The disease was first identified in China and has since established endemic foci in Japan and South Korea, but its geographic footprint is no longer confined to East Asia. Recent detections in Southeast Asia and Africa have broadened the known range of the virus, transforming what was once considered a regional public health problem into a genuine global concern. The virus is transmitted primarily through the bite of infected ticks, although person-to-person transmission through contact with blood and bodily fluids of infected patients has been documented, adding a nosocomial dimension to the outbreak risk. Clinically, SFTS begins with high fever, fatigue, nausea, and diarrhea, accompanied by the hallmark laboratory findings of thrombocytopenia and leukopenia, but in severe cases the infection rapidly evolves into a systemic illness in which hematological, hepatic, neurological, cardiac, pulmonary, and renal injuries converge, increasingly joined by pancreatic and male reproductive tract involvement.

Central to the new review is the argument that organ injury in SFTS arises from two intertwined processes: the direct cytopathic effects of the virus on infected cells and a profoundly dysregulated host immune response that turns the body’s own defenses against its tissues. The virus enters target cells through a set of identified receptors and co-receptors, including DC-SIGN, nonmuscle myosin heavy chain IIA, C-C motif chemokine receptor 2, and lipoprotein receptor-related protein 1, a receptor repertoire that helps explain the unusually broad tissue tropism of the pathogen. Once inside, the viral nonstructural protein NSs acts as a potent antagonist of innate immunity, suppressing the type I interferon response by interfering with signaling pathways downstream of pattern recognition receptors such as RIG-I and Toll-like receptors, thereby allowing unchecked viral replication in the critical early phase of infection.

The hematological system bears the most visible brunt of the disease. Thrombocytopenia, the defining laboratory feature, results from a combination of direct viral infection of platelet progenitors and megakaryocytes, immune-mediated destruction of platelets, and consumption through disseminated intravascular coagulation, a frequent and ominous complication. The review details how viral infection of hematopoietic stem and progenitor cells suppresses platelet production at its source, while activated macrophages engaged in hemophagocytosis, a feature reminiscent of hemophagocytic lymphohistiocytosis, clear platelets and blood cells from the circulation. Prolonged activated partial thromboplastin time and thrombin time, alongside falling fibrinogen, serve as clinical markers of the coagulopathy that often precedes fatal outcomes, and the authors emphasize that disentangling production failure from peripheral destruction remains an unresolved challenge in patient management.

Neurological injury represents one of the most feared manifestations of SFTS. SFTS-associated encephalopathy and encephalitis, recognized as a distinct severe phenotype, correlates strongly with mortality, and the review assembles the evidence on how the virus reaches the central nervous system, likely through infected monocytes breaching the blood-brain barrier and through direct infection of endothelial cells that compose it. Cerebrospinal fluid findings, electroencephalographic abnormalities, and neuroimaging changes provide the clinical correlates, but the underlying immunopathology, involving activated T cells, macrophages, and a storm of inflammatory cytokines, suggests that immune-mediated damage contributes substantially to the neurological deterioration even after viral loads begin to decline.

Cardiac and pulmonary involvement further complicate the clinical course. Elevated creatine kinase-MB, troponin-I, and B-type natriuretic peptide signal myocardial injury and dysfunction that can progress to cardiogenic shock, while chest imaging revealing ground-glass opacities marks the transition toward acute respiratory distress syndrome in the most severe patients. A particularly striking association highlighted in the review is with invasive pulmonary aspergillosis, a fungal superinfection that emerges when virus-induced immunosuppression, lymphocyte depletion, and corticosteroid use converge to open the door to opportunistic pathogens. This SFTS-associated pulmonary aspergillosis carries an especially poor prognosis and underscores how the immune paralysis induced by the virus extends well beyond the antiviral response itself.

Renal injury, manifesting as acute kidney injury detected through rising serum creatinine, blood urea nitrogen, cystatin C, and beta-2 microglobulin, completes the picture of systemic organ failure. The mechanisms here combine direct viral infection of renal tubular epithelial cells, cytokine-mediated inflammation, rhabdomyolysis, and hemodynamic collapse in shock states. The review also draws attention to less widely appreciated targets of the virus, including the pancreas, where elevated amylase and lipase indicate injury that may worsen systemic inflammation, and the male reproductive tract, where evidence of viral persistence raises questions about sexual transmission that remain to be definitively answered.

On the immunological front, the review synthesizes a detailed portrait of the dysregulated response that characterizes fatal cases. Early in infection, dendritic cells and monocytes are infected and functionally impaired, while granulocytic myeloid-derived suppressor cells expand and suppress T-cell activity. Neutrophils release extracellular traps that contribute to immunothrombosis, and the T-cell compartment shows expansion of aberrant double-negative and double-positive populations alongside exhaustion markers. Proinflammatory cytokines and chemokines, including interferon gamma-induced protein 10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1 alpha, reach concentrations that correlate with disease severity and mortality. Programmed cell death pathways, including apoptosis, pyroptosis driven by gasdermin D, and necroptosis, are activated in infected tissues, releasing damage-associated molecular patterns that further amplify the inflammatory cascade in a self-perpetuating loop.

A major contribution of the review is its focus on early predictive biomarkers for organ injury, a priority for clinicians facing patients who appear stable on admission but deteriorate precipitously within days. Viral load at presentation, degree of thrombocytopenia and leukopenia, elevated liver enzymes, lactate dehydrogenase, ferritin, cytokine levels, and markers of coagulation dysfunction all carry prognostic weight, and the authors argue that combining these parameters into risk stratification algorithms could identify high-risk patients early enough for intensive intervention. Single-cell RNA sequencing and other high-dimensional approaches are beginning to reveal the cellular landscape of severe disease at unprecedented resolution, offering hope that mechanistic signatures can be translated into actionable clinical tests.

Treatment, however, remains an area of unmet need. No licensed antiviral or vaccine exists, and management is largely supportive, with ribavirin showing disappointing efficacy in clinical trials, corticosteroids and intravenous immunoglobulin producing conflicting results, and plasma exchange, continuous renal replacement therapy, and even calcium channel blockers explored as organ-protective strategies based on mechanistic rationale. The review closes by identifying the critical knowledge gaps: the precise incidence and mortality risk of each individual organ injury, the relative contribution of direct viral cytopathy versus immune-mediated damage in each organ system, and the mechanisms underlying the newly recognized pancreatic and reproductive tract involvement. As the geographic range of Bandavirus dabieense continues to expand, the authors contend that a comprehensive mechanistic understanding of organ injury is not merely an academic exercise but the essential foundation for early risk stratification and the organ-protective therapies needed to bring down a mortality rate that has remained stubbornly high for nearly two decades.

Subject of Research: Pathogenic mechanisms and clinical features of organ injury in severe fever with thrombocytopenia syndrome

Article Title: Mechanisms and clinical characteristics of organ injury in severe fever with thrombocytopenia syndrome: a comprehensive review

Article References: Han, Z., Su, K., Jin, C., Song, H., Yin, C., Lum, F.-M., & Wu, W. (2026). Mechanisms and clinical characteristics of organ injury in severe fever with thrombocytopenia syndrome: a comprehensive review. Virology Journal. https://doi.org/10.1186/s12985-026-03320-0

Image Credits: AI Generated

DOI: 10.1186/s12985-026-03320-0

Keywords: SFTS, Bandavirus dabieense, tick-borne disease, organ injury, thrombocytopenia, cytokine storm, multi-organ failure, encephalitis, acute kidney injury, biomarkers, virology, emerging infectious disease