HV_13_127-138

Introduction

Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging tick-borne viral haemorrhagic fever first reported in China in 2009 and caused by the SFTS phlebovirus (SFTSV), a novel member of the Phenuiviridae family within the genus Bandavirus (Liu et al., 2014b; Lei, Liu and Yu, 2015). The disease was initially identified in rural areas of central and eastern China, particularly in Hubei, Henan, Shandong, Liaoning, and Jiangsu provinces (Zhan et al., 2017). Since that initial discovery, SFTS has been confirmed in South Korea, Japan, Vietnam, Thailand, and Taiwan, raising alarms about its potential for broader geographic spread (Kim et al., 2013; Kato et al., 2016; Tran et al., 2019; Rattanakomol et al., 2022; Lin et al., 2020).

The causative agent, SFTSV, is primarily transmitted through the bite of the Haemaphysalis longicornis tick, though person-to-person transmission via contact with infected blood or secretions has been documented in nosocomial and household settings (Liu et al., 2012; Tang et al., 2013; Gai et al., 2012a; Kim et al., 2015). The virus is classified as a trisegmented, negative-sense single-stranded RNA virus, and its emergence has been linked to ecological factors including deforestation, changing land use patterns, and expanding tick habitats (Lam et al., 2013; Casel, Park and Choi, 2021).

SFTS carries a substantial case fatality rate (CFR), ranging from approximately 6% to over 30% across different studies, making it one of the most lethal tick-borne diseases known (He et al., 2021; Gai et al., 2012b). The mortality risk is especially elevated in elderly patients, immunocompromised individuals, and those with delayed presentation (Ding et al., 2014; Shin et al., 2015). The disease course is characterised by progressive thrombocytopenia, leucopenia, elevated liver enzymes, and a hyperinflammatory state driven by dysregulated cytokine production (Sun et al., 2012; Liu et al., 2017).

Despite more than a decade of research, no specific antiviral therapy has received regulatory approval for SFTS, and management remains largely supportive. This review aims to provide a comprehensive, up-to-date synthesis of available evidence regarding the epidemiology, virology, clinical features, pathogenesis, risk factors, and treatment strategies of SFTS, to guide clinicians, public health practitioners, and researchers in their response to this continuing threat.

Virology and taxonomy

SFTSV is a negative-sense, single-stranded RNA virus with a trisegmented genome comprising large (L), medium (M), and small (S) segments. The L segment encodes the RNA-dependent RNA polymerase, the M segment encodes the surface glycoproteins (Gn and Gc) responsible for host cell attachment and entry, and the S segment encodes the nucleoprotein (NP) and a nonstructural protein (NSs) (Li et al., 2021; Lei, Liu and Yu, 2015). The NSs protein plays a significant role in viral immune evasion by antagonising the type I interferon response, thereby facilitating early viral replication and contributing to the immunopathology of disease (Jin et al., 2012) (Figure 1).

Phylogenetic analysis has identified multiple genotypic lineages of SFTSV across its geographic range, with distinct clades circulating in China, South

Korea, and Japan (Lam et al., 2013). These differences in viral genetics may partially account for observed variations in clinical severity and CFR across countries. The evolutionary analysis indicates that SFTSV likely emerged in China and subsequently spread across East Asia, facilitated by migratory birds and movement of tick-infested animals (Casel, Park and Choi, 2021; Silvas and Aguilar, 2017).

SFTSV has a broad host range among domestic and wild animals. Serological studies from China have detected SFTSV antibodies in cattle, sheep, dogs, and pigs, with high seroprevalence in areas where human cases cluster (Niu et al., 2013). These animals serve as amplifying hosts, increasing tick infection rates and, consequently, human exposure risk. Remarkably, direct cat-to-human transmission has also been reported, further expanding the recognised modes of zoonotic spillover (Kida et al., 2019).

Epidemiology

Global distribution and burden

Since the first confirmed human cases in China in 2009, SFTS has emerged as the dominant tick-borne viral disease in East Asia (Li et al., 2018). A comprehensive analysis of data from 2011 to 2018 identified over 60,000 reported cases in mainland China, predominantly concentrated in Henan, Shandong, Hubei, Anhui, Liaoning, and Zhejiang provinces (Miao et al., 2021). National surveillance data from China demonstrate a consistent seasonal pattern, with peak incidence between April and October, corresponding to the activity cycle of H. longicornis ticks (Sun et al., 2017; Huang et al., 2021).

South Korea identified its first cases in 2012 and has since reported a steadily increasing annual incidence (Kim et al., 2013; Choi et al., 2016). In Japan, SFTS was confirmed retrospectively with cases dating to 2005, and prospective surveillance from 2013 onwards has documented hundreds of confirmed cases with one of the highest CFRs globally (Takahashi et al., 2014; Kato et al., 2016; Kobayashi et al., 2020). Vietnam reported its first endemic cases in 2019, and Thailand documented confirmed infections between 2019 and 2020 (Tran et al., 2019; Rattanakomol et al., 2022). Taiwan recorded its first case in 2020 (Lin et al., 2020). A recent global systematic review and meta-analysis estimated that the pooled seroprevalence of SFTSV in humans ranges considerably across regions, with higher rates in endemic rural communities (Cui et al., 2024).

Transmission routes

The primary route of SFTSV transmission to humans is through the bite of infected H. longicornis ticks. Occupational and recreational exposure in tick-endemic rural and forested areas constitutes the main risk context, with farmers, foresters, and outdoor workers disproportionately affected (Liu et al., 2014a; Liu et al., 2015). However, the disease is not exclusively tick-borne; multiple documented clusters have confirmed human-to-human transmission.

Person-to-person transmission has been described through direct contact with the blood, secretions, or excreta of infected patients (Liu et al., 2012; Gai et al., 2012b; Tang et al., 2013). Nosocomial transmission has been documented in South Korea, where healthcare workers became infected after unprotected contact with acutely ill patients (Kim et al., 2015). Household transmission clusters have also been reported in China, including a well-characterised cluster involving blood exposure (Chen et al., 2013). These findings underscore the importance of rigorous infection control measures when managing confirmed or suspected SFTS cases.

Risk factors for infection

Epidemiological studies consistently identify residence in or frequent visits to rural or mountainous areas with tick activity as the predominant environmental risk factor for SFTS acquisition (Liu et al., 2014a; Ding et al., 2013). Agricultural activity, particularly during spring and summer months, significantly elevates exposure probability. Age is a notable demographic risk factor; most cases occur in adults over 50 years, and seroprevalence studies suggest that exposure and susceptibility both increase with age (Ding et al., 2014). Gender-specific differences in incidence have been reported, with some studies showing higher rates in men, though this likely reflects occupational exposure disparities (Guo et al., 2016).

Pathogenesis

Viral entry and early replication

Following tick inoculation, SFTSV enters cells via receptor-mediated endocytosis, with the glycoproteins Gn and Gc mediating attachment to host cell receptors (Li et al., 2021; Lei, Liu and Yu, 2015). The virus primarily targets monocytes and macrophages, dendritic cells, and endothelial cells. Early viral replication in these cell types is facilitated by the NSs protein’s capacity to suppress type I interferon production, allowing the virus to evade innate immune responses during the initial incubation period of five to fourteen days (Jin et al., 2012; Saijo, 2018).

Immune dysregulation and cytokine storm

The hallmark of SFTS pathogenesis is a profound dysregulation of the immune response, characterised by excessive cytokine and chemokine release. Studies have documented markedly elevated serum levels of interleukin (IL)-6, IL-10, interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), and multiple chemokines in SFTS patients, with levels correlating directly with disease severity (Sun et al., 2012; Deng et al., 2012; Liu et al., 2017). This cytokine storm, driven by hyperactivated monocytes and macrophages, leads to vascular leakage, organ dysfunction, and haematological abnormalities.

Thrombocytopenia, the defining laboratory feature of SFTS, arises from a combination of direct viral suppression of megakaryocyte function in bone marrow, peripheral platelet destruction by virus-infected macrophages, and consumption coagulopathy (Yang et al., 2022). Leucopenia, particularly lymphopenia, results from both direct viral cytopathic effects and activation-induced lymphocyte apoptosis. Impaired T-cell and natural killer (NK) cell function further compromises the adaptive immune response, allowing viral amplification (Sun et al., 2014).

Multi-organ involvement

The systemic inflammatory response in SFTS leads to widespread organ involvement. Hepatocellular damage is almost universally observed, manifesting as elevated transaminases and is associated with poorer outcomes (Zhang et al., 2024). Renal impairment and cardiac involvement are recognised in severe cases. Neurological complications, including encephalitis, have been reported, with evidence linking SFTSV directly to central nervous system pathology (Cui et al., 2015). The combination of coagulopathy, thrombocytopenia, and vascular inflammation may lead to haemorrhagic manifestations in critically ill patients (Seo et al., 2021).

Host signalling pathways targeted by sftsv for innate immune evasion

Beyond broadly suppressing type I interferon (IFN) induction, SFTSV interferes with several discrete steps of the host pattern-recognition and interferon-signalling cascade. Viral RNA is sensed by retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3), which normally signal through the mitochondrial antiviral-signalling protein (MAVS) and the TIR-domain-containing adaptor-inducing interferon-β (TRIF) to activate TANK-binding kinase 1 (TBK1) and inhibitor of κB kinase ε (IKKε), driving phosphorylation of interferon regulatory factor 3 (IRF3) and nuclear factor-κB (NF-κB) (Qu et al., 2012; Yang et al., 2022). The viral nonstructural protein (NSs) subverts this cascade at its earliest steps: NSs forms cytoplasmic inclusion bodies that physically sequester TBK1, IKKε, IRF3, RIG-I, and the E3 ubiquitin ligase TRIM25 away from the mitochondrial signalling platform, preventing IRF3 phosphorylation and nuclear translocation without requiring direct degradation of these factors (Wu et al., 2014; Ning et al., 2014). Downstream of IFN secretion, NSs additionally hijacks signal transducer and activator of transcription 1 and 2 (STAT1/STAT2) into the same inclusion bodies, blocking Janus kinase–STAT (JAK–STAT) signalling and abrogating interferon-stimulated gene expression; this effect is largely restricted to the human orthologue of STAT2 and may partly explain the limited pathogenicity of SFTSV in wild-type rodents (Ning et al., 2015). NSs further sequesters the tumour progression locus 2 (TPL2)/ABIN2/p105 signalling complex, biasing the inflammatory response towards interleukin-10 secretion and dampening antiviral defences while contributing to the dysregulated cytokine milieu described above (Kim et al., 2024). Collectively, these findings show that SFTSV evades innate immunity not through a single blockade but through coordinated, multi-tiered interference with RIG-I/TLR3–MAVS/TRIF–TBK1/IKKε–IRF3 signalling, JAK–STAT signalling, and NF-κB-dependent inflammatory pathways, several of which represent candidate targets for host-directed antiviral therapy.

Clinical features

Clinical presentation

SFTS typically presents with an acute febrile illness following an incubation period of five to fourteen days after tick exposure. The cardinal manifestations include high fever (often exceeding 38.5°C), thrombocytopenia, leucopenia, and gastrointestinal symptoms such as nausea, vomiting, and diarrhoea (Li et al., 2018; He et al., 2021; Li et al., 2022). Fatigue and myalgia are nearly universal, and lymphadenopathy has been reported in a significant proportion of patients.

The disease course can be divided into three phases: a febrile phase (days 1–7), a multi-organ dysfunction phase (days 7–14), and a convalescent phase. During the febrile phase, patients present with high fever, gastrointestinal symptoms, and progressive haematological abnormalities. In severe cases, the second phase is marked by haemorrhagic manifestations, neurological symptoms, respiratory failure, and circulatory collapse (Gai et al., 2012a; Wang et al., 2020). Patients who survive this phase generally recover over subsequent weeks, though fatigue may persist.

Laboratory findings

Laboratory investigations consistently reveal thrombocytopenia (platelet count <100 × 10⁹/L in most cases) and leucopenia. Elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) reflect hepatic involvement. Elevated creatine kinase (CK) indicates myositis. Proteinuria and elevated blood urea nitrogen may signal renal involvement (Xu et al., 2018; Wang et al., 2022). Coagulation abnormalities, including prolonged prothrombin time and elevated D-dimer, occur in severe cases. Viral load, measurable by RT-PCR, correlates with clinical severity and is a useful prognostic marker (He et al., 2021).

Neurological and other complications

Neurological complications including altered consciousness, convulsions, and encephalopathy occur in a subset of severe cases and are associated with high mortality (Cui et al., 2015). SFTSV has been directly detected in cerebrospinal fluid, confirming neuroinvasion. Yokomizo et al. (2022), in a systematic review of Japanese case reports, documented the diverse clinical presentations of SFTS in Japan, highlighting that neurological features disproportionately characterised fatal cases.

Risk factors for mortality

SFTS carries a significant case fatality rate, and identifying risk factors for severe outcome is of paramount clinical importance. Age is the most consistently reported predictor of mortality; patients aged over 60 years have substantially higher CFRs compared to younger individuals, likely reflecting senescence-associated immune dysfunction and greater comorbidity burden (Ding et al., 2014; Yu, 2018; Yang et al., 2023).

Laboratory parameters at admission are powerful prognostic markers. High viral load, markedly elevated AST and ALT, severe thrombocytopenia, elevated creatinine, and elevated CK have all been independently associated with fatal outcomes in multivariate analyses (Gai et al., 2012a; Xu et al., 2018; He et al., 2021; Wang et al., 2022). Neurological manifestations at presentation, including impaired consciousness, are strongly predictive of death (Deng et al., 2013; Shin et al., 2015). A meta-analysis by He et al. (2020) pooling data from multiple cohorts confirmed that older age, neurological involvement, elevated liver enzymes, and high viral load were the most robust independent predictors of fatal outcome.

Impaired immune function, including lymphocytopenia and low NK cell counts, has been associated with disease severity, consistent with the central role of innate and adaptive immunity in containing SFTSV replication (Sun et al., 2014; Dualis et al., 2021). Delayed diagnosis and presentation to healthcare facilities also worsen prognosis, reinforcing the need for clinical awareness in endemic areas.

Diagnosis

Definitive diagnosis of SFTS requires laboratory confirmation. Reverse transcription polymerase chain reaction (RT-PCR) targeting SFTSV genomic RNA in blood is the gold standard for early-phase diagnosis, with high sensitivity during the febrile phase when viraemia is greatest (Li et al., 2022). Enzyme-linked immunosorbent assay (ELISA) for SFTSV-specific IgM and IgG antibodies is useful for serological confirmation in the convalescent phase, though antibody responses may be delayed or absent in fatal cases due to severe immunosuppression (Seo et al., 2021).

Clinically, SFTS should be suspected in any febrile patient from an endemic area presenting with thrombocytopenia, leucopenia, and gastrointestinal symptoms, particularly during the spring-to-autumn tick season. The differential diagnosis includes other tick-borne illnesses (Anaplasma phagocytophilum, Ehrlichia species), viral haemorrhagic fevers, scrub typhus, and haematological disorders. The epidemiological history of tick exposure or contact with confirmed cases is critical to prompt diagnostic consideration (Li, 2015; Casel, Park and Choi, 2021).

Treatment and management

No specific antiviral therapy has been approved for SFTS, and management remains primarily supportive. Ribavirin, a broad-spectrum nucleoside analogue, has been evaluated in several clinical studies with inconsistent results; some retrospective analyses suggest potential benefit when initiated early, but robust randomised controlled trial evidence is lacking (Saijo, 2018; Li et al., 2022). Favipiravir, an RNA polymerase inhibitor, has shown in vitro activity against SFTSV and has been used clinically in Japan, where it is conditionally approved; preliminary data are encouraging, but definitive evidence from prospective trials is still awaited (Saijo, 2018).

Supportive care forms the cornerstone of SFTS management and includes platelet transfusions for haemorrhagically significant thrombocytopenia, red cell transfusions for anaemia, fluid resuscitation guided by haemodynamic parameters, and organ support including renal replacement therapy and ventilatory support for critically ill patients (Seo et al., 2021; He et al., 2020). The use of intravenous immunoglobulin and corticosteroids to attenuate the cytokine storm has been reported in case series, though evidence remains anecdotal. High-quality intensive care with vigilant monitoring of haematological and biochemical parameters is associated with improved survival (Wang et al., 2020).

Infection prevention and control is essential. Healthcare workers caring for SFTS patients should employ contact and droplet precautions, including gloves, gowns, and eye protection, given the documented risk of nosocomial transmission (Kim et al., 2015; Chen et al., 2013). In the community, personal protective measures against tick bites- including use of repellents, appropriate clothing, and prompt tick removal- remain the primary prevention strategy in the absence of a licensed vaccine (Casel, Park and Choi, 2021).

Public health implications

SFTS represents a significant and evolving public health challenge across East and Southeast Asia. The expanding geographic range of the disease, driven by tick habitat expansion associated with climate change and land use change, suggests that the burden of SFTS will continue to grow (Charoensakulchai et al., 2025; Silvas and Aguilar, 2017). The clustering of cases in elderly rural populations with limited access to specialist healthcare creates particular vulnerability.

Strengthening surveillance systems to capture both human cases and animal reservoirs is critical for early detection of outbreaks and monitoring trends in viral evolution (Liu et al., 2015; Miao et al., 2021). The development of a safe and effective SFTSV vaccine remains a priority research goal. Candidate vaccines targeting the glycoproteins Gn and Gc have shown promise in animal models, but none have yet reached clinical evaluation (Casel, et al., 2021). International collaboration in surveillance, research, and preparedness planning is essential given the potential for SFTS to emerge in new regions (Figure 2).

Progress in vaccine development and application prospects

No SFTSV vaccine has yet received regulatory approval, but preclinical development has accelerated markedly across several platforms. DNA vaccines encoding the glycoproteins Gn and Gc have induced robust humoral and cellular immunity in aged ferrets and conferred complete protection against lethal challenge, whereas constructs targeting the nucleoprotein, nonstructural protein, or RNA-dependent RNA polymerase alone have generally failed to protect, underscoring Gn/Gc as the principal protective antigen (Kim et al., 2024). Viral-vector platforms have shown similar promise: a recombinant vesicular stomatitis virus expressing SFTSV Gn/Gc protected interferon-α/β receptor-knockout mice from lethal infection and additionally conferred cross-protection against the related Heartland bandavirus (Hicks et al., 2024), while a recombinant adenovirus type 5 expressing Gn induced stronger protective immunity than an equivalent Gc-expressing construct (Qian et al., 2024). Whole inactivated-virus preparations adjuvanted with aluminium hydroxide have also demonstrated immunogenicity and accelerated viral clearance in mouse models, offering a comparatively simple manufacturing route (Li et al., 2022).

The most rapidly advancing platform is the messenger RNA (mRNA) vaccine, mirroring the success of mRNA technology against SARS-CoV-2. Lipid nanoparticle-encapsulated mRNA encoding the Gn head domain, alone or fused to a self-assembling ferritin nanoparticle scaffold, has elicited potent neutralising-antibody and T-cell responses and provided complete protection against lethal SFTSV challenge in wild-type and interferon-α/β receptor-knockout mouse models, with the ferritin-fused construct further shown to fully protect aged ferrets when delivered as a protein-subunit nanoparticle (Kim et al., 2023; Jeong et al., 2025). Because elderly patients bear the greatest burden of fatal SFTS, vaccine platforms that are both immunogenic and well tolerated in older or immunosenescent hosts, such as adjuvanted protein-subunit and mRNA formulations, are considered the most clinically translatable candidates. Nevertheless, no SFTSV vaccine candidate has yet entered human clinical trials, and important challenges remain, including the absence of an immunocompetent animal model that fully reproduces severe human disease, uncertainty over the durability of vaccine-induced protection, and the need to achieve broad cross-genotype protection given the marked genetic diversity of circulating SFTSV strains. Continued investment in comparative platform evaluation, standardised correlates of protection, and eventual first-in-human trials will be essential to translate these preclinical advances into a licensed vaccine (Kim et al., 2024).

Conclusions and Recommendations

Severe Fever with Thrombocytopenia Syndrome is an emerging tick-borne viral disease with significant morbidity and mortality across East and Southeast Asia. The disease is characterised by high fever, thrombocytopenia, leucopenia, and systemic inflammation driven by a dysregulated host cytokine response. Elderly patients and those with high viral loads or neurological involvement at presentation face the greatest mortality risk. The expanding geographic distribution of SFTS, combined with its capacity for human-to-human transmission, underscores the urgent need for heightened clinical awareness, robust surveillance, effective infection control, and continued investment in the development of targeted antiviral therapies and vaccines. Supportive care remains the mainstay of management, and early, intensive clinical monitoring is critical to improving outcomes. Future research should prioritise prospective trials of candidate therapeutics, vaccine development, and ecological studies to delineate the changing transmission landscape of this important emerging infection.

Acknowledgements

The author would like to express his sincere gratitude to the Bhuiyan Center for Interdisciplinary Research & Innovation (BCIRI) for its support and encouragement during the preparation of this manuscript.

Novelty Statement

This review integrates the latest evidence on the epidemiology, pathogenesis, diagnosis, treatment, immune evasion mechanisms, and vaccine development of SFTS, providing a comprehensive and up-to-date resource while highlighting key research gaps and future priorities.

Author Contributions

Md. Rimon Bhuiyan: Conceptualisation, literature search, writing- original draft, Data curation, writing- review and editing, Supervision, critical revision. The author approved the final manuscript.

Generative AI and AI-assisted technology statement

The author declares that no generative AI and AI assisted technology was used in the creation of this manuscript.

Conflict of interest

The author declares no conflicts of interest.

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