Unraveling the complexities: A comprehensive review of severe fever with thrombocytopenia syndrome and its associated complications

Summary

Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus (DBV), is an emerging vector-borne infection with significant global health implications, particularly in East Asia. In recent years, its geographic footprint has expanded beyond traditional endemic regions, raising global concern due to high morbidity and variable case-fatality rates of up to 30%. Clinically, SFTS presents with an acute onset of high fever, thrombocytopenia, leukocytopenia, headache, and gastrointestinal disturbances. In severe cases, rapid progression may lead to life-threatening complications, including myocarditis, neurological disorders, invasive pulmonary aspergillosis (IPA), secondary infections, systemic inflammatory response syndrome (SIRS), hemophagocytic lymphohistiocytosis (HLH), and ultimately multi-organ failure (MOF). This review synthesizes recent advances in virology, pathophysiological mechanisms, diagnostic strategies, and therapeutic interventions for DBV infections. Special attention is given to the complications most commonly associated with poor prognoses and fatal outcomes in patients with SFTS, alongside future outlooks for research and public health preparedness to mitigate the growing global burden of this high-priority tick-borne disease.

Health sciences

Introduction

In 2009, a novel phlebovirus was isolated from patients in Central China presenting with fever, thrombocytopenia, and gastrointestinal symptoms.¹ This novel virus was initially referred to as severe fever with thrombocytopenia syndrome (SFTS) bunyavirus, and later renamed severe fever with thrombocytopenia syndrome virus (SFTSV) in 2014. In 2019, the International Committee on Taxonomy of Viruses (ICTV) officially classified it as Dabie bandavirus (DBV).

Since its discovery, sporadic cases of SFTS have been reported across East Asia, leading to the identification of DBV infections in South Korea in 2010,² Japan in 2013,³ and Vietnam in 2017.⁴ DBV is widely distributed across Asia, with China bearing the highest case burden. Its expanding range correlates with significant genetic diversity, potentially explaining regional differences in disease severity. Distinct genotypes predominate regionally: genotypes A, D, E, F, and G (including the China-exclusive E) circulate in China,⁵ whereas genotype B (B1-B4) predominates in Korea and Japan. These genotypes exhibit distinct case fatality rates—ranging from 17.3% to 22.7% for genotypes D and F in China, to 47.9% for genotype B2 in Korea, with genotype E showing a lower rate of approximately 12.5%.⁶ Such disparities may reflect variations in viral virulence, host responses, and medical practices. Furthermore, specific mutations (e.g., in the glycoprotein precursor) may influence viral adaptability, cell tropism, and immune evasion.

Several genetically related viruses have been implicated in SFTS-like illnesses worldwide. The Heartland virus, a bandavirus first detected in the United States in 2009 and formally reported in 2012,⁷ has since been linked to over 35 cases across the Midwest and Southern United States within six years. Clinically, Heartland virus infection presents with symptoms similar to SFTS, and sequence analysis has shown that there is only a exist 27% and 38% divergence in the viral RNA polymerase and N protein, respectively, compared to DBV.⁸ Another related virus, Bhanja bandavirus, belonging to the Phlebovirus genus within the Bunyavirales order, has been identified in regions of Africa and central Europe.⁹ Given the rising incidence and severity of DBV infections and the emergence of related pathogens, WHO has designated SFTS a high-priority disease for research and public health preparedness.

Ticks are the primary vectors responsible for the transmission of SFTS, resulting in a higher incidence of outbreaks in regions characterized by mountainous, hilly, and forested landscapes. Populations at risk include residents, workers, and tourists who live in or frequently visit these areas, spanning a broad range of age groups. While all age groups are at risk, individuals >50 years often experience severe disease due to age-related immune decline and comorbidities.^10,11 Common symptoms include fever, myalgia, neurological signs (e.g., altered mental status), gastrointestinal disorders, and hematological abnormalities such as thrombocytopenia and leukopenia.^12,13 In the early stages of infection, the virus infects a range of host cells, with macrophages facilitating viral dissemination into the bloodstream via the lymphatic system, leading to viremia. This viremia induces a systemic inflammatory response, which, when it affects multiple organ systems such as the central nervous system, gastrointestinal tract, and cardiovascular system, leads to the development of organ-specific clinical manifestations. Additionally, macrophage-mediated phagocytosis of platelets containing the virus contributes to thrombocytopenia.¹⁴ While mild cases of SFTS often resolve without intervention, severe cases—comprising approximately 97.5% of hospitalized patients—can rapidly develop serious complications.^15,16 Ultimately, the most severely affected patients may experience rapid clinical deterioration leading to multi-organ failure (MOF), with fatal outcomes occurring within two weeks in many cases.¹³ This review summarizes current knowledge on the complications of severe SFTS, focusing on the complex virus-host interactions that drive disease progression.

Virus biology and replication

DBV is an enveloped, segmented, negative-stranded RNA virus belonging to the family Phenuiviridae and the genus Bandavirus. The virus typically presents as spherical or nearly spherical in shape, with a diameter ranging from 80 to 100 nm. Like other phleboviruses, the DBV genome consists of three negative-strand RNA segments that encode four structural proteins, along with additional smaller RNA segments producing a non-structural protein (NSs). The L segment encodes the RNA-dependent RNA polymerase (RdRp), essential for viral replication and transcription (Figure 1A). The M segment encodes the glycoproteins (GPs), which are subsequently processed into two subunits, Gn and Gc, both of which are critical for virus-receptor binding and cellular entry.¹⁷ The S segment encodes the nucleocapsid protein (NP) and NSs. Notably, NSs participates in the activation of inflammatory vesicles, immune evasion, and the regulation of critical factors involved in multiple immune pathways, contributing significantly to the viral pathogenesis.

Figure 1.

Life cycle and immune evasion mechanisms of DBV

(A) DBV possesses a tri-segmented genome (L, M, and S), encoding the RdRp, Gn/Gc, NP, and NSs, respectively. Viral entry is mediated by Gn/Gc binding to host receptors (e.g., DC-SIGN and CCR2) and lipid-dependent conformational changes (e.g., GlcCer) that enable clathrin-mediated endocytosis. After endosomal trafficking, viral RNPs are released into the cytoplasm and undergo replication and assembly in the Golgi body. Subsequently, the virus particles are transported and released through vesicle transport. During this process, NP and NSs are expressed after the release and translation of the viral genome. The NP-mediated Beclin-1 release and NSs-induced vimentin degradation disrupt host autophagy, which is part of the immune evasion.

(B) DBV employs multiple immune evasion mechanisms: NSs employs distinct strategies to antagonize the host immune response: (i) Sequestration: NSs forms inclusion bodies that sequester STAT1/STAT2, blocking their phosphorylation and nuclear translocation to inhibit type I/III IFN signaling. (ii) Capture: NSs captures RIG-I pathway signaling molecules (including TBK1), preventing the activation of downstream antiviral responses. (iii) Direct Interaction: NSs binds directly to LSM14A to suppress IFN-β production. Furthermore, the NP protein binds mitochondrial TUFM to induce LC3-dependent mitophagy, leading to the degradation of MAVS. Additionally, DBV suppresses mDC differentiation and CD86 expression, resulting in impaired antigen presentation and T cell activation.

During the attachment and entry, the Gn-Gc heterodimer undergoes a series of conformational changes to expose the Gc fusion loop, allowing insertion into the host cell membrane to complete fusion.¹⁸ This process is critically regulated by host lipid components, particularly glucosylceramide (GlcCer) and its biosynthetic enzyme, UDP-glucose ceramide glucosyltransferase (UGCG).^19,20 GlcCer forms a stable protein-lipid complex with Gc, promoting Gc’s conformational rearrangement. Since GlcCer synthesis is directly regulated by the activity and expression of UGCG, inhibition of UGCG impairs GlcCer production, thereby disrupting Gc-mediated membrane fusion.

DBV may utilize distinct host receptors depending on the cell type. The Gn/Gc glycoproteins have been shown to interact with multiple C-type lectin receptors (CLRs)—including dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), DC-SIGN-related protein (DC-SIGNR), and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin)—to facilitate viral entry into diverse human and animal cell lines.²¹ Among these, DC-SIGN, which is highly expressed on dendritic cells and macrophages, binds to Gn/Gc in a glycosylation-dependent manner and enhances viral entry.²² Another critical receptor is C-C motif chemokine receptor 2 (CCR2), which is expressed on peripheral blood mononuclear cells (PBMCs), monocytes, and endothelial cells.²³ CCR2 binds directly to the Gn glycoprotein through its N-terminal extracellular domain, mediating viral entry into these cells. Meanwhile, non-muscle myosin heavy chain IIA (NMMHC IIA) promotes DBV uptake through endocytic and phagocytic pathways. Importantly, DBV infection utilizes multiple host receptors to achieve extensive histotropism, causing pathological damage across various tissues and organs. The expression and function of these receptors vary by cell types, and DBV entry may be governed by a combination of receptors or co-receptors, resulting in a single receptor that cannot explain all the mechanisms of infections. Thus, delineating receptor usage that mediates DBV infection with key target cell types requires further investigation.

Upon receptor binding, virions are internalized via clathrin-mediated endocytosis and enclosed within clathrin-coated vesicles. Following uncoating, viral particles are sorted into early endosomes, then trafficked sequentially to late endosomes and lysosomes.²⁴ In these organelles, Gc exposes fusion loops, promotes the fusion of the viral envelope with the endosomal membrane, and finally releases viral ribonucleoprotein complexes (RNPs) into the cytoplasm to complete the invasion process.

After invasion, DBV initiates a replication program in the cytoplasm. To create a permissive environment for replication, DBV actively interplays with the cellular autophagy machinery.²⁵ This process involves two different mechanisms of autophagy. First, NP directly disrupts the inhibitory Beclin1-BCL2 complex to activate autophagosome nucleation. Second, NSs competitively blocks the formation of the Beclin-1-vimentin-14-3-3 tripartite complex to liberate Beclin-1, while simultaneously promoting K48-linked polyubiquitination of vimentin to trigger proteasomal degradation, thereby abolishing its suppression of autophagic flux.²⁶ Within this manipulated autophagic milieu, the L-segment-encoded RdRp drives DBV genome replication and messenger RNA (mRNA) synthesis in the cytoplasm.²⁷ Progeny viruses assemble at Golgi membranes, where newly synthesized RNPs coalesce with structural glycoproteins. The mature virions are transported to the cell membrane through the host secretory pathway, such as vesicle trafficking, and are ultimately released at the plasma membrane through budding, thereby completing the viral life cycle.²⁵

Common complications caused by DBV

SFTS leads to life-threatening complications and high mortality. These include myocarditis, encephalitis, invasive pulmonary aspergillosis (IPA), systemic inflammatory response syndrome (SIRS), and hemophagocytic lymphohistiocytosis (HLH), often progressing to multi-organ failure (MOF). The clinical manifestations of SFTS are not isolated events but represent distinct pathogenic trajectories. This section synthesizes the diverse complications into three interconnected themes: direct viral cytopathy, opportunistic infections stemming from immunosuppression, and systemic immunopathology. Early risk factor recognition is critical for improving outcomes (Figure 2).

Figure 2.

Common complications and multi-organ damage in severe SFTS

(A) Certain DBV genotypes can cross the BBB by infecting cerebral microvascular endothelial cells, allowing viral and cytokine entry into the CNS. This leads to perivascular inflammatory infiltration, fibrin deposition, neuronal degeneration, and necrosis, manifesting as neurological symptoms.

(B) Sustained thrombocytopenia promotes coagulopathy and microthrombus formation, impairing myocardial microcirculation and driving a thrombo-inflammatory loop. DBV-induced fever increases ROS production, exacerbating oxidative stress and myocardial hypoxia. Renal dysfunction further increases cardiac workload, potentially leading to cardiorenal syndrome.

(C) Immune dysregulation, characterized by reduced neutrophil and platelet counts, IgG deficiency, and hyperactivated NK cell responses (cytotoxicity and IFN-γ-mediated apoptosis)- compromises antifungal defenses and increases susceptibility to IPA.

(D) Besides increased susceptibility to Aspergillus, patients with SFTS are also prone to co-infections with other fungi, bacteria, and viruses. Hospital-acquired bacterial infections, particularly bacterial pneumonia and bloodstream infections, can progress to sepsis and septic shock, which are life-threatening.

SFTS-associated myocarditis

A subset of patients with SFTS (79/106, 74.5%) develop cardiovascular symptoms during the later stages of infection,¹⁵ including chest pain, palpitations, arrhythmias, and, in some cases, acute heart failure. These manifestations are increasingly recognized as viral myocarditis, an inflammatory condition of cardiomyocytes triggered by viral infections. Viral myocarditis can be caused by a wide range of pathogens, including enteroviruses, influenza viruses, and, more recently, coronaviruses such as SARS-CoV-2. While these viruses share the capacity to trigger myocardial inflammation and injury, their underlying pathogenic mechanisms vary substantially. Enteroviruses, such as coxsackievirus, directly infect and replicate within cardiomyocytes, whereas coronaviruses and influenza viruses tend to cause indirect myocardial injury through hyperinflammatory states (e.g., cytokine storms) or autoimmune responses.

SFTS-related myocarditis exhibits a uniquely severe clinical phenotype, characterized by a combination of direct viral invasion of cardiac tissue, systemic hyperinflammation, and hematological dysfunction. In the early phase of infection, marked thrombocytopenia promotes coagulopathy and microthrombus formation, impairing myocardial microcirculation and predisposing to ischemia and hypoxia. Thrombus-derived procoagulants, such as tissue factors, can further intensify inflammation, creating a self-sustaining “thrombo-inflammatory” loop that worsens myocardial ischemia and apoptosis.²⁸ Additionally, SFTS-induced fever and systemic infection disrupt metabolic homeostasis, increasing the generation of ROS and promoting oxidative stress in cardiomyocytes. Compensatory tachycardia further elevates myocardial oxygen demand, accelerating energy metabolism imbalance.²⁹

In later stages, sustained viral replication and inflammation often extend to other vital organs. Renal dysfunction, fluid overload, and electrolyte disturbances increase cardiac workload, while acid-base imbalances undermine myocardial electrophysiological stability—together contributing to a pathological “cardiorenal syndrome” that hastens clinical deterioration.^30,31 This complex interplay results in rapid cardiac decompensation, frequently culminating in acute heart failure. Clinical data indicate patients with SFTS-associated cardiac involvement experience an in-hospital mortality rate of 33.8%, significantly exceeding the approximate 19.2% mortality rate observed in myocarditis from other viral etiologies.³² The excess mortality is likely driven by the simultaneous occurrence of multi-organ dysfunction (MOD),¹⁵ including coagulopathy, hepatic abnormalities, and renal failure.

Although the molecular pathways involved in SFTS-associated myocarditis remain incompletely understood, several hypotheses have emerged. DBV may directly invade cardiomyocytes via NP interaction with host receptors such as DC-SIGN and CCR2 receptors (details in Section pathogenesis). Downregulation of these receptors may contribute to myocardial injury; however, further validations are required to confirm their expression in cardiac cells. If confirmed, these mechanisms could help elucidate the direct cytopathic effects of DBV on cardiac tissues, such as cardiomyocyte necrosis and mitophagy. Nonetheless, the dominant mechanism of myocardial injury in SFTS is thought to be cytokine-mediated.^33,34 After DBV infection, innate immune cells—particularly monocytes and macrophages-release high levels of inflammatory cytokines such as interleukin (IL)-6, IL-2, IL-7, tumor necrosis factor (TNF)-α,^35,36 interferon-γ-inducible protein 10 (IP-10), and monocyte chemoattractant protein (MCP)-1. These cytokines propagate leukocyte recruitment, amplify the inflammatory cascade through further cytokine release, and damage the myocardium. Among them, IL-6 and IL-10 levels are particularly elevated in fatal SFTS cases,³⁷ suggesting their potential as prognostic biomarkers (details in Section cytokine storm and systemic inflammatory response syndrome).

Diagnosing SFTS-related myocarditis poses clinical challenges, as systemic symptoms-fever, hemorrhage, and shock-often overshadow cardiac involvement. Endomyocardial biopsy (EMB) remains the gold standard for definitive diagnosis, but its invasiveness limits routine use.³⁸ Instead, diagnosis often relies on clinical suspicion supported by elevated cardiac biomarkers (e.g., cardiac troponin I, n-terminal pro-B-type natriuretic peptide (NT-proBNP), and creatine kinase-MB) and echocardiographic evidence of left ventricular dysfunction. Elevated lactate dehydrogenase and NT-proBNP, as well as impaired consciousness, are independently associated with critical SFTS complicated by myocarditis, and may assist in early risk stratification.^39,40 Additionally, noninvasive imaging modalities can also aid diagnosis. Cardiac magnetic resonance imaging provides sensitive detection of myocardial inflammation, edema, and fibrosis, while electrocardiographic abnormalities (e.g., ST-T changes) may enhance diagnostic accuracy when interpreted in conjunction with clinical and laboratory findings. Management of SFTS-associated myocarditis remains largely supportive, incorporating volume control with diuretics (e.g., furosemide), afterload reduction using vasodilators (e.g., nitroglycerin), and correction of electrolyte or acid—base imbalances. Immunomodulatory therapies—such as corticosteroids, intravenous immunoglobulin, and therapeutic plasma exchange—have shown promise in mitigating cytokine-driven myocardial damage,⁴¹ but robust clinical evidence remains limited.

Neurological complications

Neurological manifestations are recognized as a severe and potentially life-threatening complication of SFTS. Direct evidence of CNS invasion by DBV has been demonstrated in multiple clinical studies through the detection of viral RNA and, in some instances, infectious virus from cerebrospinal fluid (CSF) has been successfully isolated.⁴² Epidemiological data have demonstrated that neurological complications exhibit distinct geographic distribution patterns and population-specific risk factors. Neurological manifestations—such as impaired consciousness and seizures—are more frequently observed in DBV-endemic regions of China (e.g., Shandong and Henan provinces),⁴³ a clinical study found that approximately 27.5% of hospitalized patients with SFTS developed encephalitis/encephalopathy, which was associated with high mortality.⁴⁴ While SFTS cases with neurological involvement have also been documented in Japan, direct comparative analyses of neurotropism or encephalitis incidence between Chinese and Japanese viral lineages are currently lacking.

Advanced age (>60 years) and comorbid conditions (e.g., diabetes mellitus and chronic kidney disease) are significant risk factors for encephalitis progression, correlating with markedly elevated mortality. Moreover, immunocompromised patients, such as those undergoing chemotherapy, tend to exhibit earlier onset and more severe neurological symptoms.⁴⁵ Notably, while most CNS complications have been observed in adults, pediatric cases of DBV-associated brain injury are increasingly reported.¹⁹ Encephalopathy typically emerges in the critical phase of illness and often heralds progression to adverse outcomes. In a retrospective cohort of 109 patients with SFTS, 27.5% (n = 30) developed encephalopathy,⁴⁴ with an in-hospital mortality rate of 43.3% in the encephalopathy group—significantly higher than the 12.7% mortality observed in non-encephalopathy cases. The encephalopathic symptoms follow a phase-dependent pattern over the course of the disease. During the febrile phase (days 1–5), overt CNS signs are typically absent, though mild headache or confusion may occur toward the end of this phase. In the critical phase (days 6–14), encephalopathic manifestations peak, including seizures, limb tremors, impaired consciousness, speech disturbances, autonomic instability, and, in severe cases, mucosal hemorrhage or disseminated intravascular coagulation (DIC). By the recovery phase (day 15 onward), most patients experience the resolution of CNS symptoms, though some may retain cognitive deficits or neurological sequelae.

Mechanistically, DBV is capable of rapid CNS infiltration, as demonstrated in a neonatal C57BL/6 mouse model where viral particles were detected in neural tissue as early as 3 h post-infection.⁴² The virus targets both macrophages and neurons, particularly in the cerebellum and midbrain. Autopsy examination of brain tissue reveals hallmark features of viral encephalitis, including perivascular infiltration,⁴⁶ fibrin deposition, and neuronal degeneration/necrosis. DBV infection of microvascular endothelial cells upregulates IL-6 and MCP-1 expression, increasing blood-brain barrier permeability.⁴⁷ These infected cells act as “Trojan horses,”⁴⁸ enabling the transendothelial migration of virus and immune effectors into the parenchyma. In vitro models using human umbilical vein endothelial cells (HUVECs) have further demonstrated that DBV infection disrupts intercellular junctions,⁴⁹ leading to widened paracellular gaps and impaired barrier integrity. To be noted, DBV infection also induces significant neuronal injury indirectly through the triggering of cytokine storms and systemic inflammatory responses.⁵⁰ Within the CNS, this inflammatory cascade is primarily mediated by innate immune cells such as microglia and astrocytes, as demonstrated in animal models.⁵¹ In human cases of SFTS with neurological involvement, elevated levels of cytokines (e.g., IL-6, IL-8, IL-10, IFN-α, and IFN-γ), chemokines, and ROS have been observed in the central nervous system.^52,53 This excessive immune response leads to neuronal dysfunction, vascular damage, and cerebral edema.

Beyond endothelial injury, glial cell dysfunction amplifies CNS damage. In human microglial cells, NSs activates the NACHT, LRR, and PYD domains-containing NLRP3 inflammasome,⁵⁰ inducing IL-1β maturation and pyroptosis, which may represent one of the most important mechanisms causing cellular damage in the CNS. In IFNAR1^−/− mice, DBV also targets brainstem, spinal cord and motor neurons, where it activates neurotoxic A1-type astrocytes that accelerate widespread neuronal death.⁵¹ These experimental findings are mirrored in human neuropathology, with affected patients revealing pontine neuronal degeneration, hemosiderin-laden macrophages, and perivascular inflammatory cell infiltration, collectively supporting a glia-driven mechanism of CNS injury in SFTS.⁴⁶

Diagnosis of SFTS-associated encephalopathy relies on clinical suspicion and comprehensive assessment.⁵⁴ Neurological manifestations typically arise between days 2–14 of disease progression, with peak incidence around days 5–7.^55,56 Among the various CNS manifestations, confusion is the most prevalent symptom, followed by convulsions, agitation, lethargy, and coma. Other neurological signs may include dysarthria, muscle tremors, seizures, and, less frequently, epilepsy. In cases complicated by SFTS meningitis, patients may additionally exhibit meningeal signs such as nuchal rigidity, Kernig’s sign, and Brudzinski’s sign. Molecular testing plays a central role in diagnosis, with real-time quantitative polymerase chain reaction (PCR) providing a definitive means of detecting DBV RNA in blood or CSF. In some cases, metagenomic sequencing can also support viral detection in CSF, although false-negative results may occur. Other laboratory findings often reveal elevated levels of MCP-1 and IL-8 in CSF,⁵⁷ indicative of monocyte-macrophage infiltration into the central nervous system. Immunohistochemistry for the viral nucleocapsid protein in brain tissue confirms viral presence.^52,58 Furthermore, proteomic biomarkers in plasma have shown promise in predicting disease progression.⁵⁹

Neuroimaging and electroencephalogram (EEG) findings further support the diagnosis. Literature reports indicate that reversible splenial corpus callosum syndrome may appear on magnetic resonance imaging (MRI) as early as day 2 of encephalopathy onset. During the acute phase of encephalitis, MRI may reveal transient splenial corpus callosum lesions, cortical edema, or white matter hyperintensities.^58,60 Some patients exhibit white matter ischemia or hyperintense signals in the brainstem or thalamic regions, suggestive of viral encephalitis or hypoxic injury. EEG often demonstrates generalized slowing (δ-θ waves), indicative of cerebral dysfunction or encephalopathic state. Notably, these findings can mimic other forms of encephalitis, necessitating correlation with other diagnostic indicators for accurate assessment.

Currently, no vaccines or antiviral therapies specifically target SFTS-associated encephalopathy. For patients with elevated intracranial pressure (ICP), mannitol remains a first-line therapy. According to the Chinese expert consensus, the suggested dosage of mannitol is 0.25–1.0 g/kg intravenously, with the initial dose over 10–20 min and subsequent doses every 4–6 h. Nevertheless, clinicians should be aware that mannitol may induce electrolyte imbalances and renal impairment, particularly with prolonged or high-dose use. Recent studies have demonstrated that hypertonic saline may offer superior ICP reduction compared to mannitol, and has been expanded usage in conditions such as aneurysmal subarachnoid hemorrhage (aSAH), which shares pathophysiological similarities with SFTS-related encephalopathy. Renal toxicity appears minimal when serum sodium concentration is maintained below 170 mmol/L and plasma osmolality remains within 360 mOsm/L, suggesting its potential role in reducing ICP in SFTS-related cerebral edema.

Airway protection is also critical in patients with impaired consciousness. Mechanical ventilation should be promptly initiated when necessary to maintain normocapnia, preventing hypoxia and aspiration-related secondary brain injury. One case report described an SFTS encephalopathy patient who developed respiratory failure on day 11 of illness and achieved full recovery following timely respiratory physiotherapy, postural management, and ventilatory support. Adjunctive therapies such as hyperbaric oxygen therapy (HBOT) exert neuroprotective effects by scavenging oxygen free radicals, improving cerebral hypoxia, promoting cerebral metabolism, and modulating microglial activation in other encephalitic models.⁶¹ In pediatric patients with other form of viral encephalitis, HBOT shown to reduce neuroinflammation and improve clinical outcomes, suggesting its potential as an adjunctive treatment for SFTS-associated encephalopathy; however, prospective studies are required to validate its efficacy.

Invasive pulmonary aspergillosis (IPA)

In addition to myocardial injury and neurological complications, severe patients are often accompanied by pneumonia. A cohort study of 167 patients with SFTS complicated by pneumonia showed that 26.9% of the patients progressed to respiratory failure, and the mortality rate was as high as 77.8%,⁶² highlighting that pneumonia and its related complications are important factors affecting prognosis. Pneumonia in SFTS is multifactorial, but IPA has emerged as a significant complication frequently reported in severe cases of SFTS.⁶³ Similar to infections caused by SARS-CoV-2 and influenza,^64,65 intensive care unit (ICU)-admitted patients with SFTS are highly susceptible to aspergillosis infections, with mortality rates ranging from 39.5 to 53.3%.^66,67,68,69 IPA is an opportunistic infection caused by the inhalation of Aspergillus conidia. Characterized by Aspergillus hyphae’s invasion into the pulmonary vasculature, IPA is largely observed in immunocompromised patients receiving chemotherapy against cancer and viral infection.^70,71 Clinical data suggest that 2.5–4.3% of patients with ICU admission are diagnosed with IPA or probable IPA co-infections.⁷²

SFTS significantly predisposes patients to IPA, primarily due to the profound immunosuppression induced by DBV infection, including impaired antibody production, hyperactivated natural killer (NK) cells (via cytotoxicity and IFN-γ), and neutropenia (details in Section immune-mediated mechanisms). Additionally, cytokine storm-mediated tissue damage further exacerbates fungal susceptibility (details in Section cytokine storm and systemic inflammatory response syndrome).^36,73

Beyond immune dysfunction, additional factors facilitate IPA in immunocompetent individuals.⁷⁴ Platelets contribute to antifungal defense by adhering to Aspergillus hyphae and inhibiting germination.^75,76 However, patients with SFTS usually develop thrombocytopenia within 5 days of disease onset,⁷⁷ markedly reducing platelet-mediated antifungal protection. Thrombocytopenia further impairs vascular integrity, contributing to hemorrhagic manifestations and the progression of SFTS to MOD.⁷⁸ The damage to barrier tissues, such as epidermis and vascular endothelium, allows Aspergillus spp. to disseminate beyond the respiratory tract to multiple different organs, including the skin, brain, eyes, liver, and kidneys. Furthermore, invasive medical interventions, particularly mechanical ventilation, significantly elevate the risk of fungal exposure and subsequent co-infections in critically ill patients with SFTS.^67,79

The diagnostic complexities associated with SFTS-associated IPA (SAPA) contribute significantly to the high mortality among patients with SFTS. SAPA often presents with atypical manifestations, adding to the diagnostic challenge in early recognition. Aspergillus tracheobronchitis (ATB) is a notably underrecognized form of SAPA. While ATB is found in less than 10% of typical IPA cases in the general population, it occurs in approximately 60% of SAPA cases, suggesting a unique pathophysiology distinct from conventional IPA infections.⁷⁴ Similar lesions in the central airways are frequently observed in patients with chronic obstructive pulmonary disease (COPD) (18–36%) and in viral pneumonia cases (16%), further differentiating SAPA’s presentation from other diseases.^80,81 Recent clinical consensus on IPA diagnosis recommends a comprehensive diagnostic approach, including chest computed tomography (CT), CT-guided biopsy, bronchoscopy, and microbiological testing of respiratory specimens and/or serum.⁸² Among these, bronchoalveolar lavage fluid and tissue biopsy provide the most definitive evidence, with the histopathological detection of invasive fungal hyphae considered the gold standard for confirming bronchopulmonary aspergillosis. However, due to the risk of bleeding associated with SFTS-induced thrombocytopenia, biopsies are often avoided, leading clinicians to rely on less invasive yet less conclusive diagnostic methods. Chest CT scans are frequently used for IPA detection, typically showing features such as subpleural density, halo signs, air crescent signs, ground-glass opacities, and Aspergillus balls.⁸³ In patients with SAPA, however, the rapid progression of DBV-induced respiratory failure may obscure these radiological findings, reducing diagnostic sensitivity.⁸⁴ Thus, early suspicion of IPA should be raised when pulmonary infiltrates or nodules are observed on CT, especially when accompanied by positive fungal test results.⁸⁵ Although additional laboratory tests, including galactomannan enzyme immunoassay, lateral flow assays, and PCR-based fungal detecting, can aid in diagnosis, these methods are prone to false-negative results, which may complicate clinical decision-making.

The lack of high-quality evidence for SAPA treatment remains a major obstacle, largely due to limited understanding of the underlying viral-fungal interactions and a scarcity of multicenter, prospective studies. Existing data are largely derived from isolated studies of SFTS or IPA, yet recent reports of unusual IPA presentations in SAPA highlight the need for a better understanding of viral-fungal interactions. In clinical practice, treatments developed for non-SFTS IPA are often applied to patients with SAPA without considering their distinct pathophysiology. Although antifungals such as voriconazole and posaconazole have shown efficacy, the optimal timing and safety of combining them with antivirals remain uncertain.^86,87

Co-infections

While IPA represents the most extensively characterized fungal complication of SFTS, it constitutes only one component of a broader spectrum of opportunistic co-infections. Overall, co-infection occurs in 8–30% of SFTS cases, increasing the pathogenicity of opportunistic fungal, bacterial, and viral pathogens that may worsen disease outcomes.^88,89 Notably, patients with SFTS are particularly vulnerable to respiratory fungal infections, whether community or hospital-acquired fungal infections, which can exacerbate pulmonary symptoms and significantly increase disease severity. Although IPA is the most frequently reported fungal complication, a small number of co-infection cases, including Monilia albicans, Candida glabrata, Candida albicans, and Mucor species, have also been documented in patients with severe SFTS, with Candida albicans appearing to be the most prevalent.^90,91 Antifungal therapy has shown to be effective in the available cases, and no deaths were reported; however, the true burden of fungal co-infections in SFTS may be underestimated due to the empirical use of antibiotics and delays in initiating targeted antifungal treatment.

Bacterial co-infections exhibit a different epidemiologic profile, with surveys showing that only hospital-acquired infections are significantly associated with mortality.⁸⁸ Common pathogens include Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii, which cause not only respiratory pneumonia but also bloodstream infections, the latter of which tend to progress to sepsis and infectious shock.⁸⁸ Even typically benign colonizers such as Campylobacter jejuni can cause intestinal infections under immunosuppression.⁹² This highlights the need for the comprehensive clinical assessment of host immunity, infection source (community or hospital), and pathogen traits—particularly in resource-limited settings. Early identification of high-risk patients (e.g., those with diabetes, advanced age, or long-term glucocorticoid use) and prompt intervention are critical to reducing mortality from bacterial co-infections.

Studies of viral co-infections, though less studied, have identified a significant association between DBV infection and reactivation of Epstein-Barr virus,⁹³ a latent human herpesvirus with a significantly higher rate of reactivation in critically ill patients with DBV, especially those who are mechanically ventilated or admitted to the ICU, and whose reactivation is not only a marker of physiologic stress, but also associated with an increased risk of adverse outcomes. Patients may be asymptomatic in the early stages, after which they may progressively develop typical symptoms of upper respiratory tract infections, including, but not limited to, persistent fever and enlarged cervical lymph nodes. In addition, cases of DBV co-infection with other viruses have been reported—such as hantavirus-can synergistically exacerbate multi-organ damage, manifesting as a superimposed effect of acute renal failure with hemorrhagic tendencies.⁹⁴ These observations suggest that co-infections in SFTS are not merely secondary complications but integral contributors to disease progression. Importantly, many of these opportunistic infections arise in the context of profound immune dysregulation, which also underlies one of the most life-threatening features of severe SFTS—the cytokine storm.

Cytokine storm and systemic inflammatory response syndrome

Severe patients with DBV infection are frequently associated with dysregulated immune responses marked by excessive cytokine release (a phenomenon known as cytokine storm). Elevated levels of proinflammatory mediators, such as IFN-α, IFN-γ, TNF-α, IP-10, MCP-1, granulocyte colony-stimulating factor (G-CSF), and macrophage Inflammatory protein-1α (MIP-1α) are consistently observed in patients with severe disease.³⁵ This dysregulated immune response drives the development of SIRS, ultimately leading to tissue hemorrhage, vascular injury, DIC, and even MOF (Figure 3).

Figure 3.

Cytokine storm and its immunopathogenesis of DBV infection

(A) DBV infection upregulates miR-146a/b in macrophages, promoting M2-like polarization via STAT pathway inhibition. Meanwhile, CD56^dimCD16⁺ NK cells become hyperactivated, secreting IFN-γ and TNF-α during the acute phase, contributing to cytokine storm.

(B) NSs bind to TPL-2/ABIN2, activating the MEK-ERK pathway and upregulating IL-10, which suppresses T cell function, promotes IL-6 release, and inhibits TGF-β production. NSs also activates the IKKβ-NF-κB axis, inducing pro-inflammatory cytokines (e.g., IL-1β and IL-6). Additionally, DBV-induced mitochondrial damage releases oxidized mtDNA, which activates the NLRP3 inflammasome and caspase-1, promoting IL-1β maturation and amplifying the inflammatory response.

(C) DBV impairs CSR by invading germinal centers of B cell follicles, and causes T cell activation followed by depletion.

(D) Excessive cytokines damage vascular endothelium, creating a positive feedback loop that drives SIRS, culminating in MOF involving the cardiovascular, neurological, respiratory, and hematologic systems.

Innate immune dysfunction is a key driver of cytokine storm initiation. DBV infection alters NK cell levels, which may act as a critical initiator of cytokine storm by secreting IFN-γ and TNF-α to modulate immune responses and releasing inflammatory/chemotactic factors that exacerbate tissue damage and disease progression. While the prevailing viewpoint suggests that patients with SFTS generally experience NK cells exhaustion, others have identified increased activity,⁹⁵ particularly with the CD56^dimCD16⁺ subset, which exhibit strong cytotoxicity during the acute phase of infection and reflect an imbalance between sustained activation and functional decline.⁹⁶ DBV targets macrophages in the liver and spleen causing similar cellular dysfunction, where it replicates and potentially triggers inflammatory skewing.⁹⁷ Within infected macrophages, the expression of mRNAs and microRNA (miR)-146a/b is markedly upregulated, promoting M2-like polarization via STAT pathway inhibition, thus sustaining a maladaptive immune environment.⁹⁸

The adaptive immune compartment is also disrupted. DBV disrupts B-cell immunity by invading the germinal centers of B-cell follicles, leading to impaired IgG⁺ class-switch recombination (CSR).⁹⁹ This disruption results in reduced B cell counts and dysfunction, as naive B cells undergo massive activation and depletion under the pressure of robust viral replication.¹⁰⁰ This process correlates with fatal outcomes in infected patients. T cell responses are also compromised. Studies in feline infection models have revealed the collapse of germinal center architecture and widespread apoptosis of T cells within lymph nodes. Following infection, CD8⁺ T cell populations decline numerically, yet their activation status and proliferative capacity surge. These activated CD8⁺ T cells secrete elevated levels of CD107a (a degranulation marker), IFN-γ, and granzyme B, reflecting heightened cytotoxic potential but also suggesting a state of terminal differentiation and functional exhaustion.^101,102,103 CD4⁺ T cells are numerically depleted in severe cases, and a reduced CD4⁺ T cells to total lymphocytes ratio has been associated with disease severity.¹⁰⁴

Among the key cytokines, the hyperproduction of IL-10 and IL-6 and the low production of transforming growth factor (TGF-β) are closely associated with fatal outcomes. IL-6, primarily produced by macrophages and dendritic cells, drives downstream inflammatory cascades and is a pivotal mediator of cytokine storm. Patients with DBV exhibit markedly increased IL-6 concentrations, which are strongly associated with the severity of pathological manifestations.³⁷ DBV NSs has been shown to elevate the expression of IL-10 by interacting with the TPL-2ABIN2 signaling complex.¹⁰⁵ IL-10, while anti-inflammatory, promotes immunosuppression by inhibiting T cells and NK cells' responses, potentially facilitating persistent viral replication. Meanwhile, IL-10 appears to upregulate IL-6 while inhibiting TGF-β synthesis, thereby amplifying inflammation. Conversely, DBV infection significantly reduces TGF-β levels.¹⁰⁶ As an important regulator of immune homeostasis, TGF-β suppresses the activation and proliferation of both T cells and B cells, helping to restrain excessive inflammatory responses.

IL-1β induces the expression of other inflammatory cytokines and chemokines, and enhances immune cell recruitment and activation. During cytokine storms, IL-1β drives positive feedback loops and tissue damage, establishing itself as a potential central mediator in this pathological process. Mechanistically, DBV infection activates pro-apoptotic Bcl-2-associated X protein (BAX) and Bcl-2 homologous antagonist/killer (BAK), inducing mitochondrial DNA (mtDNA) oxidation and cytoplasmic release. Cytosolic mtDNA binds NLRP3, triggering its oligomerization and ASC/pro-caspase-1 recruitment to form the NLRP3 inflammasome.¹⁰⁷ Active caspase-1 generated by inflammasome autocleavage processes pro-IL-1β into mature IL-1β for secretion.¹⁰⁸ In addition, NSs-mediated activation of the nuclear factor kappaB (NF-κB) pathway may further increase the selection of IL-1β.¹⁰⁹ Interestingly, although IL-1β concentrations were elevated in patients with SFTS compared to healthy controls, an inverse correlation was observed between IL-1β levels in patients and their disease severity.

The massive release of pro-inflammatory cytokines such as IL-6, IL-10, and IL-1β, triggered by cytokine storm, damages vascular endothelial cells, induces apoptosis and proliferation, and initiates a systemic inflammatory response. These cytokines further activate other inflammatory cells, perpetuating a self-amplifying cycle of cytokine release. This positive feedback inflammatory cascade can escalate uncontrollably to MOF. Laboratory-based cytokine profiling and immune cell analysis (such as IL-6, IL-10, TGF-β, and CD4⁺ T cell counts) can serve as potential biomarkers for disease severity and prognosis.^103,110 Identifying reliable biomarkers and elucidating the mechanistic underpinnings of this dysregulation remain pressing priorities, which could inform the degree of inflammation in severe cases and formulate personalized care plans.

Hemophagocytic syndrome

The extreme immune activation observed in severe SFTS may progress to HLH, a hyperinflammatory syndrome characterized by uncontrolled macrophage and cytotoxic T cell activation. HLH may occur either as a hereditary primary disease or as a secondary condition triggered by infections or malignant tumors, with platelet count serving as one of the baseline evaluations.¹¹¹ In SFTS, profound immune dysregulation caused by DBV infection can lead to secondary hemophagocytic syndrome, which has similar characteristics to primary HLH, but is usually reversible once the viral infection is controlled. The presence of HLH features in patients with SFTS has been suggested as a critical factor attributable to poor clinical outcomes and elevated mortality.^112,113 Histopathological studies have consistently reported prominent hemophagocytosis and necrotizing lymphadenitis as defining characteristics of fatal SFTS.^114,115 In a retrospective cohort study involving 18 patients with SFTS in South Korea, HLH complications were associated with a 75% case fatality rate.¹¹⁶

Thrombocytopenia is not only a hallmark feature of HLH in SFTS but also reflects the immune regulatory role of platelets in disease pathogenesis. A recent study has shown that platelets rapidly capture DBV via the glycoprotein VI (GPVI) receptor within 30 min of exposure, leading to platelet activation, aggregation, granule release, and procoagulant activity.¹¹⁷ Activated platelets may facilitate immune defense by delivering DBV to macrophages for clearance, while also suppressing inflammasome activation in macrophages.¹¹⁸ However, following viral uptake, platelets may also act as “Trojan horses,” delivering the virus to organs such as the spleen and bone marrow, which are reticular endothelial organs.¹¹⁹ The replication of the virus within tissue macrophages triggers cell pyroptosis, which in turn activates the phagocytic function of macrophages. The activated macrophages not only engulf the virus but also engulf a large number of platelets and blood cells, resulting in a typical hemophagocytic phenomenon, which exacerbates the vicious cycle of platelet depletion, excessive inflammation, and multi-organ damage.

Based on this pathological condition, DBV infection leads to profound immune dysregulation. This manifests as a cascade of immunopathologic events, including explosive release of proinflammatory cytokines (details in Section cytokine storm and systemic inflammatory response syndrome); T cell dysfunction (the percentage of CD4⁺T and CD28⁺CD8⁺ T cells is significantly reduced)¹²⁰; humoral immune imbalance (elevated percentages of total B cells, CD27⁻IgD^- double-negative B cells, and plasmablasts, coupled with decreased immature B cells).¹⁰⁰ These aberrations collectively contribute to histiocytic hyperplasia, hemophagocytosis, and a systemic hyperinflammatory state, which are more pronounced in the bone marrow examination of fatal SFTS cases.¹¹⁶ In a Japanese study, 83% of patients with SFTS with HLH exhibited large atypical immunoblastic cells in their bone marrow samples.¹²¹ This uncontrolled immune activation and tissue destruction within the bone marrow are both a harbinger and driver of MOD.

Progression to MOD ultimately becomes the main cause of mortality in patients with HLH. It is essential to differentiate HLH-associated CNS manifestations from those caused directly by DBV infection. The CNS may be affected early or secondarily in the disease course. Pathological histochemical analysis of patients with SFTS accompanied by HLH and CNS involvement showed that there were hemophagocyte infiltration and macrophage masses surrounding the dilated microvessels in the brain tissue, accompanied by perivascular inflammatory infiltration and fibrin deposition, which further led to local neuronal degeneration and DIC in the brain, leading to fatal consequences.⁴⁶ Furthermore, this pathophysiology contributes to sustained thrombocytopenia during disease progression. Multiple mechanisms are involved, including impaired megakaryopoiesis and cytokine storm—induced bone marrow suppression, which lead to reduced platelet production, as well as increased phagocytic clearance of platelets by activated macrophages.¹¹⁷ In fatal cases, the proportion of histiocytes that exhibit phagocytosis has been as high as 60–90%, and the degree of hemophagocytosis has shown a positive correlation with mortality.¹¹⁴

In patients with SFTS presenting with persistent high fever, hepatosplenomegaly, and pancytopenia, urgent HLH risk assessment using the HLH-2004 criteria is imperative. The core of diagnosis includes a significant increase in serum ferritin (≥500 μg/L, with specificity increasing at >5000 μg/L), a decrease in fibrinogen (<1.5 g/L), detection of hemophagocytes on bone marrow smear, an increase in sCD25 levels (>2400 U/mL, indicating T cell hyperactivation), and decreased natural killer cell activity. Among these, hyperferritinemia and hemophagocytic phenomena are key indicators in differentiating HLH from the primary disease of SFTS.¹²¹ The frequent observation of markedly elevated ferritin levels and hemophagocytic histiocytes in patients with SFTS supports the diagnosis of HLH. Fulfillment of the above 5 criteria confirms HLH diagnosis, necessitating immediate intervention.

The median survival of patients with untreated HLH was no more than two months. Treatment is divided into two phases: the induction of remission phase focuses on controlling the hyperinflammatory state to block HLH progression, and the etiological treatment phase focuses on the underlying immunodeficiency and primary disease to intervene to prevent recurrence. Some mild HLH can be treated with pulse glucocorticoids alone. The HLH-1994 regimen is the first-line therapeutic protocol, which involves an 8-week induction therapy comprising etoposide and dexamethasone, supplemented with intrathecal methotrexate and dexamethasone, followed by the addition of cyclosporine A after the 8-week induction phase. Notably, induction therapy does not mean that eight weeks of treatment must be given, and patients with HLH secondary to DBV infection can achieve remission with treatment against the pathogen without the addition of immunomodulatory drugs and cytotoxic drugs. Therefore, the intensity and duration of induction therapy need to be individualized based on disease severity and etiology.

Multi-organ failure (MOF)

MOF represents the most severe clinical outcome of SFTS, typically emerging during the MOD stage approximately two weeks after DBV infection. This period serves as a critical window for determining patient prognosis.^16,77 Clinical manifestations range from hemorrhagic tendencies and neurological symptoms to progressive thrombocytopenia. Severe cases will rapidly develop into DIC and MOF, often resulting in death within one to two weeks.^13,58 The development of MOF is complex and sequential, with clinical manifestations of impaired function of the primary target organ leading to secondary failure of other organs. The liver, as the most commonly affected organ in DBV infection, leads to extensive hepatocellular necrosis when it is directly attacked by the virus, at which time the patient’s aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are markedly elevated. AST levels in critically ill patients frequently exceed ten times the normal range (>400 U/L), often peaking shortly before death, thus serving as an early marker of liver injury and a predictor of metabolic and coagulation dysfunction of the organism.^36,77 In addition to transaminase elevations, other indicators include blood glucose (BG), albumin (ALB), cystatin C (CysC), D-dimer (DD), and activated partial thromboplasting time (APTT), which are all risk factors for death within 28 days in critically ill patients.¹²² These abnormalities are often captured by the sequential organ failure (SOFA) score, an important tool for evaluating six organ systems (respiratory, coagulation, hepatic, circulatory, neurologic, and renal).^123,124 Higher SOFA scores have been strongly correlated with mortality.

Progressive hepatic dysfunction also contributes to the development of acute kidney injury through multiple pathways in fatal cases, with persistent hypotension inducing renal hypoperfusion as a contributing mechanism.^{125,126,127,128} Also, the double attack of DBV on the vascular endothelium and hematopoietic system can induce hypotension and microcirculatory disorders (details in Section pathogenesis).^129,130

Beyond the liver and kidneys, DBV infection can directly or indirectly damage multiple organ systems. The virus has been shown to directly infect pancreatic tissue through receptors CCR2 and LRP1, triggering cell death, complement activation, and intense inflammatory responses, leading to viral pancreatitis. The levels of serum amylase and lipase in such patients are positively correlated with the viral load, suggesting that pancreatic damage is closely related to the systemic immune inflammatory mechanism.¹³¹ DBV infection has also been associated with rhabdomyolysis, likely driven by a combination of direct muscle injury, metabolic disorders from high fever, and systemic inflammation caused by cytokine storm. A significant increase in creatine kinase is a common manifestation, which not only increases the burden on the kidneys, but also induces or aggravates acute kidney injury, and its breakdown products can further promote inflammation, forming a positive feedback loop.⁶²

These inter-organ interactions amplify injury over time, as damage to one organ system promotes inflammatory signaling that affects others. In parallel, coagulation abnormalities may progress to DIC, a crucial intermediate stage in the progression from severe SFTS to MOF. The damage to vascular endothelial cells caused by viral infection, combined with thrombocytopenia, jointly triggers a systemic inflammatory response associated with thrombosis, forming a vicious cycle where inflammation and coagulation mutually amplify each other. Studies have shown that patients with SFTS may present with extensive coagulation dysfunction, manifested by significantly prolonged coagulation times (PT, INR, APTT, and TT), elevated DD, and decreased platelets and fibrinogen. These abnormalities are closely related to the severity of the disease and the viral load. Among them, APTT ≥51.3 s, TT ≥ 30.5 s, and DD ≥ 2.39 μg/mL indicate a poor prognosis, and APTT is an independent risk factor for death in patients with DIC.^132,133 As DIC progresses, microthrombi formation and bleeding tendency spread to important organs, eventually leading to MOF. Therefore, early identification through dynamic coagulation monitoring is crucial for timely intervention.

Advanced age is a major risk factor for the development of severe complications and MOF in SFTS. Patients over 50 years old show a substantially higher susceptibility, which may be thought to result largely from age-related immune senescence. Recent studies using elderly ferret models have indicated that in elderly hosts, infection with the DBV can trigger multiple immune dysfunctions, including abnormal B cell function, T cell exhaustion, excessive inflammation driven by myeloid cells, and excessive consumption of immune cells. For instance, the identification of characteristic cell populations such as T-bet⁺ age-related B cells and MK167⁺ plasmacytoid cells reveals their dual roles as a viral reservoir and ineffective immune responders, leading to the persistence of the virus and immunopathology.¹³⁴ These age-associated pathogenic cell populations represent promising targets for validation in human clinical samples to obtain reliable evidence for disease progression.

Management of SFTS-related MOF requires a multidisciplinary approach encompassing prompt DBV control, hemodynamic resuscitation, and comprehensive organ support.¹³⁵ Early combination of antiviral drugs such as ribavirin and immunomodulators to reduce viral load and alleviate immune disorders mediated by inflammatory factors. Supportive treatment should be individually adjusted according to the evolution of organ dysfunction. For example, liver-protective or antihypertransaminasemia drugs may be administered, while avoiding the use of nephrotoxic drugs and timely renal replacement treatment for incurable complications if necessary. For patients with SFTS-related cardiopulmonary failure whose conventional treatment is ineffective, extracorporeal membrane oxygenation (ECMO) can be used as a salvage treatment.¹³⁶ The existing literature has reported cases of successful offline and discharge. However, strict case screening is crucial, and the indications and contraindications should be comprehensively evaluated before starting ECMO.

Pathogenesis

Immune-mediated mechanisms

The diverse and often fatal complications of SFTS are not separate clinical phenomena. Rather, they represent downstream consequences of a profoundly dysregulated host immune response. Understanding the immunopathogenic mechanisms underlying these complications is therefore central to clarifying disease progression and identifying therapeutic targets. Following DBV entry and systemic dissemination, a dysregulated host immune response is a principal driver of pathogenesis. Many innate immune sensors are engaged, triggering a profound cytokine elaboration characterized by elevated proinflammatory mediators (details in Section cytokine storm and systemic inflammatory response syndrome). Dysregulated cellular and humoral immunity, marked by abnormal NK cell activity, B cell dysfunction, and platelet depletion, contributes significantly to the disease progression.

In the early stages of acute DBV infection, patients exhibit significant reductions in peripheral blood CD4⁺ T cells, accompanied by marked NK cell depletion, while CD8⁺ T cells may remain stable or transiently increased. As disease severity escalates, both CD4⁺ and CD8⁺ T cell counts demonstrate further decline, whereas NK cells show substantial elevation.^{95,104,137,138} These findings suggest that hyperactivated NK cells driving excessive immune responses may constitute a critical pathological basis for multi-organ damage in severe cases.

Histopathological examinations of the spleen in lethal cases show marked pathological alterations, including the infiltration of atypical lymphocytes, abundant nuclear debris, necrotic cellular debris, and focal hemorrhage with splenic congestion, indicating its role as a primary target organ for DBV replication and a critical site of immunopathogenesis. As a secondary lymphoid organ, the spleen exhibits pronounced expansion of atypical B-lineage cells by DBV infection, mainly plasmablasts that partially differentiate into plasma cells.^46,99,130 Notably, these activated B-lineage cells may exacerbate disease progression through polyclonal cytokine production that amplifies immune responses.^139,140 Histopathological analyses further reveal a distinct B cell tropism of DBV, characterized by active viral replication within IgG⁺ B cells across multiple lymphoid organs. This specific tropism serves as a critical mechanism of immune evasion, leading to the depletion of functional B cells and the subsequent suppression of humoral immunity.⁹⁹

Platelet-mediated immune response also plays a certain role in the pathogenesis of SFTS. This is mainly due to the platelet activation and aggregation triggered by the virus, which further aggravates thrombocytopenia and systemic inflammation (details in Section hemophagocytic syndrome).

Viral immune evasion mechanisms

In parallel, DBV deploys multiple strategies to circumvent intrinsic immune defense.¹⁴¹ A central component of this strategy is the NSs, which plays a pivotal role in antagonizing type I and III IFN responses through distinct molecular mechanisms involving sequestration, capture, and direct interaction (Figure 1B). NSs forms cytoplasmic inclusion bodies that sequester key signaling molecules, such as signal transducer and activator of transcription (STAT)1 and STAT2, blocking their phosphorylation and nuclear translocation, thereby suppressing type I and III IFN signaling.¹⁴² It also captures retinoic acid-inducible gene-I (RIG-I) pathway proteins (e.g., RIG-I, TANK-binding kinase 1 (TBK1), IκB kinase, and interferon regulatory factors 3/7) and the ubiquitin ligase tripartite motif-containing 25 (TRIM25) to block RIG-I ubiquitination and signaling. Furthermore, NSs engages in direct interactions with specific host factors such as LSM family member 14A (LSM14A), a mitochondrial RNA sensor, to further suppress IFN activation.^143,144

Besides these inhibitory interactions, NSs can inhibit IFN-β transcription by inducing the expression of NF-κB inhibitors and through direct interactions with signaling components such as TBK1.¹⁴⁵ To be noted, inclusion bodies formed by NSs are found to co-localize with lipid droplets, which promotes DBV replication by hijacking the host’s fatty acid biosynthesis machinery.¹⁴¹ Moreover, NSs interacts with beclin-1 to promote the formation of the autophagy initiation complex, leading to the degradation of critical antiviral proteins and evasion of innate immune response.¹⁴⁶

NP inhibits the antiviral immune response by translocating to mitochondria through interaction with Tu translation elongation factor (TUFM) and recruiting microtubule-associated protein 1 light chain 3 (LC3) to mediate mitochondrial autophagy to degrade mitochondrial antiviral signaling protein (MAVS).¹⁴⁷ In addition to these intracellular mechanisms, DBV suppresses adaptive immunity by impairing myeloid dendritic cell (mDC) differentiation and downregulating CD86 expression, which leads to defective antigen presentation, diminished T cell activation, and inhibited cytokine secretion.¹⁴⁸ Collectively, these immune evasion tactics enable DBV to avoid host defenses, enhance survival, and drive the immunopathogenesis of SFTS.

Treatment strategies

The current clinical treatment must address the complex interplay between viral replication and the host’s immune pathological response as elucidated in this review. However, as there are currently no targeted treatments available, the main approach for treatment remains supportive.

Antivirals

Ribavirin, a broad-spectrum nucleoside analog, is used empirically for SFTS, but its efficacy remains controversial. It reduces mortality in patients with low viral load (<1×10⁶/mL) but shows no benefit in high viremia.¹⁴⁹ Despite the 2012 Chinese guidelines recommending ribavirin (500 mg/day IV), subsequent studies show limited impact on platelet recovery or viral clearance.

Favipiravir, an RNA polymerase inhibitor, protects mice from lethal DBV infection at 120–200 mg/kg/day when initiated by day 4 post-infection.¹⁵⁰ Despite these promising results, its efficacy and safety in human SFTS cases require further validation.

Calcium channel blockers (benidipine, nifedipine) inhibit DBV replication by reducing Ca²⁺ influx. In a large cohort (n = 2,087), nifedipine reduced fatality to 3.6% versus-20% in controls.¹⁵¹ Nifedipine also improved viral clearance and platelet counts compared to ribavirin.¹⁵² Adverse effects (hypotension, edema) require dose adjustment.

Immunomodulation

Glucocorticoids may benefit select patients with severe SFTS with hyperinflammation or encephalopathy. Two cases improved with low-to-moderate dose corticosteroids plus IVIG.⁴⁵ However, high doses or early use in mild patients may increase mortality and risk secondary infections such as IPA.¹⁵³

Other studies have introduced therapies using neutralizing monoclonal antibodies to block the interaction between DBV strains and host cells. Ab10 prolongs survival in animal models at low doses,¹⁵⁴ while MAb4-5 potently neutralizes multiple DBV genotypes.¹⁵⁵

IFN-based therapies have also been explored. Type I and II interferons, alone or with ribavirin, show synergistic antiviral effects against DBV in vitro, reducing replication and effective doses. However, their in vivo efficacy and immune-related side effects remain under investigation.¹⁵⁶

Supportive therapies

Traditional supportive care for SFTS includes fluid resuscitation, blood transfusion, antipyretics, vasopressors, and G-CSF. Recently, therapeutic plasma exchange (PE) has emerged as an adjunctive strategy for severe cases with cytokine storm or multi-organ dysfunction. PE removes pathogenic plasma components and replaces them with donor plasma or albumin, aiming to reduce hyperinflammation and viral load. However, this treatment may have a time-sensitive therapeutic window.

Additional antiviral approaches and vaccines

Multiple novel antivirals and vaccines are under investigation for DBV. VV261, a 4′-fluorouridine prodrug targeting viral RNA polymerase, is China’s first SFTS therapeutic candidate in Phase I trials.¹⁵⁷ Repurposed drugs—including 2′-Fluoro-2′-deoxycytidine, amodiaquine,^158,159 and 6-thioguanine (which downregulates EGR1)—show dose-dependent anti-DBV efficacy in preclinical models.

Vaccine development is equally critical. Live-attenuated vaccines (e.g., NS-mutated) show efficacy in aged ferrets but require safety evaluation in immunocompromised hosts.¹⁶⁰ DNA vaccines encoding Gn/Gc confer complete protection in ferrets.¹⁶¹ Viral vector vaccines (rVSV-based) protect IFNAR-knockout mice.¹⁶² Protein subunit vaccines, notably GnH-ferritin nanoparticles, achieve full protection in aged ferrets with enhanced immunogenicity.¹⁶³ However, recombinant protein and mRNA vaccines targeting Gn/Gc still face challenges in antigen delivery efficiency and cross-protection.^164,165,166

Conclusions and future directions

DBV infection triggers life-threatening complications—such as myocarditis, neurological disorders, secondary infections, cytokine storm, and hemophagocytic syndrome—that often progress to MOF and contribute to case-fatality rates as high as 30%. Current therapies remain inadequate, as poor outcomes stem not from isolated pathology but from a dysregulated systemic cascade involving immune dysfunction, excessive inflammation, pathogenic protein aggregation, and disrupted signaling networks.

The immune system plays a paradoxical role in SFTS complications: insufficient responses fail to control the virus, while excessive activation causes hyperinflammatory damage. Key mechanistic gaps persist, including NSs' dual role in IFN suppression versus NLRP3 activation, platelets' conflicting functions in viral spread versus defense, and DBV’s poorly defined organotropism, especially in immune-privileged sites such as the brain, lungs, and bone marrow. Most studies focus on single-organ pathology, overlooking inter-organ signaling axes (e.g., brain-liver-lung) and systemic immune cascades. Whether DBV directly crosses the blood-brain barrier or triggers neuropathology via cytokine storms remains unclear. Mechanistic studies on neuronal injury are urgently needed, as current animal models fail to fully replicate human organ-specific responses, particularly in the CNS and pulmonary microenvironments.

Future efforts should pursue a multi-faceted strategy. High-resolution techniques (e.g., interactome mapping and stage-specific viral tracking) can define NSs/NP/Gn/Gc functions and identify antiviral targets.^167,168 Time-resolved single-cell immune atlases and spatial transcriptomics of key organs will clarify DBV dissemination and immune disruption. Organoid and organ-on-a-chip models can replicate inter-organ communication and enable mechanistic studies. Targeted tools (NP-specific antibodies, siRNAs) with advanced delivery systems may enable organ-specific modulation. Immunotherapies targeting IL-6R or JAK/STAT, plus small-molecule inhibitors, could restore immune balance. AI-driven platforms may accelerate mRNA vaccine optimization. Further research is urgently needed to curb DBV’s rising threat.

Acknowledgments

The authors gratefully thank the technical support provided by members of Jiancang Zhou’s team. This work was supported by the Zhejiang Provincial Natural Science Foundation of China (Grant No. LMS25H090002), the Zhejiang Provincial “Leading Goose” Science and Technology Project (Grant No. 2026C02A1133), and the National Key Research and Development Program of China (Grant Nos. 2023YFC2605102 and 2023YFC2605100).

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.