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ORIGINAL ARTICLE
Year : 2006  |  Volume : 23  |  Issue : 1  |  Page : 8-14 Table of Contents   

Effect of prednisolone on lung function and bronchodilator responses in stable COPD


Department of Cardiorespiratory Physiology, Clinical Research Centre, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi- 110 007., India

Correspondence Address:
S K Chhabra
Department of Cardiorespiratory Physiology, Clinical Research Centre, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi- 110 007.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-2113.44424

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   Abstract 

Background : The effect of a short course of prednisolone on lung function and bronchodilator responsiveness in COPD is debatable.
Methodology : After baseline spirometry and measurement of response to inhaled salbutamol, 31 patients with COPD were randomized to the steroid group (given 40 mg/day prednisolone for 7 days) while 29 patients were assigned to the control group. All the patients continued on their usual medication based on published management guidelines. The lung function and response to salbutamol were reassessed on day 8.
Results : Both FEV 1 and FVC increased after salbutamol to the same extent in both the groups on the two test days. The proportions of FEV 1 and FVC responders were also similar in the two groups. The bronchodilator response was not reproducible and several responders of day I became non-responders on day 8 and vice versa in both the groups. At the end of 1 week, the prebronchodilator lung function showed similar improvement in FEV 1 and FVC in the two groups. A multiple logistic regression procedure failed to identify factors that could predict a steroid response.
Conclusions : A short course of prednisolone does not favourably affect lung function and bronchodilator responsiveness in stable COPD.


How to cite this article:
Chhabra S K, Ailawadhi M. Effect of prednisolone on lung function and bronchodilator responses in stable COPD. Lung India 2006;23:8-14

How to cite this URL:
Chhabra S K, Ailawadhi M. Effect of prednisolone on lung function and bronchodilator responses in stable COPD. Lung India [serial online] 2006 [cited 2020 Sep 24];23:8-14. Available from: http://www.lungindia.com/text.asp?2006/23/1/8/44424


   Introduction Top


Both inhaled and oral corticosteroids are used extensively in the management of patients with chronic obstructive pulmonary disease (COPD). However, indications for their use remain controversial. Whereas the usefulness of oral steroids in acute exacerbations of COPD is well-recognized [1],[2],[3] , their role in stable COPD is debatable. Several guidelines in the management of COPD have advocated a trial of oral steroids to identify patients who might benefit from inhaled corticosteroids [4],[5] . However most studies have found the response to oral steroids to be modest [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] .It has been suggested that "steroid responsive" patients of COPD may represent a distinct subset with greater eosinophilic inflammation of the airways [4],[12],[15],[17] . However, the inflammatory process in COPD was found to be resistant to steroids [18] . Indeed, the very division of patients into steroid­ responders and non-responders has been questioned16.

In the above studies, the effect of oral steroids was evaluated using FEV 1 as the primary outcome measure. We have recently shown that patients with COPD respond to bronchodilators more often with an increase in FVC than in FEV 1 [19] . Therefore, it has been suggested that in COPD, changes in both FVC and FEV 1 should be evaluated separately [20],[21] . A response may be missed if only the FEV 1 response is considered. An increase in FVC is clinically important as it would result in decreased hyperinflation. Whether a short course of oral steroids has any beneficial effect on the FVC response has either been ignored or if reported, has usually not been commented upon in the previous studies.

One of the possible mechanisms of the beneficial action of corticosteroids in asthma is a potentiation of the response to beta-adrenergic bronchodilators [22] . This has been investigated in only a few studies that failed to find any enhancement of response to bronchodilators in COPD [23],[24] . Again, only the FEV 1 response was examined and whether this holds true for the FVC response too was not investigated. The present study was therefore carried out to address these deficiencies in literature.


   Material and Methods Top


Patients diagnosed to have COPD, as defined by the GOLD guidelines [25] and regularly attending the outpatient clinic were included in the study. The study was carried out in the outpatient setting at the Vallabhbhai Patel Chest Institute, a tertiary care hospital for chest diseases in Delhi. Informed consent was obtained from all the patients.

The essential inclusion criteria were a history compatible with the diagnosis of COPD, a smoking history of at least 10 pack years, an FEV1 /FVC ratio <70%, a less than 200ml and 12% post­ bronchodilator acute increase in FEV 1 , and a stable clinical condition as indicated by no change in symptoms and drug requirements over the past 4 weeks. Patients with a history suggestive of asthma, clinical or radiological evidence of any other past or concurrent pulmonary disease, any other systemic disease, recent history of acute exacerbation of symptoms within the past 4 weeks, and those unable to perform acceptable spirometry were excluded from the study. While we would have liked to include both male and female patients, the number of male patients of COPD reporting to the Institute far outweighs the number of female patients. This is possibly related to the fact that smoking in female subjects is much less common in India [26] and therefore, smoking-related COPD is much less prevalent. Knowing from our experience that sufficient number of female subjects would not be available within the defined inclusion period, we decided to include only males. All the subjects were ex-smokers.

Initial investigations before the study included complete blood counts, sputum examination for pyogenic organisms and acid-fact bacilli, a 12 lead standard electrocardiogram, a postero-anterior plain chest roentgenogram, and spirometry.

Study design

A randomized, parallel-group design was used. After the initial investigations, the patients were randomized into two groups: (i) Steroid group: patients to receive oral prednisolone, 40mg/day given once a day for 7 days in addition to their usual medication; (ii) Control group: patients on their usual medication.

The sample size was calculated for a specified difference of 0.2 L in FEV 1 with a power of 90% setting the significance of difference at p<0.05 (alpha, two-tailed). We estimated that 23 patients would be required in each group. Finally, 60 patients were included, 31 in the steroid group and 29 in the control group.

The patients underwent spirometry followed by administration of 200µg salbutamol from a metered dose inhaler (MDI) and repeat spirometry at 20 min. on day 1. The patients were called back on day 8 for a repeat assessment of spirometry and bronchodilator responsiveness. The tests were carried out between 9 and 11 AM.

The usual medications for these patients consisted of inhaled corticosteroids (budesonide 800­1600 µg per day) or fluticasone dipropionate (250­500 µg per day), ipratropium bromide 40µg four times a day, and either salmeterol (50µg twice daily) or formoterol (12 µg twice daily). Rescue use of salbutamol was allowed. (Asthalin-Cipla Ltd.). No drug was permitted on the morning of the test. Throughout the study, the doses were kept constant. The drugs were given from an MDI and administered using a spacer device. All the MDIs were manufactured by Cipla Ltd.

Patients who showed an increase in FEV 1 or FVC of ³ 0.2L following salbutamol administrations on day 1 or day 8 were labelled as FEV 1 or FVC responders respectively. Similarly, patients showing an increase in baseline FEV 1 or FVC of ³ 0.2L in day 8 values over day 1 values were labeled as responders. The response was assessed in terms of absolute change as we have recently reported that this expression is better than expressing the response in terms of the change as a percent of the baseline value [27] . A change of 0.2 L is greater than the random variation during a test session and can be taken as representing a significant change [28] .

Measurements

Spirometry was performed on a dry, rolling-seal spirometer of the Transfer Test C model lung function machine (P.K. Morgan, Kent, UK). Maximal Expiratory Flow Volume (MEFV) curves were obtained as per the ATS 1995 recommendations [28] . Three acceptable and at least two reproducible curves were obtained in each subject. The selection of spirometry parameters, Forced Expiratory Volume in is (FEV 1 ) and Forced Vital Capacity (FVC), was done as recommended by the ATS [29] . Reference equations for north Indian adults were used to calculate the percent-predicted values [30] .

Statistical analysis

Statistical analysis was carried out with the help of SPSS 11.5 for windows and Graph Pad Prism 2.01 for windows. Paired data was evaluated using the student's paired "t" test. Between group comparison were made using student's unpaired 't' test. Proportions were compared using the chi square test. Multiple logistic regression was carried out to identify predictors of steroid response. A "p" value of < 0.05 was considered as significant.


   Results Top


The characteristics of the study population are given in [Table 1]. Patients in the steroid group were younger (p<0.05) and had a shorter duration of disease (p<0.01). However, the smoking history and the baseline lung function were not significantly different between the two groups (P >0.05).

Effect of prednisolone on bronchodilator responsiveness

All volumes are expressed as mean±SD in Litres. On day 1, in the steroid group, the FEV 1 increased from a baseline value of 1.13±0.48 to1.25±0.62 after administration of salbutamol (p<0.001) while the FVC increased from 2.34±0.65 to 2.61±0.62 (p<0.001). In the control group, FEV 1 increased from 0.99±0.28 to 1.12±0.33 (p<0.001) and the FVC increased from 2.40±0.71 to 2.77±0.67 (P<0.001)

On day 8, in the steroid group, the FEV 1 increased from a baseline 1.22±0.51 to 1.35±0.5 after administration of salbutamol (p<0.001) and the FVC increased form 2.39±0.64 to 2.76±0.53 (p<0.001). In the control group, the FEV 1 increased from a baseline value of 1.11±0.41 to 1.16±0.41 after administration of salbutamol (p<0.001) and the FVC increased from 2.58±0.75 to 2.82±0.79 (p<0.001).

The post-bronchodilator change in FEV1 and FVC on days 1 and 8 in the two groups is shown in [Figure 1] and [Figure 2]. The magnitude of bronchodilator responses did not show any significant difference between the two groups on either test day (p>0.05).

The number of patients in each group showing an FEV 1 or the FVC response on the two test days is shown in [Table 2]. The number of subjects showing an FVC response exceeded those showing an FEV 1 response. The proportions of FEV 1 and FVC responders were not significantly different on days 1 and 8 between the two groups (p>0.05).

Interestingly, several responders of day 1 became nonresponders on day 8 and vice versa. In the steroid group, out of the 9 FEV 1 responders of day 1, only 2 retained their responsiveness and 7 became nonresponders on day 8 while out of the 22 nonresponders on day 1, 6 became responders and 16 remained nonresponders on day 8. On the other hand, out of 20 FVC responders, 16 retained their responsiveness and 4 became nonresponders on day 8 while out of the 11 nonresponders on day 1,6 became responders and 5 remained nonresponders on day 8. In the control group, out of the 7 FEV 1 responders only 1 retained his responsiveness and 6 became nonresponders on day 8. On the other hand, out of 21 FVC responders on day 1, 15 retained their responsineners on day 8. Out of 22 FEV 1 non responders on day 1, three became responders on day 8 and 19 remained nonresponders. Out of 8 FVC nonresponders on day 1,2 became responders on day 8.

The reproducibility of bronchodilator responses over the 1 week interval was evaluated in the control group patients. The intraclass reliability coefficient of FEV 1 was 0.02 (p>0.05) showing a lack of repeability of response. However, the FVC response was more repeatable, the intraclass reliability coefficient being 0.58 (p<0.05).

Effect of prednisolone on lung function

This was evaluated by comparing the baseline lung function on the two test days. In the steroid group, after seven days treatment with prednisolone, the baseline FEV 1 increased form 1.13±0.46 to 1.22±0.51 (p<0.05) while the baseline FVC increased from 2.34±0.65 to 2.39±0.64 (p>0.05). In the control group, the baseline FEV 1 on days 1 and 8 was 0.99±0.28 and 1.11±0.41 respectively (p>0.05). The baseline FVC was 2.40±0.71 and 2.58±0.75, respectively, on the two test days (p>0.05). The change in baseline FEV 1 and FVC was similar in the two groups (p>0.05) [Figure 3].

The response to prednisolone was not uniformly observed in patients. Ten patients had a significant increase in baseline FVC. Fourteen patients had a significant increase in one or both the parameters after prednisolone. In the control group, 9 patients had a significant increase in baseline FEV 1 while 10 patients had a significant increase in baseline FVC. Thirteen patients had a significant increase in one or both the parameters. The proportion of responders was similar in the two groups.

A multiple logistic regression procedure was carried out to identify factors that may be associated significantly with a steroid response. The following were included as possible explanatory variables: age, duration of disease, pack-years of smoking, peripheral eosinophil count, presence or absence of wheezing, presence or absence of nocturnal attacks of wheezing, presence or absence of rhinitis and presence or absence of triggering factors for dyspnoea. None of the variables entered the model as significant determinant of steroid response.


   Discussion Top


The present study shows that a short course (1 week) of prednisolone does not improve lung function in stable patients of COPD. This is in agreement with other studies that have found the effect of upto 2 weeks treatment with prednisolone to be modest in COPD with few patients, ranging from none to less than a third showing any substantial increase in FEV1 [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] . We observed the change in the baseline FEV 1 and FVC to be small for the group as a whole and similar to the spontaneous change after 1 week observed in the control group. While 10 out of 31 (32%) subjects showed an increase of greater than 0.2 L in FEV 1 after 1 week of prednisolone treatment in the present study, 9 out of 29 (31%) patients in the control group also had a similar increase. For the FVC response, the increase was observed in 39% and 35% patients, respectively, in the two groups. Therefore, the apparent steroid responsiveness was matched by the short-term random variation in response and was thus unlikely to be a true effect.

We also failed to find any enhancement of the bronchodilator response to salbutamol with prednisolone. The FEV 1 and the FVC response to salbutamol were similar before and after treatment in both the steroid and the control group. This confirms the observations of the previous studies for the FEV 1 response [23],[24] . This is in contrast to the potentiation of bronchodilator responsiveness observed in asthmatics [22] .

The earlier studies had looked into the effects of prednisolone on lung function and bronchodilator responsiveness using the FEV 1 response as the primary outcome parameter. As both the FEV 1 and FVC response are important in COPD [19],[20],[21] , and patients with COPD are more likely to respond with an increase in FVC rather than FEV1 [19] , our concern was that an effect of prednisolone may have been missed by not considering the FVC response. The present study has provided the additional information that the lack of effect of prednisolone on lung function and bronchodilator responsiveness holds true for both the FEV 1 and the FVC response.

While the cellular infiltrate in the airways in COPD is mainly neutrophilic [31] , an eosinophilic component has also been reported and suggested to be responsible for the observed steroid responsiveness. In a few studies, it was found that steroid responders had larger number of eosinophils and higher levels of ECP compared to non-responders in their bronchoalveolar lavage (BAL) or induced sputum and these were reduced after treatment [12],[13],[15],[17] . However, Keatings et al [18] have found the inflammatory process in COPD to be resistant to the anti-inflammatory effects of steroids with no change in lung function or dyspnoea or sputum eosinophils and eosinophilic products. The latter study as well the clinical response studies [6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] , including the present one, suggest that the inflammatory process in COPD is not affected by a short course of prednisolone, highlighting the contrast with asthmatics.

Much of the apparent steroid responsiveness in COPD reported in literature may in fact be due to the effect of regression towards the mean that will results in greater response in the more obstructed patients. A selection bias towards more severe patients would favour such results. Eliasson et al [9] suggested this factor along with a failure to consider the coefficient of variation as well as the random variation over time in FEV 1 as the reasons for such conclusions in previous studies. Inclusion of a parallel control group of study confirmed that much of the steroid responsiveness can be explained by random variation in lung function.

It is doubtful if patients with COPD can be divided into distinct subsets of "responders" and "nonresponders". We found that the responses were not reproducible and the patients changed their status from responders to nonresponders and vice versa in both the groups. Calverly et al [32] have also recently questioned the division of COPD patients into responders and nonresponders. Burge et al [16] reasoned that if response to steroid identified distinct subset of patients, it should not be normally distributed and should be reproducible. Examination of data on 524 subjects however did not stand this reasoning. Therefore, it is unlikely that these terms represent distinct subsets among patients with COPD and the response on any day is likely to be determined by the bronchomotor tone, the degree of airway inflammation and intraluminal secretions and therefore is likely to vary with time. Whether steroid responsiveness identifies a subgroup of COPD that has a more favourable outcome is debatable [13],[14] . Burge et al [16] have concluded that prednisolone testing was an unreliable predictor of benefits from subsequent treatment with inhaled steroids. The GOLD and the recent NICE [33] guidelines have also not favored this practice. While a few patients may have a fairly good response to oral prednisolone, these cannot be identified by any clinical features or laboratory findings. An "asthmatic" history, age, sex, skin tests results, family history of atopy, baseline lung function, bronchodilator responsiveness age, blood eosinophil counts, serum IgE levels, sputum eosinophil counts smoking history have not been found to be predictors of response [6],[8],[11],[16] . In the present study too, age, duration of disease, pack-years of smoking, peripheral eosinophil count, presence or absence of daytime/ night-time wheezing, rhinitis and triggering factors for dyspnoea did not identify patients who would respond. Although conceptually interesting, it is doubtful if a distinct "asthmatic" phenotype of COPD can be identified from history and other investigations.

The study has a few limitations. A placebo control was not used. As the outcome parameters were objective, lack of a placebo control may not have affected the results of the study. All the patients were already receiving inhaled corticosteroids. These were not stopped as a long period of withdrawal necessary to wash-out the effects of corticosteroids may have worsened their clinical condition. It is possible that the results may have been different in steroid-naive patients. The results of this study would therefore apply to stable patients who are already on inhaled corticosteroids.

To conclude, the present study shows that a short course of prednisolone does not favourably affect lung function and bronchodilator responsiveness in stable COPD. While it is true that some patients of COPD may have a substantial improvement with a short course of oral prednisolone, evidence does not favour this as a strategy to identify patients who may have a better outcome with treatment. Such an approach should be individualized and the effects of treatment monitored objectively.

 
   References Top

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    Figures

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