Short-Term Versus Long-Term Systemic Corticosteroid Use in the Acute Exacerbation of Chronic Obstructive Pulmonary Disease Patients

Background The administration of systemic corticosteroids in chronic obstructive pulmonary disease (COPD) exacerbation is the first line of management. The duration of this administration, however, is not well established in clinical practice. The objective of this study is to compare the clinical outcomes between short-term and long-term corticosteroid use in the acute exacerbation of COPD patients. Methods A single-centre, retrospective cohort study was conducted. From 2014 to 2018, all patients over 40 years old with COPD who were admitted to the hospital with a case of COPD exacerbation and received systemic corticosteroids at presentation were included. The subjects were divided into two groups according to the duration of systemic corticosteroid therapy. The primary outcome was hospital re-admission within 180 days. The secondary outcomes were 30 days mortality and length of hospitalisation. The two groups were compared using an independent sample t-test, a Chi-square test, and a Mann-Whitney U test, according to the data type. Results Eighty patients met the inclusion criteria. A total of 52 (65%) patients completed long-term therapy, while 28 (35%) patients were on short-term treatment. A total of 15 (28.8%) patients reached the primary endpoint in the long-term treatment group versus 19 (67.9%) in the short-term treatment group (P = 0.001). The 30-day mortality was 4 (7.7%) and 0 (0%), respectively, and the median length of hospitalisation was 6.5 and 7.5 days in the long-term group and short-term group, respectively (P = 0.32, P = 0.88). Conclusion Long-term corticosteroid use in the management of acute COPD exacerbation was significantly associated with fewer 180 days re-admission. The duration of corticosteroid use remains controversial, and further studies are recommended to assess the relationship between patient profile and adherence to therapy post-discharge with re-exacerbation.


Methods
A retrospective cohort study was conducted at a tertiary academic medical centre in Jeddah, Saudi Arabia. Approval was obtained from the Institutional Review Board (IRB). The screened data were from 2014 to 2018. The criteria for eligibility were all patients over 40 years old with a primary diagnosis of acute COPD exacerbation based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria who were admitted to hospital as a case of COPD exacerbation. In addition, the patients also had to be administered systemic corticosteroids at presentation. The exclusion criteria were patients with a history of asthma, pneumonia, home use of systemic corticosteroids prior to admission and unavailability of a treatment plan.
Data was extracted from electronic medical records using a standardised collection sheet that included demographics, comorbidities such as hypertension, diabetes, cardiovascular disease, endocrine disease, kidney disease, hepatic disease, smoking history and all data related to corticosteroid therapy (name, route, dose and duration). Patient characteristics during hospitalisation were also identified, including ICU admission, the requirement of mechanical ventilation and the length of hospitalisation. The primary outcome was the next exacerbation within 180 days. The secondary outcomes were mortality within 30 days and length of current hospitalisation. Baseline characteristics were described using measures of central tendency. The frequencies were presented as numbers (percentages). The two groups (short duration and long duration) were compared using an independent sample t-test, a Chi-square test, a Mann-Whitney U test and Fisher's exact test, according to the data type. A two-sided alpha level of less than 0.05 was considered to be statistically significant. SPSS software, version 21 (IBM, Chicago, IL, USA), was used for data analysis.

Study Population
A total of 223 patients were evaluated for eligibility, of whom 80 patients met the inclusion criteria. The remaining 143 patients were excluded for various reasons. The majority Introduction Chronic obstructive pulmonary disease (COPD) is considered to be a complex, progressive life-threatening lung disease (1). It is characterised by chronic airflow obstruction that interferes with normal lung function, and it is not completely reversible (1). Acute COPD exacerbation happens when there is a deterioration of respiratory symptoms that necessitate additional therapy (1). COPD is associated with a high mortality rate; it is considered to be the fourth leading cause of death worldwide (2). By 2020, COPD is estimated to be the third leading cause of death worldwide (2). The administration of systemic corticosteroids, along with shortacting beta-2 agonists, is considered the first line of management in COPD exacerbation (3). Their rules have been established to reduce the frequency of exacerbations, minimise the urge of intubation, and lower the overall mortality rate (3,4).
Previous studies have confirmed that corticosteroids are a cornerstone in the management of COPD exacerbation (3). Systemic corticosteroids have positive impacts on clinical outcomes, such as reducing re-admission rates within 180 days and accelerating the recovery of forced expiratory volume in the first second (FEV1) (1,5). The duration of corticosteroid use in COPD exacerbation was studied in a randomised control trial (reduction in the use of corticosteroids in exacerbated COPD [REDUCE] trial), which was designed to compare the 5-day use (short-term) versus the 14-day use (longterm or conventional) (6). The study reported the non-inferiority of the short duration in terms of re-exacerbation within 6 months. On the contrary, short-term treatment significantly limited exposure to glucocorticoids and their adverse effects (6). The duration of systemic corticosteroid use is still not well established in clinical practice, and differences regarding administration were observed (7,8).
The aim of this study is to investigate whether or not there are any differences in clinical outcomes between short-term versus long-term corticosteroid administration defined as re-admission within 180 days. The study also aims to compare the length of hospitalisation and mortality rate between the long-term group and the short-term group in treating acute exacerbated COPD.
(P = 0.43). The most common comorbidities in our population were hypertension 10 (19.2%) versus 10 (35.7%), and diabetes 11 (21.2%) versus 4 (14.3%) in the long-term and shortterm groups, respectively. Other comorbidities in the short-term group included one patient with coronary artery disease, one patient with hypothyroidism and one patient with hyperthyroidism. One patient had heart failure in the long-term group. Smoking status was divided into two categories: 'ever smoke,' which accounted for 38 (73.0%) versus 22 (78.6%) and 'never smoke,' which accounted for 6 (11.5%) versus 2 (7.1%) in the long-term group and shortterm group, respectively. Twelve patients (23.1%) in the long-term group and 5 patients (17.9%) in the short-term were admitted to the intensive care unit (ICU) (P = 0.59). In addition, 11 patients (21.2%) were on mechanical ventilation in the long-term group versus 2 patients (7.1%) in the short-term group (P = 0.11). The baseline characteristics are illustrated in Table 1. of exclusions were patients who were diagnosed with community-acquired pneumonia and patients whose treatment plan was unavailable. Patients were divided into two groups based on the duration of corticosteroid therapy: longterm (conventional) duration and short-term duration. Long-term use is defined as > 5 days of systemic corticosteroids, while short-term use is defined as < 5 days of systemic corticosteroids (Figure 1).

Baseline Characteristics
A total of 52 patients completed longterm (> 5 days) therapy (65%), while 28 were on short-term treatment (35%). The mean age was 66.2 and 68.3 in the long-term and shortterm groups, respectively (P = 0.32). Regarding the sex of patients, 29 (55.8%) in the longterm group and 18 (64.3%) in the short-term group were male (P = 0.46). Saudi nationality accounted for 23 (44.2%) and 15 (53.6%) in the long-term and short-term groups, respectively

Discussion
We aimed to assess the use of corticosteroids in COPD exacerbation in a tertiary medical centre. Although GOLD guidelines state a clear recommendation of 5-7 days of treatment (1), the duration is still not well established in clinical practice, and differences regarding corticosteroid administration have been observed in previous studies (7,8), as well as in our study.

Endpoints and Outcomes
A total of 15 patients (28.8%) were readmitted within 180 days in the long-term treatment group in comparison to 19 patients (67.9%) in the short-term treatment group (P = 0.001) ( Table 2).
The 30-day mortality rates were 4 (7.7%) and 0 (0%) in the long-term group and shortterm group, respectively (P = 0.13). The median length of hospitalisation was 6.5 and 7.5 days in the long-term group and short-term group, respectively (P = 0.88).  Length of hospitalisation, days median [IQR] 6.5 [9] 7.5 [7] 0.88 7 [9] Notes: *P-values were calculated using Chi-square for re-admission within 180 days; Mann-Whitney U test was used for length of hospitalisation; Fisher's exact test was used for mortality within 30 days; n = number; IQR = interquartile range Another outcome of our study was 30day mortality, which was insignificant between the two treatment groups (P = 0.132). Only four deaths occurred in the long-term group versus no deaths in the short-term group. Such findings were consistent with those reported in the REDUCE trial (hazard ratio = 0.93; 95% CI: 0.40-2.20; P = 0.87) (6). Previous studies have revealed that a greater frequency of exacerbations is associated with an increased risk of death (18,19). In addition, early re-admission after a recent discharge -particularly within 30 days -is positively associated with a higher risk of death (20). Two patients out of the four who died were re-admitted within 180 days as a case of re-exacerbation, which reflects the severity of the cases and the positive association of early re-admission and mortality.
We acknowledge some limitations in our study. The sample size was small, especially in the short-term group. Disease severity during hospitalisation was not measured, including FEV1 values, due to the lack of documentation. As this is the nature of a retrospective design, GOLD classification was not evaluated during admission. Nevertheless, previous studies have illustrated that FEV1 values between the two groups are similar (6,21).

Conclusion
Long-term corticosteroid use in the management of acute COPD exacerbation was significantly associated with lower re-admission (180 days). The duration of corticosteroid use remains a controversy, and real clinical practice is different than the guideline recommendations. Further studies are recommended to assess patient profiles and adherence to therapy postdischarge and to establish whether these factors relate to re-admission despite corticosteroid duration.