A genome-wide association study of survival in patients with sepsis.

BACKGROUND: Sepsis is a severe systemic inflammatory response to infections that is accompanied by organ dysfunction and has a high mortality rate in adult intensive care units. Most genetic studies have identified gene variants associated with development and outcomes of sepsis focusing on biological candidates. We conducted the first genome-wide association study (GWAS) of 28-day survival in adult patients with sepsis. METHODS: This study was conducted in two stages. The first stage was performed on 687 European sepsis patients from the GEN-SEP network and 7.5 million imputed variants. Association testing was conducted with Cox regression models, adjusting by sex, age, and the main principal components of genetic variation. A second stage focusing on the prioritized genetic variants was performed on 2,063 ICU sepsis patients (1362 European Americans and 701 African-Americans) from the MESSI study. A meta-analysis of results from the two stages was conducted and significance was established at p < 5.0 × 10-8. Whole-blood transcriptomic, functional annotations, and sensitivity analyses were evaluated on the identified genes and variants. FINDINGS: We identified three independent low-frequency variants associated with reduced 28-day sepsis survival, including a missense variant in SAMD9 (hazard ratio [95% confidence interval] = 1.64 [1.37-6.78], p = 4.92 × 10-8). SAMD9 encodes a possible mediator of the inflammatory response to tissue injury. INTERPRETATION: We performed the first GWAS of 28-day sepsis survival and identified novel variants associated with reduced survival. Larger sample size studies are needed to better assess the genetic effects in sepsis survival and to validate the findings.

Clinical and biological markers for predicting ARDS and outcome in septic patients.

Sepsis is a common cause of acute respiratory distress syndrome (ARDS) associated with a high mortality. A panel of biomarkers (BMs) to identify septic patients at risk for developing ARDS, or at high risk of death, would be of interest for selecting patients for therapeutic trials, which could improve ARDS diagnosis and treatment, and survival chances in sepsis and ARDS. We measured nine protein BMs by ELISA in serum from 232 adult septic patients at diagnosis (152 required invasive mechanical ventilation and 72 had ARDS). A panel including the BMs RAGE, CXCL16 and Ang-2, plus PaO2/FiO2, was good in predicting ARDS (area under the curve = 0.88 in total septic patients). Best performing panels for ICU death are related to the presence of ARDS, need for invasive mechanical ventilation, and pulmonary/extrapulmonary origin of sepsis. In all cases, the use of BMs improved the prediction by clinical markers. Our study confirms the relevance of RAGE, Ang-2, IL-1RA and SP-D, and is novel supporting the inclusion of CXCL16, in BMs panels for predicting ARDS diagnosis and ARDS and sepsis outcome.

Whole-Blood Mitochondrial DNA Copies Are Associated With the Prognosis of Acute Respiratory Distress Syndrome After Sepsis.

Acute respiratory distress syndrome (ARDS) is an inflammatory process of the lungs that develops primarily in response to pulmonary or systemic sepsis, resulting in a disproportionate death toll in intensive care units (ICUs). Given its role as a critical activator of the inflammatory and innate immune responses, previous studies have reported that an increase of circulating cell-free mitochondrial DNA (mtDNA) is a biomarker for fatal outcome in the ICU. Here we analyzed the association of whole-blood mtDNA (wb-mtDNA) copies with 28-day survival from sepsis and sepsis-associated ARDS. We analyzed mtDNA data from 687 peripheral whole-blood samples within 24 h of sepsis diagnosis from unrelated Spanish patients with sepsis (264 with ARDS) included in the GEN-SEP study. The wb-mtDNA copies were obtained from the array intensities of selected probes, with 100% identity with mtDNA and with the largest number of mismatches with the nuclear sequences, and normalized across the individual-probe intensities. We used Cox regression models for testing the association with 28-day survival. We observed that wb-mtDNA copies were significantly associated with 28-day survival in ARDS patients (hazard ratio = 3.65, 95% confidence interval = 1.39-9.59, p = 0.009) but not in non-ARDS patients. Our findings support that wb-mtDNA copies at sepsis diagnosis could be considered an early prognostic biomarker in sepsis-associated ARDS patients. Future studies will be needed to evaluate the mechanistic links of this observation with the pathogenesis of ARDS.

Trends in Hospitalization and Mortality Rates Due to Acute Cardiovascular Disease in Castile and León, 2001 to 2015.

INTRODUCTION AND OBJECTIVES: To analyze hospitalization and mortality rates due to acute cardiovascular disease (ACVD). METHODS: We conducted a cross-sectional study of the hospital discharge database of Castile and León from 2001 to 2015, selecting patients with a principal discharge diagnosis of acute myocardial infarction (AMI), unstable angina, heart failure, or acute ischemic stroke (AIS). Trends in the rates of hospitalization/100 000 inhabitants/y and hospital mortality/1000 hospitalizations/y, overall and by sex, were studied by joinpoint regression analysis. RESULTS: A total of 239 586 ACVD cases (AMI 55 004; unstable angina 15 406; heart failure 111 647; AIS 57 529) were studied. The following statistically significant trends were observed: hospitalization: ACVD, upward from 2001 to 2007 (5.14; 95%CI, 3.5-6.8; P < .005), downward from 2011 to 2015 (3.7; 95%CI, 1.0-6.4; P < .05); unstable angina, downward from 2001 to 2010 (-12.73; 95%CI, -14.8 to -10.6; P < .05); AMI, upward from 2001 to 2003 (15.6; 95%CI, 3.8-28.9; P < .05), downward from 2003 to 2015 (-1.20; 95%CI, -1.8 to -0.6; P < .05); heart failure, upward from 2001 to 2007 (10.70; 95%CI, 8.7-12.8; P < .05), upward from 2007 to 2015 (1.10; 95%CI, 0.1-2.1; P < .05); AIS, upward from 2001 to 2007 (4.44; 95%CI, 2.9-6.0; P < .05). Mortality rates: downward from 2001 to 2015 in ACVD (-1.16; 95%CI, -2.1 to -0.2; P < .05), AMI (-3.37, 95%CI, -4.4 to -2, 3, P < .05), heart failure (-1.25; 95%CI, -2.3 to -0.1; P < .05) and AIS (-1.78; 95%CI, -2.9 to -0.6; P < .05); unstable angina, upward from 2001 to 2007 (24.73; 95%CI, 14.2-36.2; P < .05). CONCLUSIONS: The ACVD analyzed showed a rising trend in hospitalization rates from 2001 to 2015, which was especially marked for heart failure, and a decreasing trend in hospital mortality rates, which were similar in men and women. These data point to a stabilization and a decline in hospital mortality, attributable to established prevention measures.