Association of cardiovascular and musculoskeletal biomarkers with clinical outcomes in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. In addition to premature mortality, the consequent socio-economic burden is high, causing reduced quality of life, loss of productivity, and hospital admission. Diagnosis of COPD relies on lung function tests, which are inadequate and often leave the condition undiagnosed and thus untreated. There is a growing interest in the extra-pulmonary manifestations of COPD and assessing the predictive value of cardiovascular abnormalities, musculoskeletal weakness and plasma biomarkers for acute exacerbation of COPD, hospital admission and mortality, as there is currently no individual biomarker able to reliably identify or predict these common clinical outcomes. The aim of this research was to identify and evaluate the predictive value of existing and novel biomarkers for COPD, and determine if and how these biomarkers can predict the longer-term clinical outcomes using electronic health record data. Electronic databases were systematically searched and identified 61 studies, which were synthesised, including meta-analyses to estimate pooled hazard ratios of the associations between selected biomarkers and common clinical outcomes. Data derived from the Evaluating the Role of Inflammation in Chronic Airways disease (ERICA) study were linked to electronic health record data (i.e. hospital admissions) and survival data. Predictive models for mortality and cardiovascular related hospital admission were developed using stratified multivariable Cox regression, and assessed by C-indices with 10-fold cross-validation. Negative binomial regression was used to model the event rate of acute exacerbation of COPD and determine the risk of hospitalisation due to acute exacerbation of COPD, and the associated length of stay. Data from the UK Biobank were used to explore cause-specific deaths in COPD. Sex-specific all-cause and cause-specific mortality rates were age-standardised using the 2013 European Standard Population. Hazard ratios were estimated using Cox proportional hazards regression, adjusted for age and sex. Systematic review indicated that shorter six-minute walk distance, elevated heart rate, fibrinogen, C-reactive protein, and white cell count were associated with a higher risk of mortality. Shorter six-minute walk distance and elevated fibrinogen and C-reactive protein were associated with COPD exacerbation, and shorter six-minute walk distance and higher heart rate, C-reactive protein and interleukin-6 were associated with hospitalisation. Data from the ERICA cohort indicated no significant difference between the discriminative ability of a BODE Index with six-minute walk and BODE Index with short physical performance battery when predicting mortality. For most musculoskeletal measures, poorer performance was associated with higher rate or longer duration of hospitalised acute exacerbation of COPD. Measures of arterial stiffness and carotid intima-media thickness were not associated with cardiovascular events. Measures of exercise capacity were significantly associated with cardiovascular disease and improved the discriminative ability when added to Framingham risk factors. Data from the UK Biobank indicated COPD was associated with a higher risk of all-cause mortality, and cardiovascular death. In both men and women, COPD had an associated threefold higher risk of early mortality, including a fourfold higher risk of cardiovascular-related death in women, and threefold higher risk of cardiovascular-related death in men. Epidemiological evidence indicates that musculoskeletal measures have the potential to replace the six-minute walk in the BODE Index for predicting mortality in COPD. In addition, physical capacity should be considered as an important treatable trait in reducing risk of hospitalisations for acute exacerbation of COPD. Data from the ERICA cohort does not support the use of objective measures of arterial stiffness and carotid intima-media thickness in addition to Framingham risk factors for predicting cardiovascular events within COPD. Findings in the UK Biobank indicated that COPD is associated with a higher risk of cardiovascular death but cancer and respiratory disease to be the leading causes.Collaborative award by the University of Cambridge and GlaxoSmithKline (RG79358)