Epidemiology and Immune Pathogenesis of Viral Sepsis

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis can be caused by a broad range of pathogens; however, bacterial infections represent the majority of sepsis cases. Up to 42% of sepsis presentations are culture negative, suggesting a non-bacterial cause. Despite this, diagnosis of viral sepsis remains very rare. Almost any virus can cause sepsis in vulnerable patients (e.g., neonates, infants, and other immunosuppressed groups). The prevalence of viral sepsis is not known, nor is there enough information to make an accurate estimate. The initial standard of care for all cases of sepsis, even those that are subsequently proven to be culture negative, is the immediate use of broad-spectrum antibiotics. In the absence of definite diagnostic criteria for viral sepsis, or at least to exclude bacterial sepsis, this inevitably leads to unnecessary antimicrobial use, with associated consequences for antimicrobial resistance, effects on the host microbiome and excess healthcare costs. It is important to understand non-bacterial causes of sepsis so that inappropriate treatment can be minimised, and appropriate treatments can be developed to improve outcomes. In this review, we summarise what is known about viral sepsis, its most common causes, and how the immune responses to severe viral infections can contribute to sepsis. We also discuss strategies to improve our understanding of viral sepsis, and ways we can integrate this new information into effective treatment.

Keywords: dengue virus; epidemiology; herpes simplex virus; human enterovirus; human parechovirus; immune pathogenesis; influenza virus; viral sepsis.

Figure 1

Immune responses in viral sepsis. (A) Normal competent response to viral infection resulting in clearance of infection (1) When the immune system is exposed to a virus, the virus infects or is phagocytosed by macrophages, dendritic cells or other phagocytes. Phagocytes break down, process and present antigens from the virus and produce type 1 cytokines. (2) Type 1 cytokines cause T cells to differentiate into T_H1 cells and CD8 T cells. (3) T_H1 cells and CD8 T cells cause apoptosis of infected cells and activate processes such as the production of reactive oxygen species in phagocytes, which destroy the viruses. Antibody production is elevated, resulting in opsonisation, greater phagocytosis and destruction of viruses. (4) Virus is cleared and memory T cells are produced, which can rapidly respond to future infections. (B) Aberrant immune response resulting in viral sepsis and failure to clear virus. (1) When the immune system is exposed to a virus, the virus infects or is phagocytosed by macrophages, dendritic cells, or other phagocytes. Phagocytes break down, process and present antigens from the virus. Non-type 1 cytokines are produced. (2) Non-type 1 cytokines result in inappropriate type 2 or type 17 immune responses, which cause inflammation but cannot clear the virus. (3) T cells become exhausted and can no longer competently clear pathogens. (CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; PD-1, programmed death 1; TNF, tumour necrosis factor).