#19 Viral DNAemia and Viral Seropositivity are Associated with Mortality in Pediatric Patients with Severe Sepsis

Abstract Background Sepsis remains the leading cause of pediatric mortality worldwide. While sepsis recognition campaigns have improved early mortality, current contributors to mortality are unclear. Little attention has been paid to the incidence of latent viral infection in septic pediatric patients, but resultant immune remodeling may affect future host response to acute illness. We report a large multi-center study of viral DNAemia and viral seropositivity in pediatric patients with severe sepsis. Method 401 patients from 9 Pediatric Intensive Care Units (PICUs) in the Eunice Kennedy Shriver National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network were enrolled. Enrollment criteria included severe sepsis, indwelling central venous or arterial catheter, and age between 44 weeks gestation and 18 years. Blood samples were collected twice per week up to 28 days of admission or until death or PICU discharge. Viral DNAemia was defined by qPCR detection of EBV, CMV, HSV, adenovirus, TTV, HHV6, and/or parvovirus B19. CMV, EBV, HSV and HHV6 serologies (IgG) were performed on one sample from each subject. Infection status was defined as uninfected (serologically negative without detectable DNAemia), acute infection (serologically negative with DNAemia), reactivated infection (serologically positive with DNAemia), or latent infection (serologically positive without DNAemia). Results Of 401 pediatric patients with severe sepsis, 55% were male, 39% previously healthy, and 27% immunocompromised. 44 subjects (11%) died in the PICU. 56% of subjects had documented infection(s) on enrollment (63% bacterial, 50% viral, and 2% fungal). Viral DNAemia, excluding TTV, was detected in 57% of immunocompromised patients and 44% of non-immunocompromised patients. Among patients with viral DNAemia, detection was due to reactivation in 91% of subjects with EBV DNAemia, 63% of those with CMV, and 100% of subjects with HSV and HHV-6. After adjusting for age, PRISM, previously healthy and immunosuppressed status, higher mortality was observed in patients with viral DNAemia due to CMV (OR 3.29 [1.46,7.21], p=0.005), adenovirus (3.55 [1.45,8.38] p=0.006), and HHV-6 (2.29 [1.11,4.63] p=0.025). DNAemia with multiple viruses, excluding TTV, during ICU admission was also independently associated with increased mortality in both immunocompromised (OR 5.51 [1.61,22.6] p=0.001) and non-immunocompromised subjects (OR 3.93 [1.36,11.5] p=0.015). Seropositivity was common (HSV 33%, CMV 42%, EBV 61%, HHV6 98%). Mortality was significantly higher in subjects who were seropositive for EBV (OR 11.5 [2.24, 211.2], p<0.001) and HSV (OR 2.65, [1.03, 7.21], p=0.004). Mortality was increased if more than one virus antibody was detected (OR 6.89 [1.98, 43.5], p<0.001) and highest when all four virus antibodies were detected. With HHV6, DNAemia increased mortality associated with seropositivity (18% vs. 7%, p=0.024). Conclusion In this study, viral DNAemia was common in pediatric patients with severe sepsis and was associated with mortality. Detection of multiple viruses during ICU admission increased risk of mortality, even in patients without preexisting immunosuppression. CMV and adenovirus reactivation were most strongly associated with mortality. Viral seropositivity was also strongly associated with ICU mortality independent of the presence of viral DNAemia. Future analyses will investigate mechanisms by which viral DNAemia and seropositivity contribute to pediatric sepsis mortality.