Comorbidities and Burden of COPD: A Population Based Case-Control Study

Citation: Baty F, Putora PM, Isenring B, Blum T, Brutsche M ( Comorbidities and Burden of COPD: A Population Based Case-Control Study Florent Baty 0 Paul Martin Putora 0 Bruno Isenring 0 Torsten Blum 0 Martin Brutsche 0 Henrik Watz, Pulmonary Research Institute at LungClinic Grosshansdorf, United States of America 0 1 Division of Pulmonary Medicine, Cantonal Hospital , St. Gallen , Switzerland , 2 Department of Radiation Oncology, Cantonal Hospital , St. Gallen , Switzerland , 3 Clinic of Pulmonary Medicine, University Hospital Zurich , Zurich , Switzerland , 4 Department of Pulmonary Medicine, Lung Clinic Heckeshorn , Berlin , Germany COPD is associated with a relevant burden of disease and a high mortality worldwide. Only recently, the importance of comorbidities of COPD has been recognized. Studies postulated an association with inflammatory conditions potentially sharing pathogenic pathways and worsening overall prognosis. More evidence is required to estimate the role of comorbidities of COPD. Our aim was to investigate the prevalence and clustering of comorbidities associated with COPD, and to estimate their impact on clinically relevant outcomes. In this population-based case-control study, a nation-wide database provided by the Swiss Federal Office for Statistics enclosing every hospital entry covering the years 2002-2010 (n = 1298889075) was analyzed using MySQL and R statistical software. Statistical methods included non-parametric hypothesis testing by means of Fisher's exact test and Wilcoxon rank sum test, as well as linear models with generalized estimating equation to account for intra-patient variability. Exploratory multivariate approaches were also used for the identification of clusters of comorbidities in COPD patients. In 2.6% (6.3% in patients aged .70 years) of all hospitalization cases an active diagnosis of COPD was recorded. In 21% of these cases, COPD was the main reason for hospitalization. Patients with a diagnosis of COPD had more comorbidities (7 [IQR 4-9] vs. 3 [IQR 1-6]; pv0:001), were more frequently rehospitalized (annual hospitalization rate 0.33 [IQR 0.20-0.67] vs. 0.25 [IQR 0.14-0.43]/year; pv0:001), had a longer hospital stay (9 [IQR 4-15] vs. 5 [IQR 2-11] days; pv0:001), and had higher in-hospital mortality (5.9% [95% CI 5.8%-5.9%] vs. 3.4% [95% CI 3.3%-3.5%]; pv0:001) compared to matched controls. A set of comorbidities was associated with worse outcome. We could identify COPD-related clusters of COPD-comorbidities. - Competing Interests: The authors received unconditional funding from Takeda Pharma AG, Switzerland. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Chronic obstructive pulmonary disease (COPD) is an umbrella term including various and sometimes disregarded disorders or conditions [1], namely bronchitis and emphysema with its subsets and a certain overlap with asthmatic disease [2]. The definition of COPD was recently reformulated by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). It states that chronic obstructive pulmonary disease (COPD) is a common preventable and treatable disease, which is characterized by persistent airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients [3]. Beside pulmonary limitations, frequently aggravated by exacerbations, the clinical course as well as the prognosis of COPD patients seems to be significantly influenced by comorbidities, which led to the concept of COPD comorbidome [4]. Previous review articles have systematically summarized evidence demonstrating relevant associations between COPD and the following diseases [410]: N Cardiovascular diseases: ischemic heart disease, cerebrovascular disease, peripheral artery disease, left failure, right heart failure and pulmonary hypertension, arrhythmias (atrial fibrillation and flutter), arterial hypertension N Respiratory tract diseases: obstructive sleep apnea, pneumonia, lung fibrosis N Metabolic diseases: metabolic syndrome, type II diabetes mellitus, dyslipidemia N Haematological diseases/coagulopathies: secondary polycythemia, anaemia, venous thrombosis and pulmonary embolism N Musculoskeletal diseases: muscle dysfunction, muscle wasting, osteoporosis N Gastro-intestinal diseases: Gastro-oesophageal reflux disease, peptic ulcer disease, liver cirrhosis N Renal diseases: renal dysfunction N Psychiatric diseases: depression, anxiety N Neoplasias: lung, esophageal, pancreatic, breast, and all other cancers Explicit associations to COPD have not been defined for all of these comorbidities yet. Aging with generally increasing incidences of comorbidities might be considered as a potential confounder. In the same way, common causative factors (e.g. exposure to tobacco smoke) could explain co-existing, but independent diseases aside from COPD. However, there is a significantly higher prevalence for the majority of the named comorbidities in COPD patients compared to individuals without COPD when adjusted for age and risk factors [5,7,8]. Some comorbidities are evoked or at least deteriorated by means of specific anatomico-mechanical alterations within the course of COPD. For example, hyperinflation can impair ventricular filling and consequently worsen heart failure [11]. In addition, some pathophysiological sequelae of COPD are accounted for a disproportional impairment of comorbid diseases. Physical inactivity is for instance a common feature and negative predictor in COPD as well as many of the listed comorbid diseases [12,13]. Moreover, current evidence sustainably supports the hypothesis that chronic systemic inflammation constitutes the key link between COPD and some of its related comorbidities [14,15]. Nevertheless, different origins of the systemic inflammation have been postulated. Some authors favor a spill-over of inflammatory mediators originating from chronic bronchial and pulmonary inflammation in COPD [7,16]. Alternatively COPD has been interpreted to be one part of a chronic systemic inflammatory syndrome among other inflammatory entities (i.e. atherosclerotic diseases) encompassing particular local manifestations of one superordinate trigger, be they innate or acquired, might be a crucial step in the pathogenesis of these chronic systemic inflammatory syndromes including the development of COPD [17,18]. Despite the enhanced appreciation of comorbidities in COPD, there is still considerable ambiguity on their respective prevalence, as well as their specific impact in COPD patients in the context of a general population-based perspective as most related evidence has been obtained by studies with highly selected patient populations. The aim of this study is to clarify prevalence and prognostic relevance of specific COPD comorbidities in the entire and unselect (...truncated)