La van Vught

Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis

Rationale We hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are associated with mortality. Methods Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality. Results Two phenotypes were identified in 454 patients, which we named ‘uninflamed’ (N=218) and ‘reactive’ (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p<0.001) in the training cohort and 13.6% and 37.5% (p<0.001) in the validation cohort (N=207). The ‘reactive phenotype’ was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31). Conclusions Patients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.

The effect of age on the systemic inflammatory response in patients with community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Increasing age has been associated with elevated circulating levels of pro-inflammatory mediators. We aimed to determine the impact of ageing on the systemic inflammatory response to CAP. In total 201 CAP patients were enrolled. Blood samples were obtained upon presentation, and on days 2, 3 and 5. For the current analysis patients≤50 and ≥80 years were included. The Pneumonia Severity Index (PSI) score was calculated at presentation. The study encompassed 46 CAP patients aged ≤50 years (median 37 years) and 41 CAP patients aged ≥80 years (median 84 years). In both groups Streptococcus pneumoniae was the common causative microorganism. Whereas most young patients had a PSI score of I (54%), 98% of elderly patients had a PSI score≥III (p<0.001). Four elderly patients died vs. none of the young patients (p 0.045). Older patients demonstrated lower serum C-reactive protein levels on admission and during the course of their hospitalization (p 0.001) in spite of more severe disease. Serum concentrations of pro-inflammatory (interleukin (IL)-6 and IL-8) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) did not differ between age groups, although admission IL-8 levels tended to be higher in elderly patients (p 0.05). Cytokine levels were positively correlated with PSI in young but not in elderly patients. These results suggest that elderly patients show an absolute (C-reactive protein) or relative (cytokines) reduction in their systemic inflammatory response on admission for CAP.

A high anti-inflammatory response is associated with intermediate-term mortality in patients with sepsis

Sepsis is characterized by a complex systemic inflammatory response to infection. While an overwhelming pro-inflammatory response is held responsible for early deaths, subsequent anti-inflammatory cytokine production may lead to immunosuppression and secondary infections. This has been suggested as a cause of intermediate-term deaths[1].