Q J Med 1999; 92: 395-400
© 1999 Association of Physicians
Oral corticosteroid trials in the management of stable chronic obstructive pulmonary disease
From the Aintree Chest Centre, University Hospital Aintree and University Department of Medicine, Liverpool, UK
Received 17 November 1998 and in revised form 5 May 1999
Address correspondence to Professor P.M.A. Calverley, Aintree Chest Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL
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Although recent guidelines for managing chronic obstructive pulmonary disease (COPD) recommend a trial of oral corticosteroids in the initial assessment, its prognostic value remains unclear. We prospectively studied 127 adults (64% men) with stable COPD (FEV1/FVC <60%) over 1 year. At entry, we measured lung volumes, gas transfer factor, respiratory symptoms (by questionnaire), and peripheral blood eosinophil count. Skin-prick testing was done, and spirometry after nebulized 5 mg salbutamol and, after 2 weeks, oral prednisolone. Physician A gave all patients inhaled beclomethasone dipropionate (800 mcg/day), whereas physician B prescribed this only to those with a positive oral corticosteroid trial. At 1 year, spirometry and respiratory questionnaire were repeated, with an estimate of overall symptom severity on a visual analogue scale. Follow-up data were available in 104 (82%) patients. Of these, 32 (31%) were unresponsive to salbutamol and prednisolone; 48 (46%) were responsive to beta agonists but not to corticosteroids, and 24 (23%) responded to corticosteroids and salbutamol. Patients in all groups were comparable, except that the prednisolone responders had a higher mean eosinophil count (p<0.001) and more were ex-smokers (p<0.001). Only the response to oral prednisolone correlated with the change in pre-bronchodilator FEV1 over 1 year. Oral prednisolone responders had higher FEV1 at 1 year (p<0.02) and significantly lower symptom scores (p<0.02). In COPD, corticosteroid trials contribute information additional to that gained from nebulized bronchodilator reversibility testing. Patients with a positive response to a corticosteroid trial are more likely to have improved symptomatically and spirometrically at 1 year.
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Introduction |
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Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality in the USA and elsewhere.3 Symptomatic bronchodilator therapy is a cornerstone of COPD management, and an objective assessment of this treatment is recommended in all patients.1,2,4 In contrast, the role of corticosteroids orally or by inhalation remains contentious. One large meta-analysis estimated that 10% of stable COPD patients responded to a 2-week oral corticosteroid trial.5 Retrospective studies of COPD patients taking oral prednisolone suggest that some patients show initial improvement in lung function and a reduction in the subsequent rate of decline. Bronchodilator response is not particularly sensitive in identifying such patients.6 In a study of patients with COPD, lung function improved modestly over a 1-year period in those treated with inhaled corticosteroids.7 It is not known if such responses can be predicted, nor even whether they can be expected, in more severe COPD.
We have previously shown that almost 40% of patients with stable moderate and severe COPD have a bronchodilator response to a two-week trial of corticosteroids.8 However, it was not possible to differentiate oral corticosteroid responders from non-responders at presentation, since the two groups of patients presented with similar symptoms, suggesting that the `responsive' patients were not merely a subgroup of asthmatics. The aim of this study was to investigate if patients with stable moderate-to-severe COPD who have an improvement in spirometry after a steroid trial and are subsequently treated with inhaled steroids have improved lung function and improved symptoms after 1 year follow-up, compared to non responders.
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Methods |
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Patients
Participants in this study were drawn from an initial cohort of 127 patients previously described,8 who met the ATS definition of COPD4 and had been seen consecutively as new referrals to our out-patient department. All had clinically stable COPD, defined by a history of progressive continuous breathlessness of at least 1 year duration and documented airflow limitation (FEV1/FVC <60%). Patients with cardiac or other pulmonary disorders, including documented asthma, were excluded. Asthma was excluded on the basis of symptoms of intermittent wheeze and breathlessness, history of atopy or previous physician diagnosis. None of the patients had had an acute exacerbation or received oral corticosteroids within 3 months of assessment. Those entering this study had been taking
200 mcg beclomethasone or equivalent, and/or had used this for less than 1 month before assessment and/or had not complied with their treatment. Each patient attended the laboratory three times, and was asked to omit inhaled bronchodilators for 6 h and oral bronchodilators for 24 h beforehand. At the first visit, a respiratory symptom questionnaire was administered and a subjective assessment of overall symptom severity was recorded on a 10 cm visual analogue scale (VAS). Spirometry before and after 5 mg nebulized salbutamol was also performed. Helium dilution lung volumes and carbon monoxide transfer factor were measured before the bronchodilator test, and skin prick tests to five common allergens and an eosinophil count were done. The patient was prescribed a 2-week course of oral prednisolone, 30 mg per day, and returned for a further prebronchodilator FEV1 at its conclusion.
The results of both types of reversibility testing were available to the referring physicians. The patients were referred by one of two physicians and allocated in a random order to the laboratory staff, who performed the tests without knowledge of their source. The referring physicians adopted different policies in response to the results. Both advised that patients with a positive corticosteroid trial received inhaled beclomethasone dipropionate through a metered dose inhaler (with or without a spacer, depending upon the ability of the patient to use the MDI appropriately) as 800 mcg daily in divided doses. Physician A's policy was to give the same treatment to all other patients irrespective of their bronchodilator responses, whilst physician B restricted inhaled corticosteroid treatment to those with a positive corticosteroid trial. Patients were reviewed 3-monthly, when smoking cessation and compliance with treatment were encouraged and inhaler technique was checked.
All patients were invited to return for visit 3 at 1 year after their initial assessment when the questionnaire and salbutamol reversibility test were repeated. The corticosteroid challenge was not repeated. Patients were asked the same questions on the presence or absence of symptoms such as cough and sputum, and on treatment actually taken, and a VAS of symptom severity was repeated. Medical staff recording the data were unaware of the results of the initial investigations. Each patient gave informed consent to the study, which was approved by the hospital ethical committee.
All spirometric assessments were performed on the same water spirometer (PK Morgan, Rainham, Kent). The staff collecting the data were unaware of the patients' physician, initial spirometry or subsequent treatment. The best FEV1 and FVC from three technically acceptable tracings were recorded.9 The salbutamol was nebulized using a System 22 nebulizer powered by oxygen at 5 l/s. Post bronchodilator measurements were recorded 15 min after the nebulization ended.
A significant change in lung function was defined as a change in FEV1 that was both 15% or more of the baseline value and greater or equal to 200 ml. This allows for the spontaneous variability of the FEV1 between repeated measurements10 and encompasses both the European Respiratory Society's11 and American Thoracic Society's criteria for a bronchodilator response.
Statistical analysis
Statistical comparisons between group data were made using ANOVA for normally distributed data or else by non-parametric Wilcoxon rank sum tests. To make allowance for the use of multiple comparisons, we used the Bonferroni correction. As our study did not contain an initial control group, we calculated a treatment effect size using the method suggested by Kazis12 and the formula: effect size=(X2–X1)/SD, where X2 is the mean post-bronchodilator FEV1 value and X1 the mean pre-bronchodilator value. The standard deviation (SD) chosen is the SD of the baseline pre or post-bronchodilator FEV1, as appropriate. Correlations between data used the least squares method. Comparisons between baseline spirometry at visits 1 and 3 were made using the method of Bland and Altman to reduce the risk of auto-correlation.13 Data are expressed as means±SD unless otherwise stated.
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Results |
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Follow-up data at visit 3 were available in 104 (82%) of the original 127 patients, and all subsequent data relate to these patients. Of the 23 not followed-up, three had died, five had moved away from the area, and two were on regular maintenance oral corticosteroids. The remaining 13 were contacted but declined to attend. Of these 127 patients, 64% were male and 93% had smoked cigarettes. The mean FEV1 was 0.92 (0.32) l with 63% having an FEV1 below 1 l. The anthropomorphic and physiological characteristics of the non-attenders did not differ significantly from the parent group. The pre- and post-bronchodilator FEV1 at visit 1 was closely related to that at visit 3 (r=0.72 and 0.79, respectively). The variance of the data around the mean was not significantly different for either pre- or post-bronchodilator values. The mean FEV1 rose over the year from 0.96 (0.40) to 1.07 (0.53) l (p<0.01).
Patients were divisible into three groups by bronchodilator response. Thirty-two (31%) were unresponsive to salbutamol at either visits 1 or 3 and to prednisolone at visit 1 (group 1). Forty-eight (46%) were corticosteroid-unresponsive but salbutamol-responsive (group 2). Twenty-four (23%) had a positive bronchodilator response to corticosteroids and also had a bronchodilator response to salbutamol (group 3).
The characteristics of these patients at study entry are shown in Table 1
. The steroid responders had a higher mean eosinophil count (p<0.001), were more likely to be ex-smokers (p<0.0001) and had a significantly higher DLCO (p<0.001). The changes in symptoms, lung function and drug therapy over the 1-year period are summarized in Table 2. These will be considered for each group in turn.
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Symptoms, spirometry and bronchodilator reversibility were unchanged over the year despite bronchodilator-unresponsive patients receiving more treatment (group 1, Table 2
). Similarly, symptoms and spirometry (either before or after bronchodilator) did not change over the year in the corticosteroid-unresponsive but bronchodilator-responsive patients (group 2, Table 2). Thirty-five of the 80 patients in groups 1 and 2 were treated with inhaled corticosteroids over the period between visit 2 and visit 3. There were no differences in spirometry and symptoms between these two groups.
Over the year, group mean FEV1 rose from 0.88 (0.26) to 1.29 (0.58) l in the corticosteroid and bronchodilator responsive patients (group 3, Table 2). The larger the initial response to prednisolone, the greater was the chance that the baseline FEV1 would be higher at 1 year; especially in subjects whose initial change in FEV1 after an oral corticosteroid trial was at least 400 ml (Figure 1). In four patients the FEV1 at 1 year was equivalent to that after their initial course of oral prednisolone, and these patients showed no further bronchodilation with beta agonists. Eighteen patients still showed significant increases in FEV1 after beta agonist at 1 year (mean initial change 0.57 l; mean change at 1 year 0.42 l). The remaining six patients, (mean FEV1 0.88 l (0.18)) showed a smaller initial change with prednisolone (mean change in FEV1 0.46 vs. 0.87 l; p<0.05) and a smaller increase in baseline FEV1 at 1 year (FEV1 0.88 (0.18) l initially; 1.18 (0.32) l at follow-up). Only patients whose baseline FEV1 improved reported an improvement in symptoms over the year (Figure 2).
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Predictors of symptoms and FEV1 at 1 year
The percentage of patients complaining of cough, sputum production and wheeze did not differ between the physiologically-defined groups or within each group over the year of follow-up. The presence of specific clinical features, e.g. sputum production, wheeze, or laboratory findings, e.g. atopy, blood eosinophilia, did not accurately predict those patients whose baseline or post-bronchodilator FEV1 subsequently improved. This was true irrespective of the physician managing the patient. Likewise, the change in FEV1 after nebulized salbutamol was unhelpful, but the response to two weeks oral prednisolone was correlated with subsequent baseline FEV1 (Spearman coefficient; r=0.60, p<0.01) (Figure 3a, b
).
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The effect size for changes in baseline FEV1 for the whole group was 0.28 using the pre-bronchodilator FEV1 and 0.15 using the post-bronchodilator FEV1. This change was due almost entirely to patients in group 3 who had shown an initial positive oral corticosteroid trial.
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Discussion |
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The purpose of this study was to assess the long-term value, if any, of FEV1 response to an oral corticosteroid trial in patients with moderate and severe stable COPD. The results of our study indicate that a subset of patients with stable COPD who have an improvement in spirometry after a trial of oral corticosteroids, when subsequently treated with inhaled corticosteroids have an improved clinical course and improved lung function. Our results also suggest that patients with COPD have a variable response to high-dose inhaled beta agonists over time, and that the presence of a bronchodilator response in these patients does not indicate better lung function or symptoms at 1 year follow-up.
This study followed carefully-defined consecutive patients with COPD over 1 year. We were particularly anxious to exclude any patients who may have asthma as the underlying cause of their COPD. Most patients were smokers and had symptoms of COPD, and all patients were all screened for a personal history of asthma. Despite our careful exclusion of asthma, the patients who were subsequently found to be steroid-responsive had significantly higher eosinophil counts and more positive skin tests. Thus it is possible that some of the steroid-responding patients were in fact asthmatic. We believe this unlikely as all had had significant cigarette exposure, none had symptoms typical of asthma, all had significant post bronchodilator and post-corticosteroid pulmonary function impairment, there was no excess of atopy in the group 3 patients and although their peripheral blood eosinophil count was more likely to be elevated, these data were not individually predictive. In the absence of biopsy evidence to confirm asthmatic features, we consider it more likely that these patients represent a subset of COPD patients. Burrows et al. have described patients with `asthmatic bronchitis' who have blood eosinophilia and a more benign prognosis than other COPD patients.14 The existence of a corticosteroid-and bronchodilator-responsive subset in COPD has some theoretical support. Recent biopsy studies have confirmed the presence of inflammatory cell infiltrates including T lymphocytes in bronchial biopsies from COPD patients.15 Amongst COPD patients with equivalent reductions in FEV1, those with relatively less emphysema had more eosinophils in their airways and had exhibited greater bronchodilator responses during life.16,17 The physiological course of our corticosteroid-responsive group is compatible with some, or all, of the above processes.
We tested with a higher dose of beta agonist than in the IPPB study to ensure that we were high on the plateau of the dose-response relationships for bronchodilators.18 Previously we have found little difference between beta agonists and ipratropium in defining a bronchodilator response at these concentrations.19 We deliberately chose a wide range of bronchodilator responses as an entry criteria, unlike either of the current prospective trials of inhaled corticosteroids in COPD (EUROSCOP/ISOLDE), as our study was a clinical one and we did not wish to censor our data. The absence of a placebo/corticosteroid trial has limited the conclusions we can draw, but such studies cannot easily be applied to patient care as they have a cross-over and order effect.20 We used FEV1 as our principal outcome measurement because of its reproducibility (140 ml between measurements in this study).
Despite using higher doses of beta agonist than in the IPPB study, we found short-term bronchodilator responses to be quite variable among the corticosteroid non-responders, with 13 moving from non-responder to responder and 18 from responder to non-responder when reviewed at 1 year. The clinical characteristics and subsequent course of any of these subgroups were identical, and variability is likely to reflect differences in baseline cholinergic tone, reflected in the starting FEV1.21 As noted above, beta agonist reversibility in the corticosteroid responders is harder to interpret, as some may already have reached the maximum airway calibre that they can achieve anatomically, and will therefore be unable to bronchodilate further. Variations in underlying disease, response to or compliance with treatment may explain why some patients still have residual bronchodilator responses without changing their baseline FEV1 at 1 year.
Changes in smoking and treatment had little effect on the course of the illness. This could reflect different susceptibility, the relatively small numbers in each group, or the duration of follow-up. Although the study size is comparatively small, the results of this study also seem to suggest that only those patients with a positive oral corticosteroid response have a sustained improvement in pulmonary function compared to non-responders subsequently treated with inhaled steroids. The absence of improvement in those oral corticosteroid non-responder patients treated with inhaled corticosteroids is disappointing. It is possible that this reflects an inherently different natural history as suggested by Burrows22 or simply a spectrum of disease response with higher/longer dosage with inhaled corticosteroids being needed to produce an improvement. This point may be clarified when the EUROSCOP and ISOLDE studies are published.
The results of this study suggest that patients with positive corticosteroid trials do appear to behave differently from other COPD patients in terms of FEV1 and symptoms. In this study we have shown that an FEV1 response to oral corticosteroids, but not beta agonists, yields prognostically useful information. Furthermore, our data support the BTS guidelines that suggest that a trial of oral prednisolone is clinically useful in stable COPD patients. However, the interpretation of individual corticosteroid responses is likely to remain difficult given the uncertainties about the reproducibility of this measurement. When we used a change of approximately 2 SD of the FEV1 measurement (400 ml) to define a responder, most individuals showed improvements at 1 year, but even this was not entirely specific. Further information about the biological basis of response to corticosteroids is needed to explain this heterogeneity.
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References |
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