1 High dose oral steroid	13	667	WMD (Fixed, 95% CI)	54.19 [22.96, 85.43]
1.2 Low dose oral steroid	1	20	WMD (Fixed, 95% CI)	‐40.0 [‐359.99, 279.99]
2 FEV1 (ml)‐ sub‐group results	1		WMD (Fixed, 95% CI)	50.39 [‐0.60, 101.38]
2.1 Lowest baseline sputum eosinophil count tertile	1		WMD (Fixed, 95% CI)	‐5.0 [‐83.40, 73.40]
2.2 Middle baseline sputum eosinophil count tertile	1		WMD (Fixed, 95% CI)	55.0 [‐23.40, 133.40]
2.3 Highest baseline sputum eosinophil count tertile	1		WMD (Fixed, 95% CI)	190.0 [60.00, 320.00]
3 > 20% response to treatment in FEV1	10		OR (Fixed, 95% CI)	2.71 [1.84, 4.01]
3.1 High dose oral steroid	10		OR (Fixed, 95% CI)	2.71 [1.84, 4.01]
4 Quality of life‐ overall score	1		WMD (Fixed, 95% CI)	0.32 [0.17, 0.47]
4.1 High dose oral steroids	1		WMD (Fixed, 95% CI)	0.32 [0.17, 0.47]
5 Quality of life‐ dyspnoea score (CRQ)	3		WMD (Fixed, 95% CI)	0.30 [‐0.07, 0.67]
5.1 High dose oral steroids (no ICS)	1		WMD (Fixed, 95% CI)	0.42 [‐0.02, 0.86]
5.2 Concurrent ICS use with high dose OS	2		WMD (Fixed, 95% CI)	0.01 [‐0.66, 0.68]
6 Quality of life‐ fatigue score (CRQ)	3		WMD (Fixed, 95% CI)	0.33 [0.12, 0.54]
6.1 High dose oral steroids (no ICS)	1		WMD (Fixed, 95% CI)	0.36 [0.14, 0.58]
6.2 Concurrent ICS use with high dose OS	2		WMD (Fixed, 95% CI)	0.06 [‐0.61, 0.72]
7 Quality of life‐ emotional function score (CRQ)	3		WMD (Fixed, 95% CI)	0.21 [0.06, 0.37]
7.1 High dose oral steroids (no ICS)	1		WMD (Fixed, 95% CI)	0.13 [‐0.03, 0.29]
7.2 Concurrent ICS use with high dose OS	2		WMD (Fixed, 95% CI)	1.60 [0.93, 2.26]
8 Quality of life‐ mastery score (CRQ)	3		WMD (Fixed, 95% CI)	0.17 [‐0.02, 0.36]
8.1 High dose oral steroids (no ICS)	1		WMD (Fixed, 95% CI)	0.23 [0.03, 0.43]
8.2 Concurrent ICS use with high dose OS	2		WMD (Fixed, 95% CI)	‐0.28 [‐0.82, 0.27]
9 Quality of life‐ dyspnoea score (CRQ) by eosinophil tertile	1		WMD (Random, 95% CI)	0.42 [‐0.02, 0.86]
9.1 Lowest baseline sputum eosinophil count	1		WMD (Random, 95% CI)	0.15 [‐0.05, 0.35]
9.2 Middle baseline sputum eosinophil count	1		WMD (Random, 95% CI)	0.27 [‐0.11, 0.65]
9.3 Highest baseline sputum eosinophil count	1		WMD (Random, 95% CI)	0.93 [0.51, 1.35]
10 Quality of life‐ fatigue score (CRQ) by eosinophil tertile	1		WMD (Fixed, 95% CI)	0.36 [0.14, 0.58]
10.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.09 [‐0.28, 0.46]
10.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.42 [‐0.00, 0.84]
10.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.56 [0.21, 0.91]
11 Quality of life‐ emotional function score (CRQ) by eosinophil tertile	1		WMD (Fixed, 95% CI)	0.13 [‐0.03, 0.29]
11.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.08 [‐0.18, 0.34]
11.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.12 [‐0.15, 0.39]
11.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.19 [‐0.11, 0.49]
12 Quality of life‐ mastery score (CRQ) by eosinophil tertile	1		WMD (Fixed, 95% CI)	0.23 [0.03, 0.43]
12.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.03 [‐0.23, 0.29]
12.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.2 [‐0.20, 0.60]
12.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	0.82 [0.38, 1.26]
13 Change in dyspnoea score	1	92	Mean Difference (IV, Fixed, 95% CI)	0.2 [‐0.15, 0.55]
13.1 High dose oral steroid +ICS v ICS	1	92	Mean Difference (IV, Fixed, 95% CI)	0.2 [‐0.15, 0.55]
14 Change in exertional dyspnoea score	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.02, 0.62]
14.1 High dose oral steroid +ICS	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐1.02, 0.62]
15 Symptom score‐ cough	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.3 [‐0.82, 0.22]
15.1 High dose oral steroid+ICS	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.3 [‐0.82, 0.22]
16 Symptom score‐ wheeze	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.21, 0.61]
16.1 High dose oral steroid	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.21, 0.61]
17 Symptom score‐ sputum	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.75, 0.35]
17.1 High dose oral steroid	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.75, 0.35]
18 Symptom score‐ activities of daily living	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.22, 0.42]
18.1 High dose oral steroid	1	42	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.22, 0.42]
19 % decrease in symptom score: dyspnoea	1		WMD (Fixed, 95% CI)	9.51 [‐4.14, 23.17]
19.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	5.0 [‐11.49, 21.49]
19.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	14.0 [‐15.09, 43.09]
19.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	32.0 [‐12.61, 76.61]
20 % decrease in symptom score: cough	1		WMD (Fixed, 95% CI)	21.08 [‐21.04, 63.20]
20.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	2.0 [‐54.21, 58.21]
20.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	41.0 [‐39.49, 121.49]
20.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	53.0 [‐50.76, 156.76]
21 % decrease in symptom score: wheeze	1		WMD (Fixed, 95% CI)	16.71 [4.04, 29.38]
21.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	‐1.0 [‐28.15, 26.15]
21.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	21.0 [6.45, 35.55]
21.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	42.0 [‐40.43, 124.43]
22 % decrease in symptom score: sputum	1		WMD (Fixed, 95% CI)	22.84 [‐5.71, 51.38]
22.1 Lowest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	6.0 [‐33.76, 45.76]
22.2 Middle baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	34.0 [‐31.94, 99.94]
22.3 Highest baseline sputum eosinophil count	1		WMD (Fixed, 95% CI)	45.0 [‐7.37, 97.37]
23 >20% improvement in well‐being (VAS)	1		OR (Fixed, 95% CI)	1.67 [0.71, 3.93]
23.1 High dose oral steroid	1		OR (Fixed, 95% CI)	1.67 [0.71, 3.93]
24 Functional capacity (Walking distance)	3		SMD (Fixed, 95% CI)	0.44 [0.14, 0.74]
24.1 High dose oral steroid	3		SMD (Fixed, 95% CI)	0.44 [0.14, 0.74]
25 Functional capacity (Shuttle walking distance)	1		WMD (Fixed, 95% CI)	12.67 [3.82, 21.52]
25.1 LET	1		WMD (Fixed, 95% CI)	12.0 [‐3.68, 27.68]
25.2 MET	1		WMD (Fixed, 95% CI)	5.0 [‐10.68, 20.68]
25.3 HET	1		WMD (Fixed, 95% CI)	20.0 [5.30, 34.70]
26 >20% improvement in 12 minute distance after treatment	2		OR (Fixed, 95% CI)	1.80 [1.22, 2.65]
26.1 High dose oral steroid	2		OR (Fixed, 95% CI)	1.80 [1.22, 2.65]
27 Peak expiratory flow	3		WMD (Fixed, 95% CI)	26.12 [7.05, 45.19]
27.1 High dose oral steroid	2		WMD (Fixed, 95% CI)	27.37 [7.57, 47.17]
27.2 High dose oral steroid+ICS	1		WMD (Fixed, 95% CI)	10.0 [‐61.03, 81.03]
28 Change in PEF (daily mean)	1	92	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐9.68, 10.28]
28.1 High dose oral steroid	1	92	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐9.68, 10.28]
29 Forced vital capacity	7		WMD (Fixed, 95% CI)	128.01 [23.79, 232.22]
29.1 High dose oral steroid	6		WMD (Fixed, 95% CI)	133.15 [26.86, 239.45]
29.2 Low dose oral steroid	1		WMD (Fixed, 95% CI)	0.0 [‐529.99, 529.99]
30 Maximal oxygen uptake during exercise (V 02 max)	1	26	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐2.15, 3.95]
30.1 High dose oral steroid	1	26	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐2.15, 3.95]
31 Airway Hyperresponsiveness	1		WMD (Fixed, 95% CI)	‐0.22 [‐2.26, 1.82]
31.1 High dose oral steroid	1		WMD (Fixed, 95% CI)	‐0.22 [‐2.26, 1.82]
31.2 Intermediate or low dose oral steroid	0		WMD (Fixed, 95% CI)	0.0 [0.0, 0.0]
32 Withdrawal due to exacerbations COPD	3		OR (Fixed, 95% CI)	0.44 [0.17, 1.18]
32.1 High dose oral steroid	3		OR (Fixed, 95% CI)	0.44 [0.17, 1.18]
33 Adverse effect: any	3		OR (Fixed, 95% CI)	7.76 [2.34, 25.70]
33.1 High dose oral steroid	3		OR (Fixed, 95% CI)	7.76 [2.34, 25.70]
34 Blood glucose	1	42	Mean Difference (IV, Fixed, 95% CI)	1.72 [0.51, 2.93]
34.1 High dose oral steroid	1	42	Mean Difference (IV, Fixed, 95% CI)	1.72 [0.51, 2.93]
35 Serum osteocalcin	1	42	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐3.92, ‐1.48]
35.1 High dose oral steroids	1	42	Mean Difference (IV, Fixed, 95% CI)	‐2.70 [‐3.92, ‐1.48]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Decrease in FEV1 (mL/year)			Other data	No numeric data
2 Frequency of exacerbations (# exacerbations/year‐ median and range)			Other data	No numeric data
3 Duration of exacerbations (# exacerbation days/year‐ median and range)			Other data	No numeric data
4 # severe exacerbations COPD	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
4.1 Oral steroid (15mg +tetracycline) versus tetracycline	1	55	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.16 [0.34, 3.99]
4.2 Oral steroid (15mg + tetracycline) versus placebo	1	58	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.33 [0.11, 0.95]
5 Withdrawal due to frequent exacerbations or deterioration in lung function	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only
5.1 Low dose oral steroid plus ICS versus placebo plus ICS	1	40	Peto Odds Ratio (Peto, Fixed, 95% CI)	8.68 [0.52, 144.35]
5.2 Low dose oral steroid plus ICS versus placebo	1	37	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.33 [0.07, 1.70]
6 Overall beneficial effect of treatment	1	55	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.36, 3.13]
6.1 Intermediate to low dose oral steroid	1	55	Odds Ratio (M‐H, Fixed, 95% CI)	1.06 [0.36, 3.13]
7 Adverse effect: hypertension	1		OR (Fixed, 95% CI)	4.18 [0.57, 30.83]
7.1 High dose oral steroid	1		OR (Fixed, 95% CI)	4.18 [0.57, 30.83]
8 Adverse effect: glucose intolerance	1		OR (Fixed, 95% CI)	4.18 [0.57, 30.83]
8.1 High dose oral steroid	1		OR (Fixed, 95% CI)	4.18 [0.57, 30.83]
9 Plasma cortisol	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
9.1 Low dose oral steroid plus ICS versus placebo plus ICS	1	40	Mean Difference (IV, Fixed, 95% CI)	‐136.0 [‐221.46, ‐50.54]
9.2 Low dose oral steroid plus ICS versus placebo	1	37	Mean Difference (IV, Fixed, 95% CI)	‐182.0 [‐274.95, ‐89.05]

Decrease in FEV1 (mL/year)
Study	Treatment group	Median FEV1 slope	Range FEV1 slopes
Renkema 1996	Oral steroid+ICS	‐40 ml	‐340 to 60 ml
Renkema 1996	ICS	‐30 ml	‐180 to 870 ml
Renkema 1996	Placebo	‐60 ml	‐570 to 140 ml

Frequency of exacerbations (# exacerbations/year‐ median and range)
Study	Treatment	Prestudy year	Study year 1	Study year 2
Renkema 1996	ICS	1 (0‐6)	2 (0‐7)	1 (0‐4)
Renkema 1996	ICS+Prednisolone 5mg	2 (0‐3)	1.5 (0‐4)	1.5 (0‐4)
Renkema 1996	Placebo	2 (0‐3)	2 (0‐5)	2.5 (0‐5)
Renkema 1996

Methods	Setting of study: Medical centre; USA   Study design: Cross over   JADAD score (0‐5): 2 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: no withdrawals described)   Type of analysis: cases available   Compliance measured: not stated
Participants	Number of participants: 10   Gender: Males=9; Females=1   Mean age: 59 Age range: 40‐77   Inclusion criteria: diagnosis of severe pulmonary emphysema   Exclusion criteria: overt evidence of cardiac decompensation; peptic ulcer at admission; history of tuberculosis; no acute bronchial or pulmonary infection; no steroid treatment in preceding one month; no major illness   Attempted to exclude asthmatics: not specified.   Previous oral steroid use: not within preceding one month   Smoking history: 1 person did not smoke; 4 smoked 1 packet a day (20 PYH); 1 smoked 1‐2 packets a day (21‐40 PYH); 4 smoked over 2 packets a day (> 40 PHY) for over 20 years   Diagnostic criteria (COPD & stability): diagnosis established by clinical and laboratory appraisal with a first second timed vital capacity of less than one litre.   Stability: No evidence of acute bronchial or pulmonary infection based on white cell count or temperature elevation.   Severity of COPD: severe pulmonary emphysema
Interventions	Drug: prednisolone   Dose: 60 mg first day; 45 mg second day; 30 mg thereafter   Delivery: daily   Duration: 14 days   Co‐interventions: not stated   Comparison: placebo 0.1 mg prednisolone tablets   Duration of study: 1 week pretreatment, 2 weeks prednisolone, 2 weeks placebo, total 5 weeks.
Outcomes	Outcomes assessed: vital capacity, subjective well‐being (3 point scale)   Follow‐up assessment points: daily measurements throughout four weeks of study.   Outcomes included in analyses: Marked increase in VC‐ 1second
Notes	Data presented by separate treatment order groups, Group 1 Prednisolone‐placebo n=5 , Group 2 Placebo‐prednisolone n=5. No group data in paper. graphs of 1 second vital capacity show major increase for 1 subject in each group with prednisolone. Responder defined as marked improvement in 1‐second vital capacity following treatment.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Single Veterans Medical centre; USA‐ inpatient treatment   Study design: Parallel group   JADAD score (0‐5): 4 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: adequate, Description of withdrawals: yes)   Type of analysis: ITT   Compliance measured: not stated
Participants	Number of participants: 44   Gender: Males=449; Females=0   Mean age: 64 Age range: 46‐85   Inclusion criteria: symptomatic, stable COPD, FEV1< 1.5l, FEV1/FVC ratio <50%   Exclusion criteria: Received corticosteroids < 4 weeks, Congestive heart failure, diabetes, other major respiratory illness, history of TB or peptic ulcer   Attempted to exclude asthmatics: YES.   Previous oral steroid use: not within preceding one month   Smoking history: All smokers or ex‐smokers >30 year pack   Diagnostic criteria (COPD & stability): FEV1< 1.5l, FEV1/FVC ratio <50%   Stability: stable symptoms, no use of corticosteroids in past 4 weeks   Severity of COPD: moderate to severe
Interventions	Drug: prednisolone   Dose: 32 mg ( either 8 mg QDS or 64mg alternate days)   Delivery: daily or alternate days   Duration: 10 days   Co‐interventions: stable dose theophylline or beta‐agonist   Comparison: placebo   Duration of study: 10 days
Outcomes	Outcomes assessed: Lung function: lung volumes, diffusing capacity, oxygen saturation, serum glucose, electrolytes, blood eosinophils   Follow‐up assessment points: 5 days and 10 days   Outcomes included in analyses: FEV1, FVC, SaO2 , response to treatment
Notes	2 intervention groups   1. Prednisolone 32 mg daily in 4 doses   2. Prednisolone 64 mg alternate days   Results were comparable in both Prednisolone groups so results were combined for analyses.   Responder to treatment defined as > 20% improvement in FEV1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	Study investigators unaware as to order of treatment group assignment

Methods	Setting of study: Respiratory clinics; UK   Study design: Cross‐over   JADAD score (0‐5): 5 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: random number table, Method of blinding: good, Description of withdrawals: yes)   Type of analysis: Intention to treat analysis   Compliance measured: not stated
Participants	Number of participants:83 rcruited, 67 randomised, 59 completed   Gender: 41 male, 26 female   Mean age: 66; Age range: 42‐83   Inclusion criteria: COPD   Exclusion criteria: asthma; childhood history of respiratory disorders; variability of symptoms not associated with infections; history of acute wheeze, breathlessness or deterioration associated with allergens; exacerbations with 6 weeks of trial entry; taking regular oral corticosterpoids   Attempted to exclused asthmatics: yes if clinical history present.   Previous oral steroid use: excluded if regular use   Smoking history: 17 current smokers, 46 ex‐smokers, mean pack year history 35 (25)   Diagnostic criteria (COPD & stability): COPD= symptoms of chronic airflow obstruction; post bronchodilator FEV1 <70% predicted, FEV1/FVC ratio <70%; no substantial improvement in FEVi after 2.5 mg nebulised salbutamol (<15% or if FEV1<1.2L, <200mL improvement);   Stability=variability in symptoms not associated with infections or exacerbations within 6 weeks of trial entry   Severity of COPD: not stated.
Interventions	Drug: prednisolone   Dose: 30 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: beta‐agonist   Comparison: matching placebo   Duration of study: two weeks prednisolone; two weeks placebo; four weeks washout,Total 8 weeks
Outcomes	Outcomes assessed: spirometry; bronchodilator reversibility; quality of life by chronic respiratory disease questionnaire; 100 visual analogue scale for symptom score; incremental shuttle walk test; sputum induction for differential cell count   Follow‐up assessment points: before and after each treatment period.   Outcomes in analyses‐ FEV1, functional capacity, quality of life (CRQ), exacerbation, symptom score (cough, dyspnoea); for whole group and subgroups by eosinophil count
Notes	Subjects stratified into tertiles according to baseline sputum eosinophil count
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	Study investigators unaware as to order of treatment group assignment

Methods	Setting of study: Not stated   Country: UK   Study design: Cross‐over   JADAD score (0‐5): 3 (sum of: Described as randomized: yes Described as double blind: yes Method of randomization: not stated Method of blinding: good: Description of withdrawals: no)   Type of analysis: available case   Compliance measured: tablet count, mean 96% (78‐102 range)
Participants	Number of participants: 20 entered, 18 completed   Gender: Males=16; Females=2   Mean age: 69.9 Age range: 56‐81   Inclusion criteria: clinical diagnosis of COPD; over 40 years; smokers or ex‐smokers.   Exclusion criteria: asthma; diabetes mellitus; left heart failure; active peptic ulceration; positive skin test for common allergies; previous documented response to oral steroids; oral steroid use in the last three months   Attempted to exclude asthmatics: yes if clinical diagnosis asthma or positive SPTs.   Previous oral steroid use: not within last three months or documented positive response to oral steroids   Smoking history: all smokers or ex‐smokers, pack year history not given.   Diagnostic criteria (COPD & stability): COPD= FEV1 <70% predicted; FEV1/FVC ratio <60%   Stability=not stated but not used OS within past 3 months.   Severity of COPD: stated to be more severe than a previous study in mild COPD.
Interventions	Drug: prednisolone   Dose: 30 mg daily   Delivery: oral   Duration: 3 weeks   Co‐interventions: all taking inhaled beta‐adrenergic agonists; some taking inhaled anticholinergic drugs, 13/18 using ICS median dose Beclomethasone equivalent to 800mcg/day   Comparison: placebo, matching.   Duration of study: 2 study days followed by 3 week treatment phase one followed by 2 study days followed by 3 week treatment phase two followed by 2 study days
Outcomes	Outcomes assessed: FEV1 and FVC baseline, increase in FEV 1 and FVC after salbutamol and oxitropium (anticholinergic); home FEV1 and FVC daily after oxitropium.   Follow‐up assessment points: post intervention.   Outcomes included in analyses: FEV1 (post bronchodilator), FVC (post bronchodilator)
Notes	Responders defined in relation to response to either salbutamol or oxitropium, as those achieving at least 15% and 200ml improvement in FEV1 or 15% and 350ml FVC from baseline.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Outpatients followed at hospital with COPD, UK   Study design: Parallel   JADAD score (0‐5): 2 (sum of: Described as randomized: yes, Described as double blind: no, Method of randomization: yes, Method of blinding: not stated, Description of withdrawals: no)   Type of analysis: available cases   Compliance measured: not stated
Participants	Number of participants: 31 completed   Gender: Males=8; Females=4   Mean age: 67 (6), Age range: not stated   Inclusion criteria: Symptommatic with breathlessness, cough and wheeze and diagnosis COPD   Exclusion criteria: personal or family history asthma; atopy; hay fever; alpha1 antitrypsin deficiency; other chest diseases   Attempted to exclude asthmatics: yes on basis of personal and family history, atopy or hayfever.   Previous oral steroid use: not stated   Smoking history: mean pack years smoked 72(54)   Diagnostic criteria (COPD & stability): COPD defined physiologically by BTS spirometry criteria as FEV1 <80% predicted and FEV1/FVC ratio < 70%. Reversibility to SABA bronchodilator < 15% FEV1 and < 200ml.   Stability: No clinical exacerbation of COPD or antibiotics or corticosteroids within 6 weeks   Severity of COPD: Mean FEV1 43.3 (2.1) moderate to severe COPD
Interventions	Drug: Prednisolone   Dose: 30mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: concurrent medications permitted during trial   Comparison 1: placebo   Comparision 2: Ibuprofen 400 mg bd   Duration of study: Sputum collection and spirometry day 1, 14 days treatment, repeated sputum and spirometry day 15.
Outcomes	Outcomes assessed: spirometry; total and differential cell counts, gelatin degradation, ELISA and detection of TIMP‐1   Follow‐up assessment points: post intervention   Outcomes in analysis‐FEV1
Notes	Published as abstract. Requested information from authors. Authors reply‐ study was refused publication but copy of paper supplied to reviewers. Enrollment completed n=31, randomised by computer generated random numbers, not double blind.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Newington Veterans Administration Medical Centre Chest Clinic; USA   Study design: Cross‐over   JADAD score (0‐5): 4 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: adequate, Description of withdrawals: yes)   Type of analysis: case available   Compliance measured: tablet count, result not reported
Participants	Number of participants: 16   Gender: not stated   Mean age: 60.4 (7.8) Age range: not stated   Inclusion criteria: Chronic bronchitis ATS criteria   Exclusion criteria: history of asthma; atopy; clinical or laboratory evidence of major organ disease (contraindication to corticosteroid medication)   Attempted to exclude asthmatics: yes if history or history of atopy   Previous oral steroid use: not stated   Smoking history: mean 60.8 (25.6) pack years   Diagnostic criteria (COPD & stability): COPD= symptoms for at least two years; FEV1 <60% predicted; TLC >80% predicted; <15% improvement of initial FEV1.   Stability: respiratory symptoms stable over previous one month with no evidence of acute process or pulmonary disease not related to chronic bronchitis or emphysema   Severity of COPD: moderate to severe
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: not stated   Comparison: placebo   Duration of study: two weeks prednisolone; two weeks placebo; two weeks washout, total 6 weeks.
Outcomes	Outcomes assessed: spirometry; bronchodilatory reversibility; pulmonary symptoms including cough, sputum production, dyspnoea, exacerbations.   Follow‐up assessment points: before and after each treatment period.   Outcomes included in analysis: FEV1, FVC, Overall benefit of treatment, severe exacerbation COPD.
Notes	Prednisolone responder defined as an improvement in pulmonary function after prednisolone surpassing both placebo response and the coefficient of variation of spirometry indices.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Out patients, tertiary hospital, London; UK   Study design: Cross‐over   JADAD score (0‐5): 3 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: adequate, Description of withdrawals: none stated)   Type of analysis: case available   Compliance measured: not stated
Participants	Number of participants: 10   Gender: all males   Mean age: 62, Age range: 50‐72   Inclusion criteria: Chronic diffuse airways obstruction; little or no response to bronchodilator therapy   Exclusion criteria: not stated   Attempted to exclude asthmatics: yes if personal or family history atopy, or blood eosinophilia   Previous oral steroid use: not stated   Smoking history: all current or ex‐smokers ‐ no other details stated   Diagnostic criteria (COPD & stability): not stated   Severity of COPD: not stated
Interventions	Drug: prednisolone   Dose: 5 mg daily   Delivery: oral   Duration: 7 days   Co‐interventions: one person on oral orciprenaline   Comparison: placebo   Duration of study: 1 week each active and placebo treatment , total 2 weeks.
Outcomes	Outcomes assessed: Spirometry; inspiratory airways resistance; response to isoprenaline; blood gas analysis; radiological assessments   Follow‐up assessment points: immediately before starting the trial and after each treatment period   Outcomes included in analyses: FEV1, FVC
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: medical outpatients clinic, India   Study design: crossover   JADAD score (0‐5)=2 : (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: none described.)   Type of analysis: not stated, but case available in paper   Compliance measured: not stated
Participants	Number of participants: 70   Gender: 62 male, 8 female   Mean age: 52.3, Age range: not stated   Inclusion criteria: smoking history > 30 pack years. Chronic obstructive lung disease.   Exclusion criteria: History of episodic cough or wheezing, past or family history of asthma, sputum or blood esinophilia, severe heart failure, uncontrolled diabetes, active TB, peptic ulcer, osteoporosis, peripheral vascular disease.Attempted to exclude asthmatics: yes if personal history or symptoms or family history.   Previous oral steroid use: not permitted corticosteroid use within 6 weeks.   Smoking history: mean 65.3 pack year history, 13 continued smokers, 57 ex‐smokers.   Diagnostic criteria (COPD & stablility): Either chronic bronchitis with history of cough and expectoration with or without breathlessness for at least 5 years or emphysema diagnosed by increasing exertional breathlessness without significant cough, evidence of hyperinflation on chest X‐ray and airflow obstruction and air trapping on pulmonary function tests   Stability: Current acute exacerbation due to infection, use of corticosteroids within 6 weeks.   Severity of COPD: not stated.   Subjects divided into groups, chronic bronchitis and emphysema and within groups by FEV1 variablility, either spontaneous or to SABA > 10%.
Interventions	Drug: prednisolone   Dose: 0.8mg/kg for 4 weeks, reduced to 0.4mg/kg for 2‐4 weeks daily   Delivery: oral   Duration: 6‐8 weeks each treatment   Co‐interventions: pre‐randomisation all given 1 week antibiotic, (cotrimoxaxole), 4 weeks theophylline 300mg twice daily and oral salbutamol 4 mg three times daily. Stopped at randomization.   Comparison: placebo   Duration of study: 4 weeks pretreatment, 6‐8 weeks treatment prednisolone, 6‐8 weeks placebo, total up to 20 weeks.
Outcomes	Outcomes assessed: spirometry, 12 minute walk test, symptom assessement (100 point VAS scale), adverse effects.   Follow‐up assessment points: baseline and weekly on treatment.   Outcomes included in analyses: Adverse effects x 2
Notes	Results presented by subgroups only. Numbers in subgroups not available, no standard deviations. Further results requested from authors.   Dose of oral steroid varied during treatment period. Four weeks high dose followed by 2‐4 weeks intermediate dose therefore include as high dose study.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: University Respiratory Clinic; China   Study design: Cross‐over   JADAD score (0‐5): 3 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: yes)   Type of analysis: case available   Compliance measured: not stated
Participants	Number of participants: 18 randomised, 16 completed.   Gender: 16 male, 2 female   Mean age: 62.5, Age range: 44‐72   Inclusion criteria: COPD   Exclusion criteria: no known history of asthma, previous corticosteroid therapy; chest infection in preceding 4 weeks   Attempted to exclude asthmatics: Not effectively‐ only on clinical history. Measured SPT and eosinophils . 2 subjects SPT positive, 6 > 500 eosinophils per cubic mm blood.   Previous oral steroid use: none known.   Smoking history: all but one a chronic smoker ‐ mean 38 pack years (15‐75 pack years)   Diagnostic criteria (COPD & stability): COPD= diagnosis of emphysema based on Simon (1978) criteria; chronic airflow obstruction with FEV1 65% or less and FEV1/FVC ratio of 0.65 or less, reversibility of airways obstruction of not greater than 20% of initial FEV1 after inhalation of 200mg of salbutamol; respiratory symptoms > 5 years   Stability=clinically stable ‐ no chest infection within 1 month   Severity of COPD: Moderate to very severe (GOLD) FEV1 13‐65% predicted.
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: not stated   Comparison: placebo   Duration of study: 2 weeks prednisolone; two weeks placebo; two weeks washout, total 6 weeks
Outcomes	Outcomes assessed: spirometry, daily PEF monitoring, diary card symptoms, breathlessness, Wheezing score by auscultation, blood and sputum eosinophils, functional capacity‐ 12minute walk distance.   Follow‐up assessment points: before trial and at end of each treatment period   Outcomes in analysis: FEV1, FVC, Functional capacity‐12 minute walk distance
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: selected from a group involved in larger study; Canada   Study design: Cross‐over   JADAD score (0‐5): 4(sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: adequate, Description of withdrawals: yes)   Type of analysis: case available   Compliance measured: tablet count, complete in those reported.
Participants	Number of participants: 46   Gender: Males=39; Females=7   Mean age: not stated, Age range: 49‐74   Inclusion criteria: stable COPD   Exclusion criteria: arterial oxygen tension less than 55mg Hg or major disease of other organs   Attempted to exclude asthmatics: yes, no clinical diagnosis of asthma.   Previous oral steroid use: not in two weeks before larger trial   Smoking history: not stated in paper (report in another paper stated > 30 pack year history)   Diagnostic criteria (COPD & stability): COPD=FEV1 60% of predicted that did not improve to 80% of predicted with inhaled beta‐agonists; total lung capacity 80% predicted   Stability=FEV1 varying less than 15% or 0.2L on three occasions during the month before entry to larger trial   Severity of COPD: stated to be moderately severely affected on basis of lung function.
Interventions	Drug: methylprednisolone   Dose: 32mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: all using inhaled metaproterenol, fenoterol or albuterol; plus oral aminophylline   Comparison: identical placebo tablets   Duration of study: two week methylprednisolone; 2 week washout; two week placebo. Total 6 weeks.
Outcomes	Outcomes assessed: spirometry; Brochodilator reversibility, lung volume; symptoms; blood and sputum eosinophil counts   Follow‐up assessment points: 2,4,6 weeks.   Outcomes in analyses: FEV1, % responders
Notes	Responder defined as at least 20% improvement in FEV1 after treatment period.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: not stated; UK   Study design: Cross‐over   JADAD score (0‐5): 2 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: not stated)   Type of analysis: not stated   Compliance measured: not stated
Participants	Number of participants: 43   Gender: Males=33; Females=10   Mean age: 60.4, Age range: 37‐77   Inclusion criteria: not stated   Exclusion criteria: not stated   Attempted to exclude asthmatics: stated none had features suggesting asthma but did not exclude if SPT positive, or raised eosinophils, or positive RAST test for specifc allergens.   Previous oral steroid use: not stated   Smoking history: all had smoked. a mean pack year history 44.7 years. 27 were now ex‐smokers   Diagnostic criteria (COPD & stability): moderate to severe chronic airflow limitation on spirometry.   Stability: not defined.   Severity of COPD: moderate to severe airflow limitation ‐ mean FEV1/FVS ratio 44% (58% predicted)
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: all patients had oral or inhaled beta‐agonist; some had theophylline   Comparison: placebo   Duration of study: 7 day run in; 14 days prednisolone; 14 days placebo
Outcomes	Outcomes assessed: spirometry; bronchodilator reversibility, peak expiratory flow; relaxed vital capacity; breathlessness; oxygen cost diagram; general well‐being; functional capacity by 12 minute walk test, symptoms (dypnoea score 1‐5) and well‐being (VAS 10cm scale)   Follow‐up assessment points: after 7 day run in and after each treatment period   Outcomes used in analyses:1. Number with > 20% improvment in FEV1. (No standard deviation measures publishhed for any continous outcomes)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: In patient, tertiary hospital, London ; UK   Study design: Cross‐over   JADAD score (0‐5): 3 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: good, Description of withdrawals: no drop outs stated)   Type of analysis: case available   Compliance measured: All peak flow measurement supervised by nurse, In patient supervision of medication. Compliance not reported.   Confounders: No wash out at crossover but PEF data used from second week of treatment period only.
Participants	Number of participants: 33   Gender: Males=26; Females=7   Mean age: 61.7 Age range: 48‐77   Inclusion criteria: Progressive breathlessness on exertion for 5 years, followed at outpatient chest clinic for at least 2 years.   Exclusion criteria: History of episodic respiratory symptoms, FEV1 variablility greater than 20% at clinic visits, bronchodilator reversibility to SABA greater than 20% (FEV1, PEF or FVC)   Attempted to excluded asthmatics: no patients had clinical features of asthma;   Previous oral steroid use: none   Smoking history: all had smoked ‐ mean pack year history 45.5 ; most had stopped   Diagnostic criteria (COPD & stability): COPD=progressive breathlessness on exertion for at least five years   Stability= not recent variation in breathlessness and no infective exacerbation recently.   Severity of COPD: moderate to severe (mean FEV1/FVC ratio 44%, 58% predicted. The mean FEV1 was 1.011 (36% predicted; range 0.44 ‐ 1.77%) and the mean FVC was 2.29 (63% predicted)
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: most had oral or inhaled beta‐agonists; oral methylxanthines. Medication not altered during trial.   Comparison: identical placebo tablets   Duration of study: 7 day run in; 14 days prednisolone; 14 days placebo. Total 5 weeks.
Outcomes	Outcomes assessed: Peak expiratory flow; FEV1 FVC, breathlessness; general well‐being (VAS scale); exercise performance (12minute walk distance)   Follow‐up assessment points: during 7 day run in and after both treatment periods   Outcomes in analysis‐ PEF, 12 MD, general well being
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: not stated; USA   Study design: CO   JADAD score (0‐5): 3 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: all accounted for)   Type of analysis: not stated   Compliance measured: not stated
Participants	Number of participants: 7 randomised, 7 completed   Gender: all males   Mean age: 59.4 (5.1), Age range: 52‐69   Inclusion criteria: Chronic bronchitis meeting ATS and British standards for diagnosis.   Exclusion criteria: not stated   Attempted to exclude asthmatics: Yes but methods not specified. Incuded a comparison group of asthmatics by ATS criteria   Previous oral steroid use: not stated   Smoking history: all heavy smokers   Diagnostic criteria (COPD & stability): COPD= British standards and American Thoracic Society definitions ‐ associated with bronchitis with clinical and physiological evidence of emphysema manifested by the presence of an increased residual volume, obstruction of smaller airways and abnormal pulmonary gas distribution   Stability; not defined   Severity of COPD: 4=moderate; 1=moderate‐to‐severe; 1=severe
Interventions	Drug: betamethasone   Dose: 3.6 mg 3xdaily for three days then 1.8mg 1xdaily for remainder   Delivery: oral   Duration: 4 weeks   Co‐interventions: not stated   Comparison: placebo   Duration of study: four weeks baseline before both treatment periods plus 6 week washout at crossover, total 22 weeks.
Outcomes	Outcomes assessed: pulmonary function; spirometry   Follow‐up assessment points: six weeks after treatment period then weekly for eight weeks   Outcomes in analysis‐ FEV1, responders
Notes	Compared group of chronic bronchitis patients with group of asthmatics, reults presented separately.   Responder to treatment defined as at least 20% improvement in FEV1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Chest clinic; UK   Study design: Parallel   JADAD score (0‐5): 5(sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: supplied by Medical Research Council, Method of blinding: Adequate, Description of withdrawals: yes)   Type of analysis: not stated   Compliance measured: not stated
Participants	Number of participants: 86   Gender: Males=81; Females=9   Mean age: 53, Age range: 20‐67   Inclusion criteria: chronic bronchitis >2yrs (productive cough throughout the year normally associated with dyspnoea and wheeze)   Exclusion criteria: asthma (bronchitis, infected or bronchial), past or present evidence of cardiac failure, significant hypertension, peptic ulceration, mental instability   Attempted to exclude asthmatics: yes but grounds not stated.   Previous oral steroid use: not stated   Smoking history: not stated   Diagnostic criteria (COPD & stability): COPD=chronic bronchitis defined as a chronic condition of at least 2 years duration characterized by a productive cough throughout and normally associated with dyspnoea and bronchospasm   Stability=not stated   Severity of COPD: moderate‐severe
Interventions	Drug: prednisolone (plus tetracycline 200mg tds group C)   Dose: 15 mg daily   Delivery: oral   Duration: 16 weeks   Co‐interventions: other antispasmodics discouraged.   Comparison 1: Group B‐Tetracycline 200mg tds and Aminophylline 0.1 mg tds;   Comparison 2; group A‐ Aminophylline 0.1 tds and placebo   Duration of study: 4 months
Outcomes	Outcomes assessed: sputum; colds/exacerbations;dyspnoea; broncospasm; vital capacity (only in 54 cases); side effects   Follow‐up assessment points: entry and at monthly intervals.   Outcomes included in analyses: severe exacerbations COPD, marked improvment in symptoms
Notes	Severe exacerbation defined as an acute chest illnessassociated with febrile symptoms, retiral to bed and at least 5 days total incapacity.   Study carried out over winter period.   Control group data from group B used.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: not stated; Japan   Study design: Cross‐over   JADAD score (0‐5) : 3 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: yes)   Type of analysis: case available   Compliance measured: inhalation technique carefully observed, Diary card recorded daily. No results stated.   Confounders: No wash out period at crossover but diary data from last 7 days used to avoid carryover effects.
Participants	Number of participants: 23 randomised, 21 completed   Gender: all males   Mean age: 69.1(6.8) Age range: all > 50 yrs   Inclusion criteria: over 50 years; best post bronchodilator FEV1/FVC ratio<70%; FEV1<80% predicted; smoking history of more than 20 years; 1600mg Beclomethasone Dipropionate daily for >3 months; good compliance with inhalation technique   Exclusion criteria: systemic steroid within previous 3 months; history of asthma, other lung diseases; complications like diabetes   Attempted to exclude asthmatics: yes on clinical basis only.   Previous oral steroid use: not within last three months   Smoking history: at least 20 pack years   Diagnostic criteria (COPD & stability): COPD=as defined by the American Thoracic Society (see inclusion criteria)   Stability=no acute exacerbations of their airflow limitation within preceding 3 months   Severity of COPD: FEV1 % predicted ranged from 17% (very severe) to 72% (moderate) with mean 33%.
Interventions	Drug: prednisolone   Dose: 30mg daily   Delivery: oral   Duration: 3 weeks   Co‐interventions: All on Beclomethasone 1600 mcg daily, 400mcg salbutamol and 80 mcg ipratropium bromide 4xdaily; Theophylline at stable dose permitted to be continued.   Comparison: placebo   Duration of study: 2‐4 weeks run‐in period measuring PEF and dairy card scores, 3 weeks each treatment period, total 8‐10 weeks.
Outcomes	Outcomes assessed: home monitoring daily PEF, spirometry; bronchodilator reversibility, 5 subjective symptoms scored 0 best ‐6 worst: exertional dyspnoea, wheeze, cough, sputum, activities of daily living; adverse effects ( hyperglycaemia, serum osteocalcin); eosinophil count; health related quality of life (CRQ)   Follow‐up assessment points: not stated.   Outcomes included in analyses: FEV1, PEF, Symptoms score: activity, cough, wheeze, dyspnoea, sputum, CRQ, Blood glucose, serum osteocalcin   Outcomes included in analyses:   Outcomes used in analysis:
Notes	Japanese version of Guyatts Chronic Respiratory Disease Questionnaire (CRQ) used. Scores presented as Dyspnea (5‐35), Fatigue (4‐28), Emotional function 7‐49), mastery (4‐28).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: out patients clinic; Norwich, UK   Study design: Cross‐over   JADAD score (0‐5): 2 (sum of:Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: no)   Type of analysis: not stated   Compliance measured: not stated
Participants	Number of participants: 10   Gender: all male   Mean age: 61, Age range: 52‐70   Inclusion criteria: Chronic airways obstruction, 8 met MRC criteria for chronic bronchitis, 2 had radiological features of emphysema.   Exclusion criteria: not stated   Attempted to exclude asthmatics: not stated but probably not   Previous oral steroid use: not stated   Smoking history: not stated   Diagnostic criteria (COPD & stability): not stated   Severity of COPD: mean FEV 1 810ml, FVC 2560 ml
Interventions	Drug: prednisolone   Dose: 30 mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: all used SABA four times daily.   Comparison: placebo   Duration of study: two week lead in; two week prednisolone; two week placebo, total 6 weeks.
Outcomes	Outcomes assessed: spirometry; breathlessness, subjective walking ability (5 grades) and Borg scale rating of perceived exertion after walking; 12 minute walking distance; transfer factor   Follow‐up assessment points: at the beginning and after each treatment period   Outcomes in analysis‐ FEV1, 12 MD, Responders
Notes	Responder to treatment defined as > 20% improvement in FEV1
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

PERMALINK

Oral corticosteroids for stable chronic obstructive pulmonary disease

Julia AE Walters

E Haydn Walters

Richard Wood‐Baker

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Unit of analysis issues

Data synthesis

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Results of the search

Included studies

Participants

Study design

Intervention

Outcomes

Risk of bias in included studies

Effects of interventions

Primary outcomes: FEV1

1.

High dose studies

Low dose studies: short term

Low dose studies: long term

Proportion of patients who show response to therapy on FEV1

1.3. Analysis.

Health‐related quality of life.

Short term studies

Long term studies

Secondary outcomes: Symptoms

Short term studies

Long term studies

Functional and Exercise Capacity

Short term studies

Acute exacerbations of COPD

Short term studies

Long term studies

Adverse effects of medications

Other outcomes

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Acknowledgements

Data and analyses

Comparison 1. Oral steroid versus placebo‐ short term <= 3 weeks.

1.1. Analysis.

1.2. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

1.7. Analysis.

1.8. Analysis.

Methods	Setting of study: pulmonary medicine outpatient clinic; The Netherlands   Study design: Parallel   JADAD score (0‐5): 5 (sum of :Described as randomized: yes Described as double blind: yes Method of randomization: appropriate Method of blinding: good, Description of withdrawals: yes)   Type of analysis: not stated   Compliance measured: inhalation technique checked; weighing of canisters; counting tablets. 98‐100 % for tablets.   Confounders:
Participants	Number of participants: 58 randomised, 47 completed.   Gender: all males   Mean age: prednisolone +ICS (n=19) =58(8); placebo (n=18) = 54(10) ICS +placebo (n=21) =56 (8) Age range: not stated but > 70 yrs.   Inclusion criteria: clinical diagnosis of COPD based on history of persistent dyspnoea; FEV1<80% predicted; residual volume >100% predicted, specific compliance % predicted >100% after bronchodilator (unless air trapping present); stable COPD   Exclusion criteria: over 70 years of age; allergies; eosinophils in blood; severe concomitant disease; having continuous corticosteroid treatment   Attempted to exclude asthmatics: Yes , if positive SPT or IgE >200 IU/ml, eosinophilia > 250 x 103/ml   Previous oral steroid use: not continuous   Smoking history: all current or exsmokers. Cigarette years : prednisolone =746(425); placebo group=729 (495)   Diagnostic criteria (COPD & stability): COPD= COPD based on history of persistent dyspnoea; FEVi<80%predicted; residual volume>100% predicted specific compliance expressed as % of predicted value>100% after bronchodilator.   Stability= criteria not stated   Severity of COPD: Not specified. Prednisolone group = FEV 1 L 1.86(0.56) % pred 61 (15); placebo FEV1 L 2.16 (0.58), % pred 67 (15)
Interventions	Drug: prednisolone (plus 1600mcg inhaled budesonide)   Dose: 5 mg daily   Delivery: oral   Duration: 2 years   Co‐interventions: continued with usual bronchodilator medication including anticholinergics, beta agonists, theophylline   Comparison: 1. placebo tablets (plus 1600 mcg inhaled budesonide)   2. inhaled placebo plus placebo tablets   Duration of study: 2 years
Outcomes	Outcomes assessed: spirometry; symptoms, exacerbations, withdrawal due to pulmonary problems, plasma cortisol.   Follow‐up assessment points: every two months.   Outcomes used in analysis: change in FEV1, severe exacerbations COPD, adverse effect‐ plasma cortisol level
Notes	Exacerbation defined as condition with increased dyspnoea and/or cough and/or sputum production. Standard therapy: prednisolone 35 mg/day decreasing over 7 days and antibiotic. Withdrawn from study if =>3 exacerbations within 3 months or severe progressive decline in lung function without infective origin or failing to react to short course OS.   Results skewed for FEV1 slope, exacerbation rate, exacerbation duration‐ presented as median/range. Plasma cortisol mean/SE
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: outpatients; UK   Study design: Crossover   JADAD score (0‐5): 2 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: no)   Type of analysis: not stated   Compliance measured: not stated
Participants	Number of participants: 83   Gender: Males=66; Females=17   Mean age: 61 (10), Age range: not stated   Inclusion criteria: 5 year duration of clinical symptoms of COPD, fulfilled MRC criteria for chronic bronchitis   Exclusion criteria: Steroid treatment in the last 6 months   Attempted to exclude asthmatics: only on clinical history clearly asthmatic excluded .   Previous oral steroid use: not in last six months   Smoking history: current=51%; ex=41%; mean 40 (23) pack years   Diagnostic criteria (COPD & stability): COPD=chronic bronchitis; MRC questionnaire; FEVi<70% predicted   Stability=not stated   Severity of COPD: severe (mean FEV 1% predicted 44%(SD 17%))
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral,   Duration: 14 days   Co‐interventions: not stated   Comparison 1: placebo tablets;   Comparison 2: ICS beclomethasone 500 mg   Duration of study: 2 weeks run‐in, 2 weeks, each treatment, 2 weeks at each crossover, total= 12 weeks
Outcomes	Outcomes assessed: Spirometry FEV1, FVC, home PEF daily monitoring (used results from last week only).   Follow‐up assessment points: at end of each treatment period.   Outcomes included in analyses: none
Notes	Responder defined as improvement in FEV1 or FVC or mean PEF at least 20 %.   Equivocal responder defined as improvement greater than 15% in one parameter or greater than 10% in two parameters.   No results published for placebo group.   Results available for ICS and OS groups. OS = 16/83 (19.3%) responders, 6/83 (7.2%) Equivocal responders.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: Shreveport Veterans Administration Medical Centre Chest Clinic;USA   Study design: Cross‐over   JADAD score (0‐5): 4 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: identical placebo, Description of withdrawals: no)   Type of analysis: case available   Compliance measured: not stated.   Confounders: 2 week wash out at crossover.
Participants	Number of participants: 14 randomised, 13 completed.   Gender: Males=12; Females=1   Mean age: 63 (4), Age range: not stated   Inclusion criteria: clinically stable COPD; FEV1/FVC <60%   Exclusion criteria: exacerbation of pulmonary disease in last three months; history of asthma; eosinophilia; strong family history of atopy; recent use of systemic or inhaled corticoteroids; active pulmonary infections or physical conditions that exclude cycle ergometric testing   Atempoted to exclude asthmatics: yes if eosinophilia, clinical history, family atopy.   Previous oral steroid use: no   Smoking history: All smokers or ex‐smokers, 13 year mean.   Diagnostic criteria (COPD & stability): COPD= FEV1/FVC <60%;   Stablility= no exacerbation of pulmonary disease in last three months   Severity of COPD: FEV1 before bronchodilator 1.16(0.12); after bronchodilator 1.23(0.13); % FEV1/FVC before bronchodilator 48.3(2.3); after bronchodilator 48.3(2.7)
Interventions	Drug: methylprednisolone   Dose: 32mg daily   Delivery: oral   Duration: 14 days   Co‐interventions: Theophylline; beta‐agonist   Comparison: identical placebo   Duration of study: two weeks methylprednisolone; two weeks placebo; two weeks washout; total 6 weeks
Outcomes	Outcomes assessed: spirometry; exercise testing‐ minute ventilation; oxygen consumption; heart ratio   Follow‐up assessment points: beginning and after each treatment period   Outcomes in analysis‐ FEV1, FVC, Maximum oxygen consumption during exercise.
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: respiratory clinic at University Hospital Saskatoon, Saskatchewan   Study design: Crossover   JADAD score (0‐5):4 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: appropriate, Description of withdrawals: yes.   Type of analysis: case available   Compliance measured: not stated.   Confounders: Rigourous exclusion of all subjects with bronchodilator reversibility to SABA.
Participants	Number of participants: 20 randomised, 18 completed.   Gender: Males=15; Females=5   Mean age: 64.4 (5.5), Age range: 52‐74   Inclusion criteria: diagnosis of COPD related to smoking; FEV1 that improved by <200mL 15 minutes after 200mg salbutamol; no past or present use of ingested corticosteroids   Exclusion criteria: clinical features suggesting co‐existing asthma, blood esoinophils >400/mm³, presence of sputum eosinophils, atopy positive SPTs, ASA (salicylate) or NSAID (non‐steroidal agents) sensitivity.   Attempted to excluded asthmatics: yes if any of above features present.   Previous oral steroid use: none   Smoking history: current=5; ex=15; mean pack year history 45.8 years(16.5)   Diagnostic criteria (COPD & stability):COPD= FEV1 that improved by <200mL 15 minutes after 200mg salbutamol   Stability=no seasonal exacerbations or day‐to‐day variability with only two participants occasionally requiring bronchodilators during the night, no respiratory infections or other exacerbations within 4 weeks.   Severity of COPD: FEV1 0.858L range 0.55 to 1.50
Interventions	Drug: prednisolone   Dose: 30mg daily   Delivery: Oral   Duration: 14 days   Co‐interventions: bronchodilators including salbutamol, ipratropium and/or theophylline. 3 subjects used occasional ICS.   Comparison: identical placebo tablets.   Duration of study: 2 weeks prednisolone, two weeks placebo; two week washout; total 6 weeks
Outcomes	Outcomes assessed: baseline spirometry, bronchodilator reversibility, adverse effects   Follow‐up assessment points: 0, 2, 4 & 6 weeks.   Outcomes included in analyses: FEV1, > 20% response in FEV1, adverse effects:any, marked improvement in symptoms.
Notes	Responders defined as at least 250 ml improvement in FEV1. Also looked for 250ml or 500 ml increase in FVC.   Adverse effects: heartburn n=2, increased energy n=2, difficulty sleeping n=1.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: outpatient clinic 1991‐1995; Israel   Study design: Cross‐over,   JADAD score (0‐5): 3 (sum of :Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: yes)   Type of analysis: not stated   Compliance measured: diary of drug use no results given.
Participants	Number of participants: 168 (split into responders and non responders to bronchodilators)   Gender: Males=102; females =66   Mean age: non responders=64.4(4.2); responders 66.1(4.4) Age range: not stated   Inclusion criteria: stable COPD; 30+packs cigarettes per year; FEV1 %predicted<50%; FEV1/FVC<60%; no oral or inhaled steroids in last three months   Exclusion criteria: asthma, seasonal or episodic dyspnoea or wheezing, family history of asthma atopy, more than a partial response to inhaled beta‐agonist (improvement FEV1/FVC>70%)   Attempted to exclude asthmatics: yes if clinical diagnosis, family history, seasonal symptoms, positive SPTs.   Previous oral steroid use: not within last three months   Smoking history: entire sample were heavy smokers. Mean Pack Years; non responders: 41.7(2.6); responders 38.9(2.4)   Diagnostic criteria (COPD & stability): COPD=FEV1 % predicted<50%; FEV1/FVC<60%;   Stability= not stated   Severity of COPD: not stated
Interventions	Drug: prednisolone   Dose: 40 mg daily   Delivery: oral   Duration: 6 weeks   Co‐interventions: beta‐agonist only in the case of deterioration and increase in dyspnoea   Comparison 1: placebo;   Comparison 2: budesonide 800 mcg daily or 1600 mcg daily.   Duration of study: 6 weeks on budesonide; 6 weeks on prednisolone; 6 weeks placebo; 4 week washout
Outcomes	Outcomes assessed: spirometry, BD reversibility, daily use of SABA,   Follow‐up assessment points: after each treatment phase   Outcomes in analysis‐ FEV1, responders to treatment
Notes	Responder to SABA defined as subjects with an increase in FEV1 > 20% following 5mg inhaled salbutamol.   Responder to ICS defined as subjects with an increase in FEV1 > 20% compare to placebo period.   Responder to oral steroids defined as subjects with an increase in FEV1 > 20%.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Study design: PG   Setting: 1 UK   Source of subjects: OP clinic   Concealment of allocation Quality Score: B   Described as randomised: YES   Described as double blind: SINGLE BLIND (patient)   Method of randomisation well described/appropriate: No   Method of blinding well described/appropriate: Yes   Description of withdrawals/dropouts: Yes   JADAD score (5‐1): 3   Duration of study: 2wk run in, 3 wk placebo, 3 wks inhaled treatment, 3 wks OS period   Type of analysis (available case/treatment received/ ITT): not stated   Compliance measured: Yes, weighing inhalers, tablet count   Confounders: not discussed
Participants	Number of participants: 112 recruited, 105 randomised, 99 completed.   Mean age: 66   Age range: 49‐78   Gender:Males= 83 Females=29   Inclusion Criteria: > 18 years, chronic airflow obstruction defined FER< 65%, FEV1 < 70% predicted, symptoms only in adult life   Exclusion Criteria: past or present history asthma, ICS or OS treatment < 12 weeks, infective exacerbation within 4 weeks, poorly controlled concurrent disease   Asthmatics excluded: yes on history or current diagnosis,   Diagnostic criteria for COPD (describe): FER< 65%, FEV1 < 70% predicted,   Severity of COPD: described as severe   Stability= no exacerbation within 4 weeks   Smoking history: pack years; 49 SE3.1   Bronchodilator reversibility reversibility to BD not tested   ICS usage: all given ICS in first treatment period of 3 weeks, dose 750 or 1500 mcg BDP
Interventions	Drug : Prednisolone   Dose:40mg daily   Delivery: oral   Duration: 3 weeks   Placebo used: identical   Co‐interventions:ICS: all on ICS 750/1500 for 3 weeks period prior to oral steroids, matched with placebo users   Theophylline: not stated   Beta‐agonist: yes but agent not specified   Other: not stated
Outcomes	Outcomes assessed: spirometry FEV1 F VC; exertional dyspnoea score 6pt scale 1:no breathlessness to 7 worst breathlessness ever experienced, quality of life CRQ, BHR   Follow‐up assessment points: baseline and on final day of each treatment phase.   Outcomes included in analyses: FEV1, FVC, symptom score breathlessness, CRQ score
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Methods	Setting of study: not stated; Netherlands   Study design: Cross over   JADAD score (0‐5): 3 (sum of: Described as randomized: yes, Described as double blind: yes, Method of randomization: not stated, Method of blinding: not stated, Description of withdrawals: yes)   Type of analysis: cases available   Compliance measured: inhaler technique checked on each visit.   Confounders: no wash‐out at crossover.
Participants	Number of participants: 10 Gender: males = 8; females = 2 Mean age: 57.1 Age range: 49‐66   Inclusion criteria: COPD; provocation concentration of histamine causing 20% fall in FEV1 (PC20) of less than 8mg/m   Exclusion criteria: Positive skin prick test (SPT) to common allergens; abnormal concentrations of total IgE   Atempted to exclude asthmatics:Yes because nosubject had‐ a history of attacks of wheezing or asthma, positive SPTs, PC20 histamine > 8 mg/ml or abnormal IgE.   Previous oral steroid use: none had taken inhaled corticosteroid for six week or bronchodilator except for beta agonists for two weeks; oral intake not stated   Smoking history: 6 current; 4 ex‐smokers   Diagnostic criteria (COPD & stability): COPD=FEV1 40‐80% predicted, FER <70%.   Stability= no respiratory infections or exacerbations in last two months   Severity of COPD: mean FEV1 =1.86; % predicted = 58.86 GOLD 2 mild, 7 moderate, 1 severe
Interventions	Drug: Prednisolone Dose: 40 mg dailiy. Delivery: Oral   Duration: 8 days   Co‐interventions: inhaled beta‐agonist (SABA)   Comparison 1: budesonide (1.6 mg daily)   Comparison 2: placebo   Duration of study: three treatment periods of 3 weeks for ICS and placebo inhaler, 8 days for OS and placebo, each treatment period followed by 4 study days
Outcomes	Outcomes assessed: spirometry FEV1 at baseline and after > 3 doses of inhaled placebo or salbutamol or ipratropium. Bronchial challenge tests after maximum bronchodilation to inhalers, log2 PC20 histamine,   Follow‐up assessment points: 4 post‐treatment study days after each period.   Outcomes included in analyses: FEV1, airway hyperresponsiveness
Notes	Results presented as : FEV1 mean and SE, log2 PC20 histamine mean and SE and geometric mean. SE converted to SD
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	Information not available

Study	Reason for exclusion
Chanez 1997	Not an RCT, no control group
Clifton 1962	Not randomised   No placebo group
Cullen 1960	Not randomised   No placebo group
Davies 1999	Not RCT, Intervention not an oral steriod, no placebo control
Eiser 2004	No concurent placebo group. Comparison of oral prednisolone with IM methyl‐prednisolone
Gerogianni 2002	Participants did not have stable COPD. Treated for 12 weeks during and after exacerbation of COPD
Harding 1978	Not randomised
Hopkinson 2003	Not RCT, no control group
Keatings 1997	Not an RCT, no control group
Nisar 1990	Not randomised   No placebo group
Pizzichini 1998	Not randomised
Senderovitz 1999	Not randomised   Intervention not an oral steroid
Shim 1978	Not randomised
Swinburn 1986	Not randomised
Webb 1981	Not randomised
Williams 1980	Not randomised