Viral DNAemia and DNA Virus Seropositivity and Mortality in Pediatric Sepsis

Abstract

Importance: Sepsis is a leading cause of pediatric mortality. Little attention has been paid to the association between viral DNA and mortality in children and adolescents with sepsis.

Objective: To assess the association of the presence of viral DNA with sepsis-related mortality in a large multicenter study.

Design, setting, and participants: This cohort study compares pediatric patients with and without plasma cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6), parvovirus B19 (B19V), BK polyomavirus (BKPyV), human adenovirus (HAdV), and torque teno virus (TTV) DNAemia detected by quantitative real-time polymerase chain reaction or plasma IgG antibodies to CMV, EBV, HSV-1, or HHV-6. A total of 401 patients younger than 18 years with severe sepsis were enrolled from 9 pediatric intensive care units (PICUs) 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. Samples were assayed from 2019 to 2022. Data were analyzed from 2022 to 2023.

Main outcomes and measures: Death while in the PICU.

Results: Among the 401 patients included in the analysis, the median age was 6 (IQR, 1-12) years, and 222 (55.4%) were male. One hundred fifty-four patients (38.4%) were previously healthy, 108 (26.9%) were immunocompromised, and 225 (56.1%) had documented infection(s) at enrollment. Forty-four patients (11.0%) died in the PICU. Viral DNAemia with at least 1 virus (excluding TTV) was detected in 191 patients (47.6%) overall, 63 of 108 patients (58.3%) who were immunocompromised, and 128 of 293 (43.7%) who were not immunocompromised at sepsis onset. After adjustment for age, Pediatric Risk of Mortality score, previously healthy status, and immunocompromised status at sepsis onset, CMV (adjusted odds ratio [AOR], 3.01 [95% CI, 1.36-6.45]; P = .007), HAdV (AOR, 3.50 [95% CI, 1.46-8.09]; P = .006), BKPyV (AOR. 3.02 [95% CI, 1.17-7.34]; P = .02), and HHV-6 (AOR, 2.62 [95% CI, 1.31-5.20]; P = .007) DNAemia were each associated with increased mortality. Two or more viruses were detected in 78 patients (19.5%), with mortality among 12 of 32 (37.5%) who were immunocompromised and 9 of 46 (19.6%) who were not immunocompromised at sepsis onset. Herpesvirus seropositivity was common (HSV-1, 82 of 246 [33.3%]; CMV, 107 of 254 [42.1%]; EBV, 152 of 251 [60.6%]; HHV-6, 253 if 257 [98.4%]). After additional adjustment for receipt of blood products in the PICU, EBV seropositivity was associated with increased mortality (AOR, 6.10 [95% CI, 1.00-118.61]; P = .049).

Conclusions and relevance: The findings of this cohort study suggest that DNAemia for CMV, HAdV, BKPyV, and HHV-6 and EBV seropositivity were independently associated with increased sepsis mortality. Further investigation of the underlying biology of these viral DNA infections in children with sepsis is warranted to determine whether they only reflect mortality risk or contribute to mortality.

Figure 1.. Viral DNAemia and Seropositivity by Immunocompromised Status

A detailed breakdown of patient characteristics and all statistical comparisons can be found in eTable 1 in Supplement 1. The analysis of the number of viruses detected via polymerase chain reaction analysis excludes torque teno virus (TTV). Patients younger than 18 months or those who had intravenous immunoglobulin administration on the same day or before serology sample collection are excluded from serology analyses, leaving a sample size of 264. BkPyV indicates BK polyomavirus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; and HSV-1, herpes simplex virus 1. ^aP ≤ .01.

Figure 2.. Forest Plot Showing Adjusted Odds Ratios (AORs) for Mortality Associations With Viral DNAemia and Seropositivity

Odds ratios were adjusted for age, Pediatric Risk of Mortality (PRISM) score, previously healthy status, and immunocompromised status. Forest plots are presented on log scale due to large confidence intervals for some estimates. BkPyV indicates BK polyomavirus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; HSV-1, herpes simplex virus 1; NA, not applicable; and TTV, torque teno virus. ^aMissing AORs indicate that an insufficient number of patients were available to support the logistic regression model. ^bExcludes patients younger than 18 months and/or those who received intravenous immunoglobulin prior to sample collection. In addition to age, PRISM score, having been previously healthy, and immunocompromised status, receipt of blood products prior to serology sample collection is also included as a covariate.

Figure 3.. Pediatric Intensive Care Unit (PICU) Mortality by Number of Viruses Detected by Plasma Quantitative Real-Time Polymerase Chain Reaction (qPCR) Analysis and Herpesvirus Serology

TTV indicates torque teno virus.

Figure 4.. Association Among Plasma Quantitative Real-Time Polymerase Chain Reaction Analysis, Viral Seropositivity, and Mortality

All pairwise comparisons were performed and can be found in eTable 5 in Supplement 1. P values were not adjusted for multiple comparisons. CMV indicates cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; and HSV-1, herpes simplex virus 1. No infection indicates IgG negative and DNAemia negative; acute infection, IgG negative and DNAemia positive; reactivated infection, IgG positive and DNAemia positive; and latent infection, IgG positive and DNAemia negative. ^aP = .04, no infection vs latent infection. ^bP < .001, no infection vs reactivated infection. ^cP = .008, no infection vs reactivated infection. ^dP = .001, no infection vs latent infection. ^eP = .02, latent infection vs reactivated infection.