Reactivation of Multiple Viruses in Patients with Sepsis

Abstract

A current controversy is whether patients with sepsis progress to an immunosuppressed state. We hypothesized that reactivation of latent viruses occurred with prolonged sepsis thereby providing evidence of clinically-relevant immunosuppression and potentially providing a means to serially-monitor patients' immune status. Secondly, if viral loads are markedly elevated, they may contribute to morbidity and mortality. This study determined if reactivation of herpesviruses, polyomaviruses, and the anellovirus TTV occurred in sepsis and correlated with severity. Serial whole blood and plasma samples from 560 critically-ill septic, 161 critically-ill non-septic, and 164 healthy age-matched patients were analyzed by quantitative-polymerase-chain-reaction for cytomegalovirus (CMV), Epstein-Barr (EBV), herpes-simplex (HSV), human herpes virus-6 (HHV-6), and TTV. Polyomaviruses BK and JC were quantitated in urine. Detectable virus was analyzed with respect to secondary fungal and opportunistic bacterial infections, ICU duration, severity of illness, and survival. Patients with protracted sepsis had markedly increased frequency of detectable virus. Cumulative viral DNA detection rates in blood were: CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. The 50% detection rate for herpesviruses was 5–8 days after sepsis onset. A small subgroup of septic patients had markedly elevated viral loads (>104–106 DNA copies/ml blood) for CMV, EBV, and HSV. Excluding TTV, DNAemia was uncommon in critically-ill non-septic patients and in age-matched healthy controls. Compared to septic patients without DNAemia, septic patients with viremia had increased fungal and opportunistic bacterial infections. Patients with detectable CMV in plasma had higher 90-day mortality compared to CMV-negative patients; p<0.05. Reactivation of latent viruses is common with prolonged sepsis, with frequencies similar to those occurring in transplant patients on immunosuppressive therapy and consistent with development of an immunosuppressive state. Whether reactivated latent viruses contribute to morbidity and mortality in sepsis remains unknown.

Is this critically ill patient immunocompromised?

“…Most importantly is a failure to clear the primary infection despite source control and adequate antibiotics as well as development of ICU-acquired infections with opportunistic pathogens such as Acinetobacter, Stenotrophomonas, Enterococci, or fungal organisms [1,2,8]. Illustratively, over 40 % of septic patients have evidence of reactivation of latent viruses, through detection of HSV in upper or lower respiratory tract with or without oropharyngeal herpetic lesions, or increased plasma HSV or cytomegalovirus DNAemia [9]. Though rarely responsible for specific organ failures, viral reactivation may add to the risk for further bacterial or fungal infections by subverting the functions of immune cells.…”

Post–Acute Care Use and Hospital Readmission after Sepsis

“…First, the evidence in support of sepsisinduced immunosuppression is growing (37), and readmissions after sepsis are frequently due to an infection (38,39). In a study of septic shock survivors that focused on the cause of readmission, Ortego and colleagues found that 46% of 30-day readmissions were infection-related, including new, unresolved, and recurrent infections (17).…”

The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases

“…In one study of plasma EBV DNA quantification among hospitalized patients and healthy controls, the frequency of EBV DNA detection corresponded to the severity of illness, where 32% of septic patients had EBV DNA detected in plasma, whereas only 5% of critically ill, nonseptic patients and 0.6% of healthy controls had EBV DNA detected in plasma. 25 In a retrospective study of 62 hospitalized, nontransplant patients with detectable EBV DNA in plasma, the majority had lymphoid malignancies and/or was receiving T-cell-depleting agents, although the study only included 8 patients with EBV 1 lymphoma and thus provided limited comparison of potential differences in copy number between those with and without EBV 1 diseases. 26 In HIV 1 patients, EBV DNA was detected in the plasma more frequently and at higher levels in those with EBV 1 lymphomas as compared with HIV 1 patients with EBV 2 lymphomas and HIV 1 patients without lymphoma but with opportunistic infections.…”