Epstein-Barr virus seropositivity was associated with higher mortality and immune dysregulation in pediatric patients with sepsis, according to a multicenter cohort study of 320 patients.
Among the total patients, 172 were Epstein-Barr virus (EBV) seropositive and 148 were EBV seronegative. Mortality occurred in 15% of patients who were seropositive compared with 3% of patients who were seronegative. In patients without prior transfusions, mortality was 8% in those who were seropositive vs 1% in those who were seronegative. Causal modeling showed that EBV seropositivity was directly associated with mortality and also acted through mediators such as hyperferritinemia and macrophage activation syndrome in 54% of patients.
Mediation analyses confirmed EBV seropositivity remained associated with death even when ferritin and macrophage activation syndrome were considered. Structural equation modeling validated these associations and showed additional links between EBV seropositivity, reduced tumor necrosis factor (TNF) response to endotoxin, and decreased ADAMTS13 activity. During the 28-day follow-up, patients who were EBV-seropositive had higher cumulative mortality and more organ failures than patients who were seronegative. “To our knowledge, this is the first report to provide a causal inference analysis of the association of EBV seropositivity with mortality in pediatric sepsis,” wrote lead study author Aditya Sriram, MS, of the Department of Human Genetics at the Graduate School of Public Health, University of Pittsburgh in Pennsylvania, and colleagues.
EBV seropositivity was also linked to markers of immune dysregulation. Specifically, these patients showed higher levels of C-reactive protein (CRP), ferritin, soluble CD163, interleukin (IL)-18 binding protein (BP), IL-6, IL-8, IL-10, and TNF, and lower levels of soluble FAS ligand and TNF-related apoptosis-inducing ligand. Patients who did not receive a transfusion and who were EBV-seropositive (44%) also showed increased CRP, ferritin, IL-18BP, and IL-8 levels with decreased TNF-related apoptosis-inducing ligand levels compared with patients who were EBV-seronegative.
The researchers analyzed pediatric patients who were enrolled in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Data were collected from 2015 to 2018 across nine pediatric intensive care units. Patients ranged in age from infancy to 18 years. Blood samples and clinical data were collected 24 to 48 hours following the onset of sepsis. Patients who had received intravenous immune globulin were excluded to avoid interference with EBV antibody testing. The researchers measured EBV viral capsid antigen immunoglobulin G to determine seropositivity and examined immune biomarkers, including CRP, ferritin, cytokines, ADAMTS13 activity, and ex vivo TNF response to endotoxin. Mortality and organ failure outcomes were followed for 28 days.
The study had limitations. Because EBV seropositivity was measured following the onset of sepsis, temporal ambiguity is possible. The study did not include a control group of critically ill patients without sepsis, "hence, it is difficult to disentangle whether the observed associations are specific to the pathobiology of sepsis or generalizable to mechanisms of immune dysregulation in critical illness," the authors wrote. Unmeasured confounding also could not be excluded.
The authors concluded, "Further study is warranted to address the possibility that latent EBV infection immune reprogramming poses an important public health problem that contributes to not only chronic disorders of immune dysregulation but also acute disorders of immune dysregulation, such as sepsis."
Full disclosures can be found in the study.
Source: JAMA Network Open
