Severe fever with thrombocytopenia syndrome virus

INTRODUCTION — Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious zoonosis in China and other countries in southeast Asia [1].The causative agent is commonly designated SFTS virus (SFTSV), a newly identified bunyavirus that appears to be carried by ticks (ie, Haemaphysalis longicornis).

VIROLOGY — SFTSV, or Dabie bandavirus (Bandavirus davieense), is a member of the genus Bandavirus in the family Phenuiviridae and in the order Bunyavirales [2]. The closest relative is Bhanja virus, a tickborne human pathogenic phlebovirus that causes febrile illness and meningitis [3]. Bunyaviruses are largely spherical, enveloped particles with a diameter of 80 to 120 nm. Particles carry three genomic segments designated large (L), medium (M), and small (S).

The L segment encodes the RNA-dependent RNA polymerase, the M segment the glycoproteins Gn and Gc, and the S segment the nucleoprotein (N) and a nonstructural protein (NSs) using an ambisense coding strategy [4]. The N protein encapsulates the genomic RNA; this complex is further associated with the L protein and forms the active transcriptase/replicase complex. The Gn and Gc glycoproteins form a heterodimer and shape the spikes on the surface of the virion. The glycoproteins mediate receptor binding and virus entry and are the target for neutralizing humoral immune responses [4].

The C-type lectin, DC-SIGN, has been identified as one of the factors for SFTSV attachment and entry into cells [5]. Glucosylceramide, the glucose-modified lipid, is required for efficient SFTSV entry into cells [6]. The NSs protein serves as a type-I interferon antagonist that suppresses activation of innate immune responses via the IPS-1/IRF-3 and NF-kappaB pathways. SFTSV inhibits exogenous interferon-alpha-induced Jak/STAT signaling through its encoded NSs [7].

Phylogenetic analysis shows SFTSV can be clustered into six genotypes [8]. SFTSV has been classified into Chinese and Japanese lineages, consistent with the geographical distribution; the two lineages are further divided into six and four sublineages, respectively [9]. At least four different genotypes of SFTSV are cocirculating in South Korea [10].

EPIDEMIOLOGY — SFTS was first reported in China in 2009 [11]. Since then, cases have emerged from Japan, South Korea, and other countries in eastern Asia.

Cases in China — In 2009, SFTS was identified as a new disease in the Huaiyangshan mountain range in China [12-15]. A new virus, designated SFTSV, was isolated from patient blood; the case-fatality rate was 30 percent. In retrospect, SFTS occurred in China as early as 2006, but the cases were misdiagnosed as human granulocytic anaplasmosis.

Enhanced surveillance using a new case definition and advanced laboratory testing expanded the endemicity zone of SFTSV to neighboring provinces and designated SFTS as a major public health concern in rural eastern China [12-18]. Since 2009, SFTS cases have been identified in central China in the Henan, Hubei, Shandong, Anhui, Zhejiang, Jiangsu, and Liaoning provinces, and endemic areas have expanded from 27 to over 1500 townships [12-14,19,20]. The coastal plains of Dongtai County also have reported cases, but most cases in China are reported in hilly or mountainous areas covered by woods, shrubs, and crops.

Between 2009 and 2019, the average annual incidence of human SFTS infections in China increased over 20-fold with over 7000 laboratory-confirmed SFTSV cases in total [12,13,20-23]. Cases are reported predominantly between the months of May and August, the peak time of tick and farming activities in China. In reports, cases typically occur in residents ≥60 years of age in rural areas with crop fields and tea farms. Among healthy Chinese individuals, one report noted SFTSV seroprevalence of approximately 4 percent.

Cases in countries other than China

●Japan – In 2014, 11 cases of SFTS (including 6 fatalities) were reported in western Japan [24-27]. By August of 2019, 434 cases (including 66 fatalities) had been identified. All patients were from western Japan, and the median age of the patients was 74 years. Most cases occurred between April and August, and many were farmers. Among healthy individuals >50 years of age living in an endemic area in Japan, seroprevalence was 0.14 percent. Phylogenetic analyses indicated that the Japanese SFTSV isolates comprised a genotype independent from those in China, suggesting that the Chinese clade and the Japanese clade may have evolved separately over time.

●South Korea – In South Korea, the first case of SFTS was reported in 2013 [28,29]. By December 2018, 866 patients (including 174 fatal cases) had been confirmed. Most cases occurred between May and October, and the disease was observed in rural areas throughout the country.

●Other countries – In Vietnam in 2017, a retrospective analysis of blood samples from 80 patients with unexplained acute febrile illness identified two patients who were positive for SFTSV by polymerase chain reaction (PCR) [30-33]. In Myanmar in 2018, 5 of 152 patients suspected of having scrub typhus actually had SFTSV by PCR. In Taiwan in 2019, a case of SFTS was confirmed in a 70-year-old man who had not traveled outside the country. A seroprevalence study in Pakistan in 2016 and 2017 found that 2.5 percent of more than 1600 livestock farmers had micro-neutralizing antibodies against SFTSV. In Thailand, three of over 700 hospitalized patients studied from October 2018 to March 2021 had SFTS with a positive SFTS virus PCR [34].

Tick vector and transmission of infection

Identification of tick vector — The primary mode of spread of SFTSV to humans and other animals appears to be via tick bite from the Asian longhorned tick, H. longicornis [11,12,14,35-38]. In prevalence testing of numerous tick species, live virus has only been isolated from H. longicornis ticks. Studies of infected H. longicornis ticks reveal virus in the ticks’ salivary glands, further supporting the capacity of this tick species to transmit the virus.

Molecular tests such as PCR have detected SFTS viral RNA in multiple other tick species, including H. hystricis, H. flava, Amblyomma testudinarium, Ixodes nipponensis, Rhipicephalus microplus, Dermacentor nuttalli, and Hyalomma asiaticum [11]. Further studies are needed to assess the role of these other species in transmission.

Geographic distribution and lifecycle of H. longicornis ticks — H. longicornis ticks are endemic in southeast Asia, Australia, New Zealand, and several island nations of the western Pacific Region (figure 1) [11,39-41]. In 2017 in the United States, the tick was found on a native sheep in New Jersey; since then it has been detected in vegetation and on animals in a wide area of the eastern United States (figure 2) [42].

It is unclear how H. longicornis ticks spread to distant locales [11,43]. Geospatial studies suggest that migratory birds infested with H. longicornis ticks may be responsible for introducing the virus into new regions of Asia [44]. In the United States, the tick species was more likely introduced via importation of domestic pets, horses, or livestock, or on people. The United States Department of Agriculture first detected the ticks on imported quarantined horses and livestock several years before 2017.

Since 2018, H. longicornis ticks have been designated an invasive species in the United States [43,45]. The tick species has several features that allow it to rapidly establish large populations following introduction to a new location. First, females can lay viable eggs without mating with males; this allows a single female tick to create an entire population of ticks. Additionally, the tick can tolerate a wide range of environmental temperatures and can feed on a wide range of mammalian and avian hosts.

Adult female ticks must feed on animal hosts before they can lay eggs [11,39,42,46]. In the United States, the tick has been found on wildlife including white-tailed deer and birds, domestic livestock and horses, companion dogs and cats, and humans. The tick is an aggressive biter and can cause massive infestations on animals.

SFTSV in ticks and animals — The SFTSV has been found by culture and by PCR in H. longicornis ticks throughout east Asia and the western Pacific islands (see 'Identification of tick vector' above). As of 2021, SFTSV has not been detected in ticks in the United States.

H. longicornis ticks become infected with SFTSV by feeding on infected hosts or possibly by maternal transmission [37]. Feeding on infected hosts introduces the infection into the tick population. It is unclear if there is a reservoir host that harbors SFTSV (reservoir hosts are animal species that have a high prevalence of infection and are typically favored meal sources for ticks). Maternal transmission of the virus to tick offspring is suggested by studies of infected ticks that show SFTS viral RNA in the ticks’ ovaries and laid eggs.

Animal serosurveys in China and South Korea have demonstrated SFTSV-specific antibodies in multiple species such as cattle, goats, sheep, dogs, pigs, chickens, and hedgehogs [35,36,47-50]. In addition, cats have been found to be highly susceptible to SFTSV; high levels of viral RNA have been detected in cats’ serum, eye swabs, and saliva [51].

Transmission of SFTSV to humans — The primary mode of SFTSV transmission to humans is via the bite of the H. longicornis tick.

Possible direct transmission from infected cats and dogs to humans via exposure to the animals’ bodily fluids has been reported [11,35,36,39,46-50,52-54].

Human-to-human transmission via close contact with blood and body secretions has also been reported. For example, family members may be infected during patient care, nosocomial transmission may occur at emergency department and intensive care unit settings, and transmission via needle-stick injury has been reported. In addition, SFTSV RNA has been detected by PCR in semen after disappearance from serum, raising the possibility of sexual transmission [16,55-61].

PATHOGENESIS — Important factors in the pathogenesis of SFTSV infections likely include high viral load, inflammatory responses similar to systemic inflammatory response syndrome (SIRS), coagulation abnormalities, and multiorgan dysfunction. Uncontrolled upregulation of several cytokines (including interleukin [IL]-1RA, IL-6, IL-10, granulocyte colony-stimulating factor [G-CSF], induced protein [IP]-10, and monocyte chemoattractant protein [MCP]-1) appears to correlate with disease severity, suggesting that SIRS is a significant factor in pathogenesis [62-64]. SFTSV nonstructural protein promotes the hyperinduction of cytokine/chemokine genes [65,66]. SFTSV can infect and replicate in macrophages [67]. SFTSV-infected B cells secrete factors that induce B-cell differentiation into plasmablasts, suggesting that the SFTSV-B cell axis may play an important role in pathogenesis [68]. A unique virus clade (IV) with a specific co-mutation pattern has been associated with a higher case fatality rate (32.9 percent), compared with other three common clades (I, 16.7 percent; II, 13.8 percent; and III, 11.8 percent), suggesting an association between specific viral clades and SFTS mortality [69].

Autopsy studies have demonstrated that lymph node architecture is replaced with massive necrosis containing histiocytes, immunoblasts, nuclear debris, and eosinophilic ghosts. SFTSV nuclear protein can be detected in the liver, spleen, adrenal, bone marrow, and lymph nodes [24,70,71]. SFTSV-infected cells in lymph nodes are macrophages and class-switched B cells with a similar immunophenotype to that of plasmablasts [72].

Hemophagocytes are commonly observed in the bone marrow [73]. In a surviving patient, fludeoxyglucose F 18 positron emission tomography imaging demonstrated hypermetabolism in regional lymph nodes and the spleen [74].

In animal models of SFTS using C57/BL6 mice and alpha/beta interferon knockout mice, viral replication is most active in the spleen and mesenteric lymph nodes [75,76]. The characteristic histologic findings of the lymph nodes include extensive necrosis and histiocytic proliferation [77]. SFTSV and platelets are colocalized in cytoplasm of macrophages in the spleen. SFTSV adheres to mouse platelets and facilitates their phagocytosis. Splenic clearance of virus-bound, circulating platelets may be important in the pathogenesis of thrombocytopenia in SFTS [76].

CLINICAL MANIFESTATIONS — Following an incubation period of 7 to 14 days (average 9 days), SFTS begins with a nonspecific prodrome including fever, malaise, headache, myalgia, arthralgia, and dizziness, which persists for about a week. Gastrointestinal manifestations such as nausea, vomiting, and diarrhea are also common [1,12-14,29,36,58,78-83]. SFTSV viral loads peak on days 7 to 10 after fever onset [84].

Laboratory abnormalities may include leukopenia (<4,000/mm³) and thrombocytopenia (<100,000/mm³); elevated serum levels of alanine/aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, and creatine kinase; and prolongation of activated partial thromboplastin time. SFTSV is also associated with elevated serum ferritin levels [85]. Atypical lymphocytes may appear in the peripheral blood four to eight days after onset of disease [86].

During the second week of illness, multiorgan dysfunction may develop, including acute kidney injury and cardiac involvement (myocarditis, arrhythmia) [87]. Meningoencephalitis may occur [88]. Bleeding tendency may be observed in the form of mucosal hemorrhage and/or disseminated intravascular coagulation. In surviving patients, these manifestations begin to resolve after 8 to 11 days of illness.

Invasive pulmonary aspergillosis (IPA) has been observed in 20 to 32 percent of patients hospitalized with SFTS [89,90]. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Pulmonary aspergillosis'.)

Secondary hemophagocytic lymphohistiocytosis (HLH) has been associated with SFTS, with hyperferritinemia and evidence of hemophagocytosis in the bone marrow. Rapidly deteriorating mental status due to HLH with infiltration of activated lymphocytes and macrophages into the meninges and brain has been described [91]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Case-fatality rates range from 6 to 21 percent [20,21,29,82]. The time from symptom onset to death is typically 8 to 10 days.

Poor prognostic factors include longer delay in admission [92], older age, decreased level of consciousness, elevated serum levels of lactate dehydrogenase or aspartate aminotransferase, low lymphocyte percentage, and prolonged activated partial thromboplastin times [29,82,93]. A high level of cell-free DNA at initial presentation, IL-6 and IL-10 levels, and inadequate antibody responses may predict severe illness [94-96]. In a study from China, females had a lower-case fatality rate than males (OR 0.73, 95% CI 0.61–0.87) [97].

DIAGNOSIS — The diagnosis of SFTSV infection should be suspected in patients with fever, thrombocytopenia, and leukopenia together with a history of tick exposure in an endemic area (central and eastern China, western Japan, and rural areas of South Korea).

During the first week of illness, a laboratory diagnosis of SFTSV infection may be established by detection of viral RNA in serum via reverse-transcriptase polymerase chain reaction (RT-PCR) or loop-mediated isothermal amplification [98-103].

During the second and third weeks of illness, a laboratory diagnosis of SFTSV infection may be established by detection of virus-specific immunoglobulin (Ig)M and IgG in serum via enzyme-linked immunosorbent assay using inactivated virus particles or recombinant expressed viral proteins as antigens [47,104,105]. The average time of seroconversion for IgM and IgG is 10 and 17 days, respectively, from symptom onset [106].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of SFTS includes:

●Dengue fever – The cardinal features of dengue hemorrhagic fever include fever, increased vascular permeability, hemorrhagic manifestations, and marked thrombocytopenia (≤100,000 cells/mm³). The virus is transmitted by Aedes aegypti mosquitoes, which have broad global distribution; the incubation period is four to seven days. The diagnosis is established via serologic testing. (See "Dengue virus infection: Clinical manifestations and diagnosis".)

●Scrub typhus – Scrub typhus infection is caused by Orientia tsutsugamushi and characterized by fever, headache, anorexia, and malaise; an eschar or rash may develop in a subset of patients. It is transmitted by larval mites (chiggers) in Asia and northern Australia. The incubation period is 6 to 20 days. The diagnosis may be established via serology or polymerase chain reaction (PCR). Altered mental status, leukopenia, thrombocytopenia, and normal C-reactive protein favor SFTS rather than scrub typhus [107,108]. (See "Scrub typhus".)

●Candidatus Rickettsia tarasevichiae (CRT) – Human infection with CRT was initially described in northeastern China in 2012, and coinfection with SFTSV may occur [109]. Clinical manifestations include fever, malaise, myalgia, cough, and gastrointestinal symptoms; eschar was observed in a minority of patients. Laboratory manifestations include thrombocytopenia, leukopenia, and elevated levels of lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. The diagnosis of CRT may be established via PCR.

●Kyasanur forest disease (KFD) – KFD is characterized by fever, headache, gastrointestinal symptoms, and bleeding. It is transmitted by ticks or contact with infected animals (incubation period of three to eight days). Infection is endemic in India; cases have been reported in China. The diagnosis is established via PCR, virus isolation from blood, or enzyme-linked immunosorbent serologic assay.

●Spotted fever Rickettsia – Rickettsial infections are characterized by fever, headache, and myalgia, often in association with a rash and/or eschar. They are usually transmitted by ticks with an incubation period of 2 to 14 days and span a broad geographic distribution. The diagnosis may be established via serology or PCR. (See "Other spotted fever group rickettsial infections".)

●Hemorrhagic fever with renal syndrome (HFRS) – HFRS is caused by hantavirus infection; it is characterized by fever, hemorrhage, hypotension, renal failure, and thrombocytopenia. It is transmitted by contact with or inhalation of aerosolized rodent urine or feces. Infection occurs worldwide, including Asia, Europe, and the Americas. The diagnosis is established via serology. (See "Kidney involvement in hantavirus infections" and "Epidemiology and diagnosis of hantavirus infections".)

●Crimean-Congo hemorrhagic fever (CCHF) – CCHF is characterized by fever and hemorrhage. It is transmitted by ticks (incubation period of 1 to 9 days) or contact with infected humans or rodents (incubation period of 3 to 13 days) and is endemic in parts of southern Europe, the Middle East, Africa, and northwestern China. The diagnosis is established via reverse-transcriptase polymerase chain reaction (RT-PCR) or serology. (See "Crimean-Congo hemorrhagic fever".)

●Other hemorrhagic fevers – Other hemorrhagic fevers, such as Ebola and Marburg, may be difficult to distinguish from SFTSV based on symptoms but may be excluded by geography (both are endemic to Africa). (See "Clinical manifestations and diagnosis of Ebola virus disease" and "Marburg virus".)

●Leptospirosis – Leptospirosis is characterized by fever, rigors, myalgia, conjunctival suffusion, and headache. Less common symptoms and signs include cough, nausea, vomiting, diarrhea, abdominal pain, and jaundice. It is transmitted via exposure to animal urine or contaminated water or soil and occurs worldwide, particularly south and Southeast Asia and South America. The diagnosis is established via serology. (See "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

●Ehrlichiosis and anaplasmosis – Clinical manifestations of ehrlichiosis and anaplasmosis include fever, chills, malaise, myalgia, and headache; laboratory manifestations include leukopenia, thrombocytopenia, and elevated serum aminotransferase levels. The diagnosis is established via indirect fluorescent antibody test. (See "Human ehrlichiosis and anaplasmosis".)

●Heartland virus disease – Heartland virus, or Heartland bandavirus, is a likely tickborne virus associated with nonspecific symptoms and signs (fever, anorexia, headache, confusion, nausea, and myalgias and/or arthralgias); it has been observed primarily in the midwestern and southeastern United States. The diagnosis may be established via serologic studies and/or real-time RT-PCR. (See "Emerging viruses", section on 'Heartland virus disease'.)

●Hemophagocytic lymphohistiocytosis (HLH) – HLH is syndrome of excessive immune activation; it is often associated with viral infections, including SFTS. Common findings include fever, hepatosplenomegaly, rash, lymphadenopathy, neurologic symptoms, cytopenias, high serum ferritin, and liver function abnormalities. The diagnosis is established by diagnostic criteria as summarized separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

●Langya henipavirus (LayV) infection – Langya henipavirus is a novel zoonotic virus identified in febrile patients in China. Common symptoms and laboratory abnormalities include fever, fatigue, cough, anorexia, myalgia, leukopenia, and thrombocytopenia. Six of the 35 patients with LayV infection also had SFTSV infection [110].

TREATMENT — There is no antiviral therapy available for treatment of SFTS; management consists of supportive care. Early recognition of severe disease and complication is important.

Use of ribavirin for treatment of patients with SFTS has been described, but there is no convincing evidence for a therapeutic effect [92,111]. Favipiravir, a pyrazine derivative, has stronger antiviral activity than that of ribavirin in vitro and in a mouse model [112,113]. A study of favipiravir in 23 SFTS patients in Japan found lower mortality rates compared to other case series of SFTS patients in Japan, but adverse events, including elevated hepatic enzymes, were more frequent [114]. In an investigator-initiated, single-blind, randomized controlled trial in China, fatal outcomes occurred in 9.5 percent (7 of 74) of favipiravir-treated patients and 18.3 percent (13 of 71) of controls (OR, 0.466; 95% CI, 0.17–1.25). The dosage of favipiravir in the trial was lower than that used for treating Ebola virus disease, and severe adverse events were not observed [115]. Some data suggest that favipiravir may more beneficial for patients ≤70 years of age compared with patients over 70 [116]. Although preliminary data with favipiravir are promising, more data from carefully controlled trials are necessary.

In areas where anaplasmosis and scrub typhus are endemic, empiric treatment with doxycycline for these infections may be reasonable until diagnostic test results are available. Coinfection of SFTS and scrub typhus or Rickettsia japonica may occur [33,117-119]. (See 'Differential diagnosis' above.)

Bleeding complications should be managed via transfusion of fresh frozen plasma or fresh whole blood, guided by international normalized ratio/prothrombin time [120]. Some reports suggest that plasma exchange may be beneficial [121-123]; controlled clinical trials are needed. Based on limited data, steroid treatment does not appear to improve prognosis and may increase complications, including secondary infections like invasive aspergillosis [124-126].

Early diagnosis and treatment of invasive pulmonary aspergillosis are important [90,127,128]. (See "Diagnosis of invasive aspergillosis" and "Treatment and prevention of invasive aspergillosis".)

PREVENTION — There is no vaccine available for prevention of SFTS. Individuals in areas with risk for transmission should take measures to avoid tick bites. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

Standard precautions should be implemented while taking care of patients with suspected SFTS. Patient rooms should be disinfected after discharge [129]. (See "Infection prevention: Precautions for preventing transmission of infection".)

In endemic areas, direct contact with bodily fluids of cats, particularly those that are sick, should be avoided [51,52].

SUMMARY AND RECOMMENDATIONS

●Overview – Severe fever with thrombocytopenia syndrome (SFTS), also known as fever, thrombocytopenia, and leukopenia syndrome, is an emerging tickborne infection. The causative agent is a bunyavirus, commonly designated SFTS virus (SFTSV). (See 'Introduction' above.)

●Epidemiology (see 'Epidemiology' above)

•Human cases – Since 2009, human cases of SFTS have been reported in China, Japan, South Korea, and other countries in eastern Asia. (See 'Cases in China' above and 'Cases in countries other than China' above.)

•Transmission to humans – The primary mode of spread of SFTSV to humans is via a bite from the Asian longhorned tick, Haemaphysalis longicornis. Possible direct transmission from infected cats and dogs to humans has been reported, as has human-to-human spread via close contact to blood and body secretions. (See 'Transmission of SFTSV to humans' above.)

•Tick vector – The H. longicornis tick is found throughout southeast Asia and the islands of the western Pacific, as well as in the United States. SFTSV has been detected in H. longicornis ticks throughout eastern Asia. As of 2021, the virus has not been detected in ticks in the United States. (See 'Geographic distribution and lifecycle of H. longicornis ticks' above and 'SFTSV in ticks and animals' above.)

●Clinical manifestations (see 'Clinical manifestations' above)

•Clinical presentation – Following an incubation period of 7 to 14 days, patients develop fever, headache, myalgia, and arthralgia, sometimes accompanied by vomiting and diarrhea. During the second week of illness, some individuals develop mucosal hemorrhage, hemorrhagic rash, altered mental status with or without meningoencephalitis, and multiorgan failure.

•Laboratory findings – Laboratory findings include leukopenia and thrombocytopenia. Some cases have elevated liver enzymes, lactate dehydrogenase, and creatine kinase, as well as disseminated intravascular coagulopathy.

•Complications – Invasive pulmonary aspergillosis has been observed in 20 to 32 percent of hospitalized patients with SFTS. Secondary hemophagocytic lymphohistiocytosis (HLH) has also been reported.

●Diagnosis – SFTSV infection should be suspected in patients with fever, thrombocytopenia, and leukopenia together with a history of tick exposure in an endemic area. Laboratory diagnosis is based on serum polymerase chain reaction (PCR; during the first week of illness) or antibody detection (during the second or third week of illness). (See 'Diagnosis' above.)

●Treatment and prevention – Treatment consists of supportive care. There is no antiviral therapy available for treatment of SFTSV, and no vaccine is available for prevention of SFTSV. (See 'Treatment' above.)

●Mortality – Case-fatality rates range from 6 to 21 percent. (See 'Clinical manifestations' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Hideki Ebihara, PhD, and Heinz Feldmann, MD, who contributed to an earlier version of this topic review.