Novel Biomarkes in Acute Respiratory Failure and Chronic Obstructive Pulmonary Disease

Sammanfattning: Abstract Background: Dyspnea is a common manifestation of a range of conditions and diseases, sometimes with multiple contributing factors. A subgroup of these patients present with acute hypecapnic respiratory failure (AHRF) and are treated with non-invasive positive pressure ventilation (NPPV). Despite the biomarkers and clinical signs available to predict outcome in patients with respiratory failure of differing etiologies, further knowledge is needed to stratify patients according to risk of treatment failure or mortality at early stages of disease before the source of the deterioration may be apparent. Chronic obstructive pulmonary disease (COPD) is a common cause of dyspnea and, in its advanced stages, of respiratory failure. COPD is to some extent preventable, e.g. with smoking avoidance or cessation. Identification of predictors of COPD development in the general population is essential to recognise individuals at high risk of developing COPD and initiating preventive measures and early treatment. Aims: The aim of Study I was to evaluate whether the biomarkers interleukin-8 (IL-8) and growth differentiation factor 15 (GDF-15) are predictive of 28-day mortality in patients with AHRF of different underlying causes receiving NPPV treatment. In Study II, suppression of tumorigenicity 2 (ST2) was evaluated as predictive of 28-day and 18-month mortality, in the same cohort as in Study I. A secondary goal was to test the hypothesis that a decrease in ST2 concentration during the first 12 hours of NPPV treatment could indicate treatment efficacy. Study III evaluated the prognostic value of ST2 with respect to all-cause mortality in patients suffering from acute dyspnea, with stratification of the study cohort according to the suggested ST2 cut-off points for risk stratification in cardiac disease, 35 ng/mL and 70 ng/mL. Study IV assessed the value of IL-8, ST2, and GDF-15 in predicting diagnosis of COPD in secondary care and of all-cause mortality in a large population-based prospective cohort study. Subjects: Studies I and II were based on a small cohort (n=46) of patients with AHRF treated with NPPV in the Intermediate Emergency Care Department of Skåne University Hospital, Malmö, Sweden. Study III comprised a population presenting to the emergency department (ED) at Skåne University Hospital, Malmö, Sweden with acute dyspnea of differing etiologies (n=1251). Study IV was based on the cardiovascular cohort of the population-based Malmö Diet and Cancer Study (n=4292). Methods: Biomarker analysis was conducted with the Proseek biomarker panel (Proximity extension assay) and with the Presage ST2 assay for ST2. Statistical analysis was conducted with SPSS. In Studies I and II, patients were analysed in subgroups according to primary discharge diagnosis. The Study III subgroup analysis was based on hospital admission status, and Study IV according to COPD diagnosis in secondary care over a mean follow-up period 21 years. Cox proportional hazard models were used to determine the prognostic value of the biomarker concentrations for mortality and COPD diagnosis. Data regarding mortality was confirmed by the Swedish National Cause of Death Registry. Results: In Study I and II, the small cohort of 46 patients with AHRF treated with NPPV included three subgroups categorized by primary diagnosis: acute exacerbation of COPD (AECOPD, n=34), acute heart failure (AHF, n=8), and acute exacerbation in obesity hypoventilation syndrome (AEOHS, n=4). Plasma concentrations of IL-8 and ST2 were predictive of 28-day mortality independent of CRP concentration. This association was maintained when the subgroup with AECOPD was analyzed. In Study II, plasma ST2 was an independent predictor of 18-month mortality, although these findings may have been driven by deaths within the first 28 days. Decrease in ST2 values during the first 12 hours was not indicative of concurrent clinical improvement. In Study III, ST2 concentrations in patients seeking the ED with acute onset dyspnea (n=1251) were predictive of 3-month and 12-month mortality independent of NT-proBNP levels. Stratification of the Study III cohort according to the ST2 cut-off levels of 35 and 70 ng/mL was shown practicable in identifying high risk patients. In Study IV, comprising a large general population cohort (n=4292), GDF-15 was found positively associated with COPD diagnosis in secondary care during a mean follow-up period of 21 years, adjusted for smoking and other confounding factors. GDF-15, ST2, and IL-8 demonstrated a significant association with all-cause mortality during a mean follow-up period of 21.5 years, with GDF-15 showing the strongest association. Conclusions: IL-8 and ST2 concentrations show association with acute clinical deterioration in respiratory failure and present targets for further exploration of prognostic value. The ST2 cut-off points of 35 ng/mL and 70 ng/mL used for risk stratification in acute cardiac disease can adequately identify high risk patients with acute dyspnea. Plasma GDF-15 concentration shows an association with long-term prognosis and mortality in respiratory failure, and, in the general population, can identify which individuals might develop COPD.