Viral sepsis: diagnosis, clinical features, pathogenesis, and clinical considerations

Abstract

Sepsis, characterized as life-threatening organ dysfunction resulting from dysregulated host responses to infection, remains a significant challenge in clinical practice. Despite advancements in understanding host-bacterial interactions, molecular responses, and therapeutic approaches, the mortality rate associated with sepsis has consistently ranged between 10 and 16%. This elevated mortality highlights critical gaps in our comprehension of sepsis etiology. Traditionally linked to bacterial and fungal pathogens, recent outbreaks of acute viral infections, including Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among other regional epidemics, have underscored the role of viral pathogenesis in sepsis, particularly when critically ill patients exhibit classic symptoms indicative of sepsis. However, many cases of viral-induced sepsis are frequently underdiagnosed because standard evaluations typically exclude viral panels. Moreover, these viruses not only activate conventional pattern recognition receptors (PRRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) but also initiate primary antiviral pathways such as cyclic guanosine monophosphate adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of interferon genes (STING) signaling and interferon response mechanisms. Such activations lead to cellular stress, metabolic disturbances, and extensive cell damage that exacerbate tissue injury while leading to a spectrum of clinical manifestations. This complexity poses substantial challenges for the clinical management of affected cases. In this review, we elucidate the definition and diagnosis criteria for viral sepsis while synthesizing current knowledge regarding its etiology, epidemiology, and pathophysiology, molecular mechanisms involved therein as well as their impact on immune-mediated organ damage. Additionally, we discuss clinical considerations related to both existing therapies and advanced treatment interventions, aiming to enhance the comprehensive understanding surrounding viral sepsis.

Keywords: Definition; Epidemiology; Immunopathology; Treatment strategies; Viral sepsis.

Fig. 1

Timeline of virus outbreak associated with organ dysfunction and the evolution of sepsis definition. Reports of illnesses clinically compatible with dengue fever can be traced back to a Chinese medical encyclopedia from 992 a.d. The first documented epidemic of dengue virus (DENV) occurred between 1953 and 1954, presenting clinical symptoms involving DHF, DSS, and AKI. RSV was first identified in infants in 1955, with critical cases progressing to ARDS. Hantavirus infection causing HFRS was first recorded in Russian clinical records as early as 1913, while HPS was identified for the first time in 1993. Lassa virus (LASV) was recognized as the causative agent of Lassa fever in 1969. In 2003, SARS-CoV triggered an epidemic outbreak that resulted in ARDS and myocarditis. Influenza viruses have caused several global outbreaks, including H1N1 pandemics in 1918, 1976, and 2009, along with H7N9 outbreaks in 2013. All of these strains can capable of inducing ARDS, myocarditis, AKI, and DIC. Dabie bandavirus was discovered for the first time in 2010 and is linked to SFTS and DIC. MERS-CoV, which can induce ARDS and myocarditis, emerged in 2012. Zika virus (ZIKV) has been associated with GBS since its identification in 2007 and meningitis during the period from 2015 to 2016. Between 2013 and 2016, Ebola virus (EBOV) led to a significant outbreak characterized by clinical manifestations including DIC, myocarditis, and acute hepatic failure. Most recently, SARS-CoV-2 has instigated a global pandemic since its emergence in 2019, leading to multiple organ dysfunctions such as ARDS, myocarditis, acute hepatic failure, AKI, and DIC. a.d. Anno Domini, DHF dengue hemorrhagic fever, DSS dengue shock syndrome, AKI acute kidney injury, RSV respiratory syncytial virus, HFRS haemorrhagic fever with renal syndrome, ARDS acute respiratory distress syndrome, DIC disseminated intravascular coagulation, MERS-CoV Middle East respiratory syndrome coronavirus, SFTS severe fever with thrombocytopenia syndrome, HPS hantavirus pulmonary syndrome, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, AHF acute heart failure

Fig. 2

Diagnostic framework for viral sepsis. In cases where a patient exhibits infection markers or there is suspicion of an infection, and concurrently has a SOFA score ≥ 2 compared to baseline, it is imperative to exclude bacterial, parasitic, and fungal sources. If viral antigen or nucleic acid assays yield positive results, especially when supported by relevant epidemiological findings, the clinical presentation suggests a diagnosis of viral sepsis. Molecular diagnostic testing methods include viral-specific PCR, high-throughput sequencing, nanopore sequencing, and CRISPR-based FIND-IT. FIND-IT Fast Integrated Nuclease Detection in Tandem, PCR polymerase chain reaction, CRISPR clustered regularly interspaced short palindromic repeats, SOFA Sequential Organ Failure Assessment, PaO₂/FiO₂ the ratio of arterial oxygen partial pressure to fractional inspired oxygen

Fig. 3

Viral sepsis pathogenesis and targeted organ vulnerability. The predominant etiological agents in viral sepsis are respiratory and vector-borne viruses. Respiratory viruses primarily transmit via the respiratory system, while vector-borne counterparts, such as tick-transmitted viruses, rely on insect vectors for transmission. Hantavirus and DBV spread through contact with rodents and exposure to their excreta. a Upon encountering these viruses, hosts often experience targeted cellular infections, and weaken the endothelial barrier in the vasculature. b Specifically, respiratory viruses penetrate alveolar epithelial cells or alveolar immune cells, multiplying within them. After inducing cellular damage, these pathogens migrate into the bloodstream, jeopardizing organs like such as liver, heart, kidneys, and intestines. c Conversely, arboviruses access the host circulatory system through skin contact or insect bites, and primarily target cells like platelets and fibrin meshwork. d The above mechanisms eventually induce coagulation disorders, manifesting symptoms reminiscent of hemorrhagic fever. Severe cases may result in extensive organ damage. Moreover, certain viruses, such as HSV, preferentially affect the nervous system, whereas others target the intestinal lining, including noroviruses and rotaviruses. The inherent cytotoxic effects of these viruses combined with host immune defenses heighten the potential for systemic organ damage that may culminate in multi-organ dysfunction. DBV Dabie bandavirus, HSV herpes simplex virus, ADEM acute disseminated encephalomyelitis, AKI acute kidney injury, CVB3 coxsackievirus B3, LASV Lassa virus, ARDS acute respiratory distress syndrome