Herpes DNAemia and TTV Viraemia in Intensive Care Unit Critically Ill Patients: A Single-Centre Prospective Longitudinal Study.

François Mallet,Julien Textoris,Philippe Leissner,Thomas Rimmelé,Laurence Quemeneur,Virginie Moucadel,Magali Perret,Boris Meunier,Alexandre Pachot,Frédéric Reynier,Lionel K Tan,Léa Diouf,Andrew D Griffiths,Alain Lepape,Karen Brengel-Pesce,Fabienne Venet,Guillaume Monneret

doi:10.3389/fimmu.2021.698808

Abstract

IntroductionWe analysed blood DNAemia of TTV and four herpesviruses (CMV, EBV, HHV6, and HSV-1) in the REAnimation Low Immune Status Marker (REALISM) cohort of critically ill patients who had presented with either sepsis, burns, severe trauma, or major surgery. The aim was to identify common features related to virus and injury-associated pathologies and specific features linking one or several viruses to a particular pathological context.MethodsOverall and individual viral DNAemia were measured over a month using quantitative PCR assays from the 377 patients in the REALISM cohort. These patients were characterised by clinical outcomes [severity scores, mortality, Intensive Care Unit (ICU)-acquired infection (IAI)] and 48 parameters defining their host response after injury (cell populations, immune functional assays, and biomarkers). Association between viraemic event and clinical outcomes or immune markers was assessed using χ2-test or exact Fisher’s test for qualitative variables and Wilcoxon test for continuous variables.ResultsThe cumulative incidence of viral DNAemia increased from below 4% at ICU admission to 35% for each herpesvirus during the first month. EBV, HSV1, HHV6, and CMV were detected in 18%, 12%, 10%, and 9% of patients, respectively. The incidence of high TTV viraemia (>10,000 copies/ml) increased from 11% to 15% during the same period. Herpesvirus viraemia was associated with severity at admission; CMV and HHV6 viraemia correlated with mortality during the first week and over the month. The presence of individual herpesvirus during the first month was significantly associated (p < 0.001) with the occurrence of IAI, whilst herpesvirus DNAemia coupled with high TTV viraemia during the very first week was associated with IAI. Herpesvirus viraemia was associated with a lasting exacerbated host immune response, with concurrent profound immune suppression and hyper inflammation, and delayed return to immune homeostasis. The percentage of patients presenting with herpesvirus DNAemia was significantly higher in sepsis than in all other groups. Primary infection in the hospital and high IL10 levels might favour EBV and CMV reactivation.ConclusionIn this cohort of ICU patients, phenotypic differences were observed between TTV and herpesviruses DNAemia. The higher prevalence of herpesvirus DNAemia in sepsis hints at further studies that may enable a better in vivo understanding of host determinants of herpesvirus viral reactivation. Furthermore, our data suggest that EBV and TTV may be useful as additional markers to predict clinical deterioration in ICU patients.

Highlights

We analysed blood DNAemia of Torque teno virus (TTV) and four herpesviruses (CMV, Epstein–Barr virus (EBV), HHV6, and herpes simplex virus (HSV)-1) in the REAnimation Low Immune Status Marker (REALISM) cohort of critically ill patients who had presented with either sepsis, burns, severe trauma, or major surgery
At Intensive Care Unit (ICU) admission, serological testing (IgG) against CMV and HSV-1 antigens was used to determine whether viraemia was a primary viral infection or secondary to reactivation
APercentage of healthy volunteers and patients presenting single-or multiple-positive herpes and/or TTVh viral DNAemia during the first 7 days following admission in the ICU. bp-value obtained by comparing the number of patients with positive and negative DNAemia in sepsis group versus a group consisting of trauma, burns, and surgery patients; as sepsis group and other group are frequently unbalanced in term of numbers, we only considered p values significant (*) when

Summary

Introduction

We analysed blood DNAemia of TTV and four herpesviruses (CMV, EBV, HHV6, and HSV-1) in the REAnimation Low Immune Status Marker (REALISM) cohort of critically ill patients who had presented with either sepsis, burns, severe trauma, or major surgery. Herpesviruses (e.g., CMV, EBV, HHV6, HSV1) have been shown to be reactivated in adult [9, 10, 12, 13] and in paediatric patients with sepsis [11], and in ostensibly immunocompetent critically ill patients [14, 15]. Detection of EBV in patients with sepsis due to community-acquired pneumonia was associated with sepsis response signature (SRS) endotype, Abbreviations: CCTIRS, Comité Consultatif sur le Traitement de l’Information en matière de Recherche en Santé; CMV, cytomegalovirus; CNIL, Commission Nationale Informatique et Liberté ; CT, crossing threshold; DNA, desoxyribonucleic acid; EBV, Epstein–Barr virus; EFS, Etablissement Français du Sang; HAI, healthcare-associated infection; HHV, human herpesvirus; HSV, herpes simplex virus; IAI, ICU-acquired infection; IC, internal control; ICU, Intensive Care Unit; LOD, limit of detection; LOQ, limit of quantification; PCR, polymerase chain reaction; SOFA, Sequential Organ Failure Assessment score; TTV, Torque teno virus

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