Predictive Factors of Multiple Hospitalizations for Acute Exacerbations of COPD

Background: Multiple hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with considerable morbidity and mortality. Objectives: To identify predictive factors of multiples hospitalizations for AECOPD. Methods: This is a retrospective single center study of consecutive patients with COPD hospitalized at the Department of Respiratory Medicine between January 1990 and December 2015. We calculated for each patient the mean number of hospitalizations for AECOPD/year (H/y). We distinguished 2 groups (G) of patients. G1: <2 H/y and G2: ≥2 H/y. Predictors of multiple admissions identified by univariate analysis were included in the multivariate analysis. Results: The study included 1167 COPD patients (mean age 67 ± 10 years, 97% males). Three hun-dred six (26%) COPD patients had a mean number of hospitalizations per year ≥ 2. Multivariate logistic regression analysis demonstrated that an mMRC ≥ 2 (Odd ratio [OR] 1.8, 95% confidence interval [CI] 1.08 - 2.99, p = 0.022), a low PaO 2 (PaO 2 OR 0.97, 95% CI 0.95 - 0.99, p = 0.007) and frequent exacerbations (OR 2.95, 95% CI 2.56 - 3.39, p < 0.001) are independent factors associated with multiple admissions for AECOPD. Conclusions: An mMRC ≥ 2, a low PaO 2 and frequent exacerbations are independently associated with multiple hospitalizations for AECOPD. The identification of these high risk COPD patients will be helpful in the decision of intervention strategies.

the fourth leading cause of death in the world and will be the third by 2020 [1].
Exacerbations of COPD are defined as an acute worsening of respiratory symptoms that results in additional therapy [1]. An acute exacerbation (AE) leading to hospitalization is considered as severe exacerbation [1]. Hospital admissions for AECOPD are associated with considerable health-care costs, morbidity and mortality [2]. In fact, the majority of health care expenditure related to COPD arises from hospitalization. Thus, preventing exacerbations and especially hospitalizations is a major component of COPD management strategies. Despite the importance of hospitalization for AECOPD, little is known about the factors related to these events and their recurrence. Indeed, some COPD patients have an increased risk of recurrence of an AECOPD following hospitalization [3]. Readmissions for AECOPD are known to have pejorative consequences [4]. The hospital readmission rate for AECOPD remains high through the world despite improvement in the management of COPD. In some studies, the rate of readmission within one year reached 60% [5] [6]. The reasons for readmission are not fully clarified. Therefore, establishing the profile of patients who tend to be readmitted by identifying the risk factors of multiple admissions of AECOPD is a core issue. Approximately 10% to 55% of readmissions for AECOPD may be preventable [7]. Factors associated with readmission provide important information for health care planning. Reducing readmissions has become a policy target in different countries and an important goal for health-care institutions [7]. Some predictors have been identified [8] [9] and certain strategies have been proposed [10]. But there is not enough evidence at present to recommend standardized approach for this problem [10] [11].
The aim of this study is to identify predictive factors of multiples hospitalizations for AECOPD. We believe that the identification of these factors will be helpful in the decision of intervention strategies, leading to better standards of care and better outcomes for patients.

Study Design and Subjects
This is a retrospective single center study of consecutive patients with COPD posures to noxious stimuli) [1]. We defined AECOPD according to GOLD definition as an acute event characterized by a worsening of the patient's respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication [1]. We defined severe exacerbation as an exacerbation requiring hospital admission and moderate exacerbation as AE requiring treatment with antibiotics and/or short course of oral corticosteroids [1]. Admission was defined as a medical ward stay of greater than 24 h duration. After the first hospitalization, the included patients had a period of follow-up post-discharge of at least one year. We calculated for each patient the mean number of AE (moderate and severe) per year. We considered also hospitalizations for AECOPD in other hospitals reported by patients during the period of follow-up. We categorized patients according to COPD severity based on FEV1 (GOLD grades 1-4). Potential participants were not included based on the following criteria: hospitalizations for other reasons than AECOPD like community-acquired pneumonia, heart failure, pneumothorax, pulmonary embolism …, and a co-existing pulmonary disease which may lead to multiple admissions like Asthma-COPD Overlap, suspected underlying malignancy or active pulmonary tuberculosis.

Grouping
We calculated for each patient the mean number of hospitalizations for AECOPD/year (H/y). We distinguished 2 groups (G) of patients. G1: <2 H/y and G2: ≥2 H/y defining the multiples hospitalization's group. No patient consent was required as it is a retrospective study utilizing the COPD database of our department and no specific patient identifiable information was utilized. Patient confidentiality was maintained by de-identification of all data.

Statistical Analysis
Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS) V. 20 for Windows. Categorical variables were expressed in absolute values and proportions. Continuous variables were expressed as mean ± SD. Means Open Journal of Respiratory Diseases were compared using the Student's t-test for independent samples. Proportions between groups were compared using the chi-square test. Factors that were significantly associated to multiple hospitalizations in univariate analysis were included in the multivariate analysis using binary logistic regression, and odds ratios (OR) were calculated. Results were expressed as odd ratios (OR) with 95% confidence intervals (CI). Difference in the survival rates between the two groups was analyzed with the use of the Kaplan-Meier survival curves, log-rank and Breslow tests. A P value < 0.05 was considered significant.

Baseline Characteristics of COPD Patients
A total of 1167 patients fulfilled the eligibility criteria and were included in the study. The clinical characteristics of the COPD patients are presented in Table 1.
The mean age of the total sample was 67 ± 10 years, with 97% males and 96% current or former smokers. The mean FEV1 was 1.16 ± 0.48 (43% ± 16% of predicted). Patients were followed for a mean period of 4.1 ± 3 years. Three hundred six (26%) COPD patients had a mean number of hospitalizations per year ≥ 2 ( Figure 1).

Impact of Multiple Hospitalizations on Survival Rates of COPD Patients
Kaplan-Meier-estimated cumulative survival was significantly shorter in G2 than in G1 (Log Rank < 0.001, Breslow: 0.014) with a median overall survival of 48 and 84 months respectively ( Figure 2).

Univariate Analysis of Risk Factors Associated with Multiple Hospitalizations among COPD Patients
No significant differences were found between the 2 groups in terms of age, gender, BMI, presence of co-morbidities or smoking status. However, several other variables were significantly associated with multiples hospitalizations in the univariate analysis. Patients with multiple hospitalizations were more likely to be diabetics, had higher mMRC dyspnea scores, an altered respiratory function, a greater number of AE per year, with more AE due to pyocyanic, than those with infrequent admissions (Table 2).

Discussion
Hospitalizations for AECOPD are associated with a poor prognosis. This study aimed to identify the factors associated with multiple hospitalizations for AECOPD. The results suggest that having an mMRC ≥ 2, a low PaO 2 and frequent exacerbations, are independent factors associated with multiple admissions for AE of COPD. Open Journal of Respiratory Diseases   The major strengths of the present study were: a considerable sample size, an acceptable period of follow-up, and the availability of data having allowed to study several parameters related to the severity of the disease. Furthermore, our data were based on records. COPD patients were hospitalized and treated re- Published data about multiple hospitalizations analyzed several factors that can be associated to readmissions. But there is a lack on the definition of readmission after hospitalization for AECOPD [7]. In fact, readmission may be defined as rehospitalization for AECOPD or it may be due to any other cause. In a large study conducted in the United States, 26% of readmissions 30-days post discharge are due to AECOPD and, overall 50% are due to respiratory-related causes [7]. Also, the majority of rehospitalizations in COPD patients are not respiratory-related [11]. This may lead to confusion if readmissions for AECOPD are compared with all-cause readmissions [11]. Another problem is that there is no standardized definition for multiple admissions or rehospitalization regarding the time to next admission. The latter is varying in publications from early Open Journal of Respiratory Diseases readmissions (30-day) to a 2 year period [7].
There is a great discrepancy in the readmission rates of COPD patients in the literature. In the study of Tsui et al., 73% of COPD patients were readmitted at least once for AECOPD during the year after hospital discharge [12]. A retrospective study carried out in a Hong Kong regional hospital, 59% of COPD patients had been readmitted at least once by the end of 1 year after discharge from the index admissions [13]. In the latter study, a 24-h emergency department stay was considered as an admission. Garcia Aymerich et al. get 63% as a rate of readmission during a mean period of follow-up of 1.1 years [5]. A lower rate of 45% of readmission in one year after discharge was found in the study of Wei et al. [4].  [12]. Readmission rates are varying according not only to the characteristics of the COPD population but also the considered interval time to readmission. One in three patients hospitalized due to AECOPD was readmitted within 90 days according to an England healthcare commission [14]. In another study, performed at a single centre in the United States, nearly 20% of patients discharged for AECOPD were readmitted within 30 days [15].
The rate of readmission within 30 days of discharge for AECOPD is about 17% in Spain [16] and 14% in the Netherlands [17]. These differences are probably due to the different methodology used in each study.
In the present study, the median overall survival was significantly shorter in G2 than in G1. This is in accordance with several other reports. In a Spanish cohort study, a history of at least two hospitalizations for AECOPD the previous year was independently associated with a higher overall mortality (OR, 7.63; 95% CI, 3.41 -17.05 with p < 0.001) [18].
Previous studies of multiple admissions for AECOPD identified a number of risk factors. Readmission is still considered to be avoidable and led to the establishment of a penalty system for readmission within 30  ripheral edema, impaired consciousness, poor coping at home, significant comorbidities, and failure to initial treatments as main factors for rehospitalization [26]. In the prospective observational study of Tsui et al.: previous non-invasive ventilation for AECOPD, high COPD Assessment Test (CAT) score, reduced 6-minute walk distance and a high number of admissions for AECOPD in the previous year were independently associated with time to first readmission.
Subgroup analysis showed that anxiety was strongly associated with very frequent readmissions [12]. In our study, mMRC scale was used to appreciate symptoms instead of the CAT core since the retrospective type of the research.
In a retrospective study carried out in Hong Kong [13], within1 year after dis- study [31].
On another hand, we found that a low level of PaO 2 is an independent factor associated to multiple admissions. In the study of Garcia-Aymerich et al., oxygen tension (0.88, 95% CI 0.79 to 0.98) was one of the independent factors related to readmission in the final multivariate model. Other factors were also identified such: >3 admissions for COPD in the year before recruitment, low FEV1, reduced levels of usual physical activity and taking anticholinergic drugs [5]. In some studies, use of long-term home oxygen in COPD patients with chronic respiratory failure was independently associated with a shorter time to first readmission for AECOPD [2]. However in other studies, this association was not significant or it did not remain significant after adjustment [2]. Other abnormalities of gas exchange like an increased PaCO 2 were significantly related to multiple admissions [13].
Additional studies are still necessary to identify other risk factors for AECOPD especially modifiable factors that are independently associated with a higher risk of readmission to the hospital. A standard definition of "readmission" in terms of delay and cause is necessary.
There is emerging scores predicting readmission for AECOPD like The Readmission After COPD Exacerbation (RACE) Scale [32], LACE index (length of stay, acuity of admission, co-morbidities, and emergency department visits within the last 6 months) [33], or The PEARL score (Previous admissions, the Extended MRC dyspnea score, Age, Right-sided heart failure and Left sided heart failure) [14]. These scores may guide readmission-reduction strategies by the identification of patients at high risk of readmission. The purpose is to implement evidence-based interventions. In fact, the identification of the risk factors highly associated with readmission rate would allow the implementation of a well defined post-discharge action plan for these patients.
Coping with this scope, some developed countries are now implementing programs to reduce readmissions for AECOPD after discharge tending to ameliorate care quality with better control of COPD's costs [37].

Conclusion
In summary, our results suggest that an mMRC ≥ 2, a low PaO 2  to such predictors may help identify a subgroup of COPD patients with a high risk of readmission in order to initiate specific readmission reduction programs.