Steroid response in stable chronic obstructive pulmonary disease. A controlled trial of prednisone, in low dosage, in patients with chronic airways obstruction. Prediction of nonresponse to corticosteroids in stable chronic airflow limitation. Long-continued treatment with tetracycline and prednisolone in chronic bronchitis; a controlled trial. Value of serial peak expiratory flow measurements in assessing treatment response in chronic airflow limitation. Additive effects of prednisolone and beclomethasone dipropionate in patients with stable chronic obstructive pulmonary disease. A controlled study of the effect of prednisone on air-flow obstruction in severe pulmonary emphysema. Treatment of chronic obstructive pulmonary disease with corticosteroids. Comparison of daily vs alternate-day therapy. Effect of steroid therapy on exercise performance in patients with irreversible chronic obstructive pulmonary disease. Effects of long-term treatment with corticosteroids in COPD. The effect of oral corticosteroids on bronchodilator responses in COPD. The use of the 12 minute walking test in assessing the effect of oral steroid therapy in patients with chronic airways obstruction. Response to oral corticosteroids in chronic airflow obstruction. A double-blind comparison of oral prednisolone 40 mg/day with inhaled beclomethasone dipropionate 1500 ug/day in patients with adult onset chronic obstructive airways disease. Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction. Corticosteroid trials in non-asthmatic chronic airflow obstruction: a comparison of oral prednisolone and inhaled beclomethasone dipropionate. Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease. The response to inhaled and oral steroids in patients with stable chronic obstructive pulmonary disease. Corticosteroids in COPD. A clinical trial and reassessment of the literature. Role of corticosteroids in the management of chronic obstructive lung disease: factors predicting response.
We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease. Placebo and steroid trials were separated by 2 weeks when no tablets were given. Response was assessed by measuring forced expiratory volume in 1 second (FEV1.0). Placebo responses were normally distributed (mean, 0.8% change in FEV1.0; range, -30% to 33%). Six patients showed a greater than 50% increase of FEV1.0 in response to steroid; a seventh showed a 36% increase and an eighth, a 29% increase. Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo. The eight steroid responders did not differ from nonresponders in age, sex, smoking history, or duration and intensity of symptoms including wheeze. Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups. Patients who responded to steroids also responded to inhaled beta agonists: Acute bronchodilator response averaged 25% in steroid responders and 13% in nonresponders, a difference that was statistically significant although there was overlap between the two groups. nan The efficacy of corticosteroids in chronic airflow limitation is variable and nonpredictable. We believe that the corticosteroid-induced improvement seen in a few subjects with chronic airflow limitation indicates coexistent bronchial asthma. Therefore, we hypothesize that by carefully excluding all features (other than corticosteroid response), either objective or subjective, that might be consistent with coexisting asthma, we could predict non-response to corticosteroids. Twenty patients with chronic airflow limitation related to cigarette smoking were chosen. Features that might suggest coexisting asthma were carefully excluded; these included rhinitis, nocturnal symptoms, atopy, large response to bronchodilator, and sputum or blood eosinophilia. Eighteen of these 20 subjects completed a double-blind random-order cross-over placebo-controlled trial of 30 mg of prednisone for 14 d (with a 14 d washout between treatments). There were no significant differences, individually or collectively, in objective or subjective determinations. Based on a greater than or equal to 250 mL improvement in FEV1, there were two placebo responders and two prednisone responders. Although it may be difficult to predict corticosteroid response in chronic airflow limitation, it appears that careful exclusion of 'asthmatic tendencies' may predict nonresponse to corticosteroids. nan A double blind, randomised, placebo controlled, crossover trial of prednisolone (40 mg/day for 14 days) was carried out in 33 patients with chronic airflow limitation (mean age 62 years, mean FEV1 1.01 litres, mean FEV1/FVC ratio 44%), to assess the value of serial peak expiratory flow (PEF) measurements, taken five times daily in evaluating treatment response by comparison with other objective measurements and with measurements of symptoms. The mean serial PEF after a one week run in period was 189 1 min-1, during the second week of placebo 193 1 min-1, and during the second week on prednisolone 231 1 min-1. The difference in mean PEF values between placebo and prednisolone was significant (p less than 0.01). With regard to the response to steroids of the individual patients, 13 of the 33 had a detectable trend of improvement on visual inspection of serial PEF measurements during prednisolone treatment but only one during placebo administration. Of all the objective measurements made after the run in and after each treatment phase (12 minute walking distance, FEV1, forced vital capacity (FVC), serial PEF), the serial PEF chart provided the best discrimination between placebo and prednisolone treatment. There was no statistically significant association between steroid induced improvement in serial PEF measurements and in breathlessness, partly because of placebo improvements in symptoms in those who had no improvement in serial PEF values. This study indicates the importance of making objective measurements to identify a genuine steroid response rather than relying on symptomatic improvement alone. The best simple measurement to make is serial PEF during steroid trials. This is more sensitive in detecting a steroid response than are the 12 minute walking distance, FEV1, or FVC, and is also less likely than these measurements to show spurious placebo responses. It remains unclear whether inhaled corticosteroids can produce the maximum benefits of corticosteroids in patients with chronic obstructive pulmonary disease (COPD). To assess the additive effects of 30 mg/day prednisolone to high-dose, inhaled beclomethasone dipropionate (BDP), we conducted a randomised double-blind, placebo-controlled cross-over trial. The study population consisted of 21 men with stable COPD. The mean age of the patients was 69.1 +/- 6.8 years, and FEV(1)was 0.86 +/- 0.28 l. Seventeen out of the 21 patients (81%) were considered susceptible to steroids in a previous trial (FEV(1)increased at least 15% from baseline after receiving 14 days of 30 mg/day prednisolone). All of the patients had been on 1600 microg/day BDP for more than 3 months. Spirometry was performed before the entry, and at the end of 3-week placebo and prednisolone periods. The peak expiratory flow (PEF), symptoms, and Guyatt's Chronic Respiratory Disease Questionnaire (CRQ) as a disease specific health-related quality of life over the last seven days of each period were also evaluated. Although a marginal increase in PEF was found during the prednisolone period, no significant differences in FEV(1), FVC, symptoms or CRQ scores were observed between the two treatment periods. We conclude that the therapeutic effects of steroid therapy may be achieved by the long-term use of high-dose, inhaled corticosteroid in some patients with stable COPD.
                Copyright 2000 Academic Press. nan We compared the efficacy of corticosteroid therapy initiated as an alternate-day regimen to that of a four-times-daily regimen in patients with stable chronic obstructive pulmonary disease. In this double-blind study, 44 patients with moderate to severe COPD (mean FEV1 740 +/- 310 ml) were hospitalized and randomly allocated to receive methylprednisolone, 8 mg qid, 64 mg qod, or placebo for a ten-day period. The mean FEV1 and FVC improved significantly to a comparable degree in both steroid-treated groups, but not in the placebo-treated group. Eight of the 29 steroid-treated patients (28 percent) had improved FEV1 of more than 25 percent compared with only one of the 15 placebo-treated patients. Those in the qod group also had notable improvement in SaO2. Although the correlation between the improvement after the administration of nebulized bronchodilators and that after corticosteroid therapy was significant, some patients had more than a 25 percent improvement in their FEV1 with corticosteroids, but less than a 10 percent improvement after nebulized bronchodilators. We conclude that a substantial proportion of all patients with stable COPD will have a greater than 25 percent improvement in their flow rates with corticosteroid administration. Since the response to a qod regimen is comparable to that of a qid regimen, and since the qod regimen is associated with fewer side effects, we recommend that a qod regimen be tried initially. Many patients with irreversible chronic obstructive pulmonary disease (COPD) claim symptomatic improvement with steroid therapy, despite a lack of objective improvement in their spirometric data. To determine if steroids actually increase the exercise capacity of these individuals, 13 clinically stable patients (mean age, 63 +/- 4 years; 12 male patients) were given methylprednisolone (32 mg once daily) or placebo in a randomized double-blind crossover fashion. Spirometric data and minute ventilation, oxygen consumption (VO2), carbon dioxide production, and heart rate during incremental exercise were measured at each visit. Methylprednisolone did not produce a significant change in any of the measured parameters. Three patients had an increase in maximal VO2 of greater than 2 ml/kg/min during therapy with methylprednisolone, while two experienced a decline in maximal VO2 of similar magnitude. The change in exercise capacity was unrelated to the change in the forced expiratory volume in one second in individual patients (r = 0.08). We conclude that in the absence of any improvement in the usual tests of airway mechanics, steroid therapy does not improve exercise performance in patients with COPD. To determine the effectiveness of treatment with corticosteroids in patients with COPD.
                In this study, we investigated the effect of a 2-year treatment with corticosteroids on clinical symptoms and the decline of lung function in 58 nonallergic patients with COPD. Subjects were treated in a double-blind, randomized, placebo-controlled, parallel way with inhaled budesonide (bud), 1,600 micrograms/d; inhaled budesonide, 1,600 micrograms/d, plus oral prednisolone, 5 micrograms/d (bud + pred); or placebo (plac). Clinical assessment (history, physical examination, and spirometry) was carried out every 2 months. The rate of decline in FEV1 was assessed by calculating individual regression co-efficients from linear regression of FEV1 on time for each subject.
                Eleven patients dropped out. The number of withdrawals due to pulmonary problems was significantly higher in the plac group (n = 5 out of 18) than in the actively treated groups (n = 2 out of 40). Treatment with corticosteroids significantly reduced pulmonary symptoms. Median decline of FEV1 was 60 mL/yr in the plac group, 40 mL/yr in the bud + pred group, and 30 mL/yr in the bud group. Variation was large and differences were not statistically significant. No treatment effect was found on frequency or duration of exacerbations, possibly because of the high number of withdrawals due to pulmonary deterioration in the plac group. Treatment with a combination of inhaled plus oral corticosteroids was not more effective than inhaled corticosteroids alone. Morning plasma cortisol levels remained within the normal range in all three groups.
                Our study shows beneficial effects of long-term daily treatment with inhaled corticosteroids in patients with COPD with regard to symptoms and drop out due to pulmonary problems. Lung function decline tends to decrease during treatment with inhaled corticosteroids. The observed effects are limited but warrant further studies on the effectiveness of corticosteroids in larger numbers of patients with COPD. There have been suggestions that corticosteroid treatment might improve bronchodilator responses in chronic obstructive pulmonary disease (COPD). We have studied bronchodilator responses to salbutamol and to oxitropium bromide in 20 patients with stable moderate to severe COPD. Dose responses to the two bronchodilators were tested before and after 3 week courses of placebo and 30 mg prednisolone. Thirteen patients were taking inhaled corticosteroids. There were no significant changes in numbers of responses or maximum bronchodilator effects from either bronchodilator, although there was a trend towards higher maximum levels after 3 weeks of prednisolone. Spirometry measured at home each morning before and after oxitropium bromide showed no difference between prednisolone and placebo periods. This study provides no evidence for a significant effect on bronchodilator responses to beta-agonists or anticholinergic agents from 3 weeks of oral prednisolone in moderately severe COPD. The reproducibility of the 12 minute walking distance (12 MD) was assessed in ten men with chronic airways obstruction, and the 12 MD was used, together with spirometry, transfer factor and three subjective assessments of breathlessness to evaluate the effects on respiratory function of prednisone 30 mg daily given orally in double-blind placebo-controlled fashion for two weeks. Like others, we found the 12 MD reproducible on a single day with a mean variation of 3.1%. Tests performed two weeks apart showed greater variability ranging from 0.2% to 30.9%, (mean 9.1%). During placebo and prednisone therapy the 12 MD and assessments of breathlessness correlated significantly with each other and with TLCO, but not with spirometry. Following steroid therapy there was a significant increase in mean TLCO but no significant change in 12 MD, spirometry or subjective assessments. Changes in 12 MD and TLCO correlated significantly with each other and with changes in subjective assessments. Changes in FEV1 correlated with changes in breathlessness, and also with variability in FEV1 while receiving placebo. Individuals with the greatest changes in 12 MD and FEV1 were those with the greatest variability on placebo. The variability of the 12 MD and FEV1 should be measured in individuals before using these tests to assess response to steroid therapy. Sixteen Chinese patients with chronic fixed airflow obstruction (mean age 62.5 years; mean forced expiratory volume in 1 second (FEV1) of 0.85 litres, and mean ratio FEV1/forced vital capacity (FVC) of 0.45) entered a randomized double-blind crossover trial comparing prednisolone 40 mg orally daily for 2 weeks with placebo. Nine of the 16 patients (56%) had an increase in FEV1 of 15% or more after prednisolone. Compared with placebo, prednisolone significantly improved objective measurements (mean FEV1 by 21.4%, mean FVC by 11.9%, mean daily peak expiratory flow rate by 22.6%), subjective measurement (mean dyspnoea score by 16%) and exercise performance assessed by the distance walked in 12 minutes (12MD, by 5.5%). Objective improvements in FEV1 and PEFR were correlated with subjective upgrading of the dyspnoea score, but were not paralleled by an improvement in 12MD. Changes in FVC correlated with neither. FEV1 was thus the best index of objective measurement. The following characteristics were examined for reliability in predicting steroid responsiveness: variability of symptoms, wheezing score, prick skin test positivity, initial bronchodilator response, peripheral blood and sputum eosinophilia, and serum and sputum immunoglobulin E (IgE) level. None was found to be useful. A therapeutic trial of oral corticosteroid should be considered in patients with chronic fixed airflow obstruction on an individual basis. A double-blind cross-over trial was carried out on 83 sequential out-patients presenting with adult onset chronic airflow obstruction who were not clearly asthmatic. The study consisted of three treatment phases each lasting two weeks with a two week interval between each phase. The treatment phases were prednisolone 40 mg daily, beclomethasone dipropionate 500 ug three times a day and placebo, administered in a random order. FEV1 and FVC were measured at the end of each of the treatment phases and peak expiratory flow rate five times a day throughout. Over the study period 25 (30%) patients responded with an improvement of greater than or equal to 20% in at least one of the parameters measured as compared with the best of either baseline or placebo measurements. A further eight patients were classified as partial responders with an improvement of greater than 15% in any single parameter or greater than 10% in any two parameters. A similar number responded to beclomethasone [15] as responded to prednisolone [16]. Only six patients, however, responded fully to both forms of steroid therapy. A number of patients responded to one form of steroid treatment only which was also comparable between the two groups (prednisolone 10, beclomethasone 9). For full and partial responders mean improvement in FEV1, FVC and PEFR was greater during the prednisolone phase than during the beclomethasone phase, however, the difference did not achieve statistical significance. The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear.
                A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire.
                Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease.
                High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment. One hundred and twenty seven adults considered on clinical grounds to have non-asthmatic chronic airflow obstruction entered a randomised, double blind, placebo controlled, crossover trial comparing the physiological response to inhaled beclomethasone dipropionate 500 micrograms thrice daily with oral prednisolone 40 mg a day, both given for two weeks. One hundred and seven patients completed the study. Response was assessed as change in FEV1 and FVC measured on the last treatment day, and as change in mean peak expiratory flow (PEF) over the final seven days of treatment from home PEF recordings performed five times daily. A full response to treatment was defined as an increase in FEV or FVC, or an increase in mean daily PEF over the final seven days of treatment, of at least 20% from baseline values. An improvement in one measurement of at least 15%, or of 10% in any two measurements, was defined as a partial treatment response. Response to placebo showed a significant order effect, suggesting a carry over effect of active treatment of at least three weeks. Response to active treatment was therefore related to initial baseline values, and compared with placebo by considering responses in the first treatment phase only. A full response to oral prednisolone (16/38) was significantly more common than to placebo (3/35). The number of full responses to inhaled beclomethasone (8/34) did not differ significantly from the number responding to oral prednisolone or placebo in the first treatment phase, though full and partial responses to inhaled beclomethasone (12/34) were significantly more common than those to placebo (4/35). When all three treatment phases were considered 44/107 patients showed a full response to one or both forms of corticosteroid treatment, a response to prednisolone (39) occurring more frequently than to inhaled beclomethasone (26). Only 21 of the 44 responders showed a response to both forms of treatment. Inhaled beclomethasone dipropionate 500 micrograms thrice daily was inferior to oral prednisolone 40 mg per day, but better than placebo, in producing improvement in physiological measurements in patients thought to have nonasthmatic chronic airflow obstruction. It was, however, an effective alternative in over half of those showing a response to prednisolone. Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide.
                Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed.
                At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant.
                In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium. A significant minority of patients with COPD have favourable response to corticosteroid treatment. In addition, the benefit of corticosteroid treatment may be outweighed by the side-effects. Long-term administration of inhaled steroids is a safe means of treatment. However, only a few studies have addressed the role of inhaled steroids in patients with COPD, with conflicting results.
                Forty-four patients with stable COPD were defined as 'responders to bronchodilators' (increase in FEV1 > or = 20% following administration of beta 2-agonist) (group A), and 124 as 'non-responders to bronchodilators' (group B). All patients were randomized to receive a 6-week course of either a daily dose of 800 micrograms of inhaled budesonide or placebo, separated by 4 weeks when no medication was taken; were randomized again to receive a 6-week course of either 1600 micrograms day-1 of inhaled budesonide, or 800 micrograms day-1 of inhaled budesonide plus placebo; and were randomized once again to receive a 6-week course of either 40 mg day-1 of prednisone or placebo. All stages were performed in a double-blind cross-over design.
                Following administration of 800 micrograms day-1 of inhaled budesonide, there was an increase in the mean FEV1 from 1.40 +/- 0.20 to 1.92 +/- 0.22 L (P < 0.001) and a significant decrease in inhaled beta 2 agonist consumption in group A. These changes remained almost stable during the increased dose of inhaled budesonide or during prednisone treatment. The mean FEV1 did not change during the placebo period, or in group B in either treatments.
                Treatment with inhaled steroids improved spirometry data and inhaled beta 2-agonist consumption in about one-quarter of patients with stable COPD, and this rate increased to about three-quarters in patients who responded to beta 2-agonist inhalation. There was no additional benefit in using a higher dose of inhaled budesonide or prednisone. A placebo-controlled, double-blind cross-over trial was conducted to assess whether 16 men with chronic obstructive pulmonary disease (COPD) would benefit from orally taken corticosteroids. Two weeks of treatment with 40 mg of prednisone daily did not result in improvement of pulmonary symptoms or function in the group as a whole, although one patient had small improvement in airflow. The baseline spirometric data and beta-agonist responsiveness of the patients in the study were then compared to a reference population consisting of 264 men who fulfilled a criteria for chronic obstruction out of 730 men who comprised a systematic sample drawn from all patients referred for spirometry at three hospitals. Our study subjects and those of five similar trials of corticosteroids in COPD had more severe obstruction than this reference group. Furthermore, the proportion of steroid responders found in each study was inversely related to the baseline FEV1 of the patients examined. It appears that previous studies of corticosteroids in COPD may have overestimated the number of COPD patients who might benefit from corticosteroids, due to a bias resulting from the selection of severely obstructed subjects. A double-blind crossover trial of prednisolone was conducted in 70 patients of chronic obstructive lung disease (COLD). Emphysema dominated the clinical picture in 38, rest being chronic bronchitis with varying degrees of air trapping. None of the patients had clinical asthma. All the patients had obtained maximal benefit from an optimal dose of bronchodilators prior to entering the study. Prednisolone in a dose of 0.8 mg/kg was prescribed in a double blind crossover manner with identical appearing placebo tablets. Patients were evaluated on a weekly basis for an objective as well as a subjective response and side effects of therapy. Thirty-four patients demonstrated a statistically significant improvement in pulmonary functions. In 20 others only subjective response was observed. A good objective response was predicted by a pre-study variability in FEV1, disease duration of less than 10 years and a history of smoking less than 50 pack years.
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.