Abstract
According to previous investigations, CD14 is suggested to play a pivotal role in initiating and perpetuating the pro-inflammatory response during sepsis. A functional polymorphism within the CD14 gene, rs2569190, has been shown to impact the pro-inflammatory response upon stimulation with lipopolysaccharide, a central mediator of inflammation in sepsis. In this study, we hypothesized that the strong pro-inflammatory response induced by the TT genotype of CD14 rs2569190 may have a beneficial effect on survival (30-day) in patients with sepsis. A total of 417 adult patients with sepsis (and of western European descent) were enrolled into this observational study. Blood samples were collected for rs2569190 genotyping. Patients were followed over the course of their stay in the ICU, and the 30-day mortality risk was recorded as the primary outcome parameter. Sepsis-related organ failure assessment (SOFA) scores were quantified at sepsis onset and throughout the observational period to monitor organ failure as a secondary variable. Moreover, organ support-free days were evaluated as a secondary outcome parameter. TT-homozygous patients were compared to C-allele carriers. Kaplan-Meier survival analysis revealed a higher 30-day mortality risk among C-allele carriers compared with T homozygotes (p = 0.0261). To exclude the effect of potential confounders (age, gender, BMI and type of infection) and covariates that varied at baseline with a p-value < 0.2 (e.g., comorbidities), we performed multivariate Cox regression analysis to examine the survival time. The CD14 rs2569190 C allele remained a significant covariate for the 30-day mortality risk in the multivariate analysis (hazard ratio, 2.11; 95% CI, 1.08-4.12; p = 0.0282). The 30-day mortality rate among C allele carriers was 23%, whereas the T homozygotes had a mortality rate of 13%. Additionally, an analysis of organ-specific SOFA scores revealed a significantly higher SOFA-Central nervous system score among patients carrying the C allele compared with T-homozygous patients (1.9±1.1 and 1.6±1.0, respectively; p = 0.0311). In conclusion, CD14 rs2569190 may act as a prognostic variable for the short-term outcome (30-day survival) in patients with sepsis.
Highlights
Worldwide, sepsis is one of the most frequent complications due to infection among critically ill patients and is increasing in prevalence [1,2,3]
This finding indicates that, despite baseline differences in certain variables and in other potential confounders, the CD14 rs2569190 C allele remained a prognostic variable with a significant effect on the short-term outcome (30-day survival) in our cohort of sepsis patients (Table 3)
To the best of our knowledge, these findings underscore for the first time the beneficial potential clinical impact of the CD14 rs2569190 TT genotype on 30-day survival in a cohort of septic patients of exclusively western European descent while remaining consistent with observations from Brazilian cohorts that revealed a beneficial effect of the TT genotype on the survival of critically ill patients
Summary
Sepsis is one of the most frequent complications due to infection among critically ill patients and is increasing in prevalence [1,2,3]. Lipopolysaccharide (LPS) or endotoxin, the major component of the outer membrane of gram-negative bacteria, plays a major role in initiating the pro-inflammatory response associated with sepsis [8]. CD14 was initially described as the essential co-receptor mediating the LPS activation of monocytes, subsequent investigations have shown that it participates in immune cell activation by gram-positive cell-wall components, such as peptidoglycan [14]. Findings of numerous investigations suggest a pivotal role for CD14 in initiating and perpetuating the pro-inflammatory response during the course of sepsis [14,15,16]. The proinflammatory response is essential to eradicate primary infections and prevent the acquisition of secondary infections in patients with sepsis [17]
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