Severe Fever With Thrombocytopenia Syndrome Research Articles

A new emerging pandemic of severe fever with thrombocytopenia syndrome (SFTS).

The aim of this study is to make aware every one of the deadliest diseases named severe fever with thrombocytopenia syndrome (SFTS). It has become the worldwide pandemic in recent few years. It is a kind of haemorrhagic fever, caused by SFTS virus (SFTSV), a novel phlebovirus of family Bunyaviridae. This syndrome is also a tick-borne zoonosis that means the virus transmitted from tick bite (having virus) into human body, i.e. infection spread from animals to humans and also transmitted from human to human. Epidemiological data of SFTS was collected to know the nature/symptoms of SFTSV. First case of this disease has been reported in China, followed by Japan, South korea, Taiwan, USA and many other countries. Vertebrates are the host of this disease and tick functions as a vector, where the virus can undergo brisk changes using gene mutation, homologous recombination and reassortments. The major symptoms of hemorrhagic fever are fever, thrombocytopenia, leucopenia and gastrointestinal abnormalities. Sometimes in very severe cases, full body organ failure may also take place and average death rate in humans is nearly 10 %. Old aged peoples are more prone to SFTSV infection. Apart from the fact of increasing SFTSV related health problems to humans, the pathogenesis of SFTS virus in human is not entirely understood and no treatment to this virus is still available. The simplest way to protect our self from this infection is to refrain from tick bite. Therefore, this disease has evolved to produce serious health issues to humans in various countries of world including china. This review discussing about causative agent, epidemiology, pathogenesis, diagnosis and treatment of SFTS. In order to control the spread of SFTSV, we have to stop the viral transmission or to protect the easily vulnerable population from tick bites, avoiding direct contact of infectious and also to use personal protective devices for SFTS patients. So, the weather conditions, mode of transmission and creation of new therapeutics like vaccines and drugs are the main areas of forthcoming research.

Corticosteroids May Have Negative Effects on the Management of Patients with Severe Fever with Thrombocytopenia Syndrome: A Case-Control Study.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever in China, Korea, and Japan. To date, no standardized treatment protocol for SFTS has been established. Corticosteroids (CS) may be administered to patients with SFTS and hemophagocytic syndrome, but its effectiveness and safety are still debatable. We conducted a retrospective case series review at four medical facilities in Miyazaki, Japan. Based on the medical records, clinical data, including the patients background, symptoms, physical findings, laboratory data at initial presentation, treatment, and outcome, were compared between the CS-treated and the non-CS-treated group. A total of 47 patients with confirmed SFTS in each hospital were enrolled in this study; there were 14 fatal cases and 33 nonfatal cases. The case fatality ratio was 29.8%. After adjusting patients’ background by propensity score matching, the case fatality ratio was higher (p = 0.04) and complications of secondary infections, including invasive pulmonary aspergillosis, tended to be more frequent (p = 0.07) in the CS-treated group than in the non-CS-treated group. These data suggested that administration of CS to patients with SFTS should be carefully considered.

A rabies virus vectored severe fever with thrombocytopenia syndrome (SFTS) bivalent candidate vaccine confers protective immune responses in mice

The Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic zoonotic disease, which is potentially fatal in human with mortality rates ranging from 16.2%–32%. The rabies virus (RABV) LBNSE vector expressing foreign antigens have shown considerable promise as vaccines against viral diseases, which is effective and safe. In the present study, we generated a recombinant RABV rLBNSE-Gn expressing a SFTSV glycoprotein Gn by reverse genetic technology to control rabies and SFTS in animals. An extra insertion of Gn gene did not impact replication of the recombinant virus rLBNSE-Gn in NA and BHK-21 cells compared to the parent rLBNSE strain. The SFTSV Gn gene together with RABV N and G genes were efficiently expressed in rLBNSE-infected Vero cells by immunostaining and immune blots. A single dose of 107 FFU of the rLBNSE-Gn intramuscularly inoculated in BALB/c mice induced rapid and robust humoral responses against both RABV and SFTSV without any signs of disease or weight loss. Compared to the rLBNSE and DMEM groups, the extra Gn expression contributed to the recruitments and/or activations of the dendritic cells and B cells from inguinal lymph nodes of BALB/c mice vaccinated with rLBNSE-Gn. The protective efficacy of rLBNSE-Gn against SFTSV in C57BL/6 mice was evaluated, and the virus loading in the spleens reduced to 10 TCID50/mg at 7 days post SFTSV infections, which indicated that the rLBNSE-Gn conferred efficacious protective immune responses from SFTSV in C57BL/6 mice. All the mice immunization with rLBNSE-Gn and rLBNSE survived after a lethal RABV challenge, suggesting a 100 % protection from RABV. Therefore, the rLBNSE-Gn would be a promising bivalent candidate vaccine against SFTS and rabies in animals.

Clinical effect and antiviral mechanism of T-705 in treating severe fever with thrombocytopenia syndrome

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus with high fatality and an expanding endemic. Currently, effective anti-SFTSV intervention remains unavailable. Favipiravir (T-705) was recently reported to show in vitro and in animal model antiviral efficacy against SFTSV. Here, we conducted a single-blind, randomized controlled trial to assess the efficacy and safety of T-705 in treating SFTS (Chinese Clinical Trial Registry website, number ChiCTR1900023350). From May to August 2018, laboratory-confirmed SFTS patients were recruited from a designated hospital and randomly assigned to receive oral T-705 in combination with supportive care or supportive care only. Fatal outcome occurred in 9.5% (7/74) of T-705 treated patients and 18.3% (13/71) of controls (odds ratio, 0.466, 95% CI, 0.174–1.247). Cox regression showed a significant reduction in case fatality rate (CFR) with an adjusted hazard ratio of 0.366 (95% CI, 0.142–0.944). Among the low-viral load subgroup (RT-PCR cycle threshold ≥26), T-705 treatment significantly reduced CFR from 11.5 to 1.6% (P = 0.029), while no between-arm difference was observed in the high-viral load subgroup (RT-PCR cycle threshold <26). The T-705-treated group showed shorter viral clearance, lower incidence of hemorrhagic signs, and faster recovery of laboratory abnormities compared with the controls. The in vitro and animal experiments demonstrated that the antiviral efficacies of T-705 were proportionally induced by SFTSV mutation rates, particularly from two transition mutation types. The mutation analyses on T-705-treated serum samples disclosed a partially consistent mutagenesis pattern as those of the in vitro or animal experiments in reducing the SFTSV viral loads, further supporting the anti-SFTSV effect of T-705, especially for the low-viral loads.

Development of an RT-LAMP Assay for the Rapid Detection of SFTS Virus.

Detection of severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) during the early phase of the disease is important for appropriate treatment, infection control, and prevention of further transmission. The reverse transcription loop-mediated isothermal amplification (RT-LAMP) is a nucleic acid amplification method that amplifies the target sequence under isothermal conditions. Here, we developed an RT-LAMP with a novel primer/probe set targeting a conserved region of the SFTSV L segment after extraction of viral RNA (standard RT-LAMP). Both the Chinese and Japanese SFTSV strains, including various genotypes, were detected by the standard RT-LAMP. We also performed RT-LAMP using the same primer/probe set but without the viral RNA extraction step (called simplified RT-LAMP) and evaluated the diagnostic efficacy. The sensitivity and specificity of the simplified RT-LAMP were 84.9% (45/53) and 89.5% (2/19), respectively. The simplified RT-LAMP can detect SFTSV in human sera containing >103.5 copies/mL viral RNA. The two RT-LAMP positive but quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) negative samples were positive in the conventional RT-PCR, suggesting that there was no false positive reaction in the RT-LAMP. Both the standard and simplified RT-LAMP are useful for detecting the SFTSV genome in patients during the early phase of the disease.

Comorbidity and Its Impact on the Fatal Outcome of Patients With Severe Fever With Thrombocytopenia Syndrome

Background: Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne disease with high mortality. However, a disaggregated data has been lacking to explore the effect of demography on the mortality. Methods: A retrospective cohort study was performed among 2,938 SFTS patients entered during 2011-2020 in Xinyang, China. The case fatality rate (CFR) was estimated for their association with comorbidities stratified by age and sex. The immune response was explored for the age and sex differences. Findings: The associations between comorbidities and SFTS fatal outcome were age- and sex-dependent. The effect of comorbidity on death was reduced with age, until to non-significant effects among patients >70 years old. Sex-stratified analysis disclosed significant associations between death and comorbidities for females (OR: 1·87, 95% CI: 1·40-2·49, p <0·001), while no effect in males. Older males had significantly decreased levels of B-cell, CD4-cell, anti-SFTSV IgM antibody and selected cytokines/chemokines than younger males, while no age differences in females. Among all comorbidities, chronic viral hepatitis displayed the greatest effect on SFTS mortality both alone and combined with other comorbidities. Ganulocytic myeloid-derived suppressor cells were expanded to a higher level in HBV-SFTS patients. Interpretation: Males are more likely to be affected by aging for SFTS mortality, relating to inequities of comorbidities for their risk of death from both age and sex. It is essential to take a sex- and age-based approach to SFTS treatment and management. Funding Information: National Natural Science Foundation of China and China Mega-project for Infectious Diseases. Declaration of Interests: The authors have declared that no conflict of interests exist. Ethics Approval Statement: The study was conducted in accordance with guidelines approved by the Ethics Committees from the 154 hospital of the Chinese people’s liberation Army. All participants provided written or verbal informed consent. All the data were analyzed anonymously.

Vaccine Development for Severe Fever with Thrombocytopenia Syndrome.

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), is a tick-borne emerging zoonosis with a high case-fatality rate. At present, there is no approved SFTS vaccine, although the development of a vaccine would be one of the best strategies for preventing SFTS. This article focused on studies aimed at establishing small animal models of SFTS that are indispensable for evaluating vaccine candidates, developing these vaccine candidates, and establishing more practical animal models for evaluation. Innate immune-deficient mouse models, a hamster model, an immunocompetent ferret model and a cat model have been developed for SFTS. Several vaccine candidates for SFTS have been developed, and their efficacy has been confirmed using these animal models. The candidates consist of live-attenuated virus-based, viral vector-based, or DNA-based vaccines. SFTS vaccines are expected to be used for humans and companion dogs and cats. Hence for practical use, the vaccine candidates should be evaluated for efficacy using not only nonhuman primates but also dogs and cats. There is no practical nonhuman primate model of SFTS; however, the cat model is available to evaluate the efficacy of these candidate SFTS vaccines on domesticated animals.

Histopathological Characterization of Cases of Spontaneous Fatal Feline Severe Fever with Thrombocytopenia Syndrome, Japan.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease caused by SFTS virus (SFTSV). We report 7 cases of spontaneous fatal SFTS in felines. Necropsies revealed characteristic lesions, including necrotizing lymphadenitis in 5 cases and necrotizing splenitis and SFTSV-positive blastic lymphocytes in all cases. We detected hemorrhagic lesions in the gastrointestinal tract in 6 cases and lungs in 3 cases, suggesting a more severe clinical course of SFTS in felids than in humans. We noted necrotic or ulcerative foci in the gastrointestinal tract in 3 cases, the lung in 2 cases, and the liver in 4 cases. We clarified that blastic lymphocytes are predominant targets of SFTSV and involved in induction of necrotic foci. We also found that thymic epithelial cells were additional targets of SFTSV. These results provide insights for diagnosing feline SFTS during pathological examination and demonstrate the similarity of feline and human SFTS cases.

Neutralizing Antibodies to Severe Fever With Thrombocytopenia Syndrome Virus Among Survivors, Non-Survivors and Healthy Residents in South Korea.

Severe fever with thrombocytopenia syndrome (SFTS), a newly emerging tick-borne viral disease, has been detected in Asia since 2009, and person-to-person transmission is possible. SFTS is characterized by atypical signs, including mild to severe febrile illness similar to that associated with hemorrhagic fever, with 16.2 to 30% mortality. We found that the titers of neutralizing antibodies, play an important role in protective immunity, to SFTS virus (SFTSV) in survivors and healthy residents who lived in endemic areas and who were positive for SFTSV IgG, were higher than those in non-survivor patients. Moreover, the titers were maintained in surviving patients and healthy residents but not in non-surviving patients in South Korea.

Epidemiological Characteristics of Severe Fever with Thrombocytopenia Syndrome from 2010 to 2019 in Mainland China.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease and that is a severe threat to public health considering its high fatality and person-to-person transmission. In order to obtain an updated and deep understanding of the epidemiological characteristics of SFTS in mainland China, we used Pearson’s chi-squared test to compare the fatality rate and demographic characteristics in different groups. Data were analyzed in R3.6.1 (R Development Core Team 2018), while the visualization was performed in ArcGIS 10 (ESRI, Redlands, CA, USA), and the statistical significance was set at p < 0.05. A total of 13,824 SFTS cases involving 8899 lab-confirmed cases and 4925 probable cases were reported and included in the epidemiological analysis. Our study found that the number of SFTS cases showed an increasing trend with a small decrease in the past three years. The laboratory-confirmed rate was about 64.4%, which varied between different years and areas. Although most cases (99.3%) were distributed in 7 provinces (Henan, Shandong, Anhui, Hubei, Liaoning, Zhejiang, and Jiangsu), the regional distribution of SFTS gradually expanded from 5 provinces in 2010 to 25 provinces by 2019, especially at the town level. The SFTS cases were mainly sporadic. A total of 96.5% occurred from April to October, and 93.3% of cases were concentrated in middle-aged and elderly people (40–84 years old). Farmers were the main high-risk population. Female cases were slightly more than male cases; however, there were differences between different provinces. The mortality rate showed an increasing trend with age. Overall, the SFTS cases were mainly middle-aged and elderly farmers that sporadically distributed throughout seven provinces with a spatially expanding trend. The laboratory-confirmed rate varied in different years and provinces, which implied that the diagnosis and report criteria for SFTS should be further updated and unified in order to get a better understanding of its epidemiological characteristics and provide scientific data for SFTS control.

Survey on tick distribution and tick-borne pathogens in Daejeon and adjacent areas in South Korea

Ticks (Ixodidae, also known as hard ticks) as principal vectors of zoonotic diseases such as severe fever with thrombocytopenia syndrome (SFTS), Lyme borreliosis, relapsing fever, anaplasmosis, ehrlichiosis, babesiosis, coxiellosis (Q fever), and tularemia pose a major public health threat. This study was conducted to identify the distribution profile of ticks and tick-borne pathogens in Daejeon and the adjacent areas in South Korea, where no such epidemiological study has been conducted. From April to October 2019, 16,765 ticks were collected from three genera and four species: Haemaphysalis longicornis (n = 14,949; 89.2 %), Haemaphysalis flava (n = 987; 5.9 %), Ixodes nipponensis (n = 828; 5.0 %), and Amblyomma testudinarium (n = 1; 0.01 %). Homogenized samples of ticks were screened by real-time reverse transcription polymerase chain reaction (PCR), real-time PCR, and PCR for the presence of the following tick-borne pathogens: SFTS virus (SFTSV), Borrelia spp., Babesia microti, Coxiella burnetii, Francisella tularensis, Anaplasma phagocytophilum, and Ehrlichia spp. As a result, SFTSV (2 cases), Borrelia spp. (32 cases), and Babesia microti (7 cases) were detected. The findings of this study will contribute to the prevention and management of tick-borne zoonoses.

Changes in peripheral blood cytokines in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is recognized as an emerging infectious disease. This study aimed to investigate the pathogenic mechanism of SFTS. A total of 100 subjects were randomly included in the study. Cytokine levels were detected by enzyme‐linked immunosorbent assay and the viral load was detected by micro drop digital PCR. The results showed that levels of interleukin‐6 (IL‐6), IL‐8, IL‐10, IFN‐inducible protein‐10 (IP‐10), monocyte chemoattractant protein‐1 (MCP‐1), macrophage inflammatory protein‐1α (MIP‐1α), transforming growth factor‐β1 (TGF‐β1), and regulated upon activation normal T cell expressed and secreted factor (RANTES) differed significantly among the SFTS patient group, healthy people group, and asymptomatic infection group (p < .05). Compared to the healthy people group, the patient group had increased cytokine levels (IL‐6, IL‐10, IP‐10, MCP‐1, and IFN‐γ) but reduced levels of IL‐8, TGF‐β1, and RANTES (p < .0167). IL‐6, IL‐8, IL‐10, IP‐10, MCP‐1, MIP‐1α, TGF‐β1, and the RANTES levels had different trends after the onset of the disease. IL‐6, IL‐10, IP‐10, and MCP‐1 levels in severe patients were higher than those in mild patients (p < .05). There was a positive correlation between viral load and IL‐6 and IP‐10 but a negative correlation between viral load and RANTES. SFTSV could cause a cytokine change: the cytokine levels of patients had different degrees of fluctuation after the onset of the disease. The levels of IL‐6 and IL‐8 in the asymptomatic infection group were found between the SFTS patients group and the healthy people group. The levels of IL‐6, IL‐10, IP‐10, and MCP‐1 in the serum could reflect the severity of the disease, and the levels of IL‐6, IP‐10, and RANTES were correlated with the viral load.

The Nonstructural Protein NSs of Severe Fever with Thrombocytopenia Syndrome Virus Causes a Cytokine Storm through the Hyperactivation of NF-κB.

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging highly pathogenic phlebovirus. The syndrome is characterized by the substantial production of inflammatory cytokines and chemokines, described as a cytokine storm, which correlates with multiorgan failure and high mortality. SFSTV nonstructural (NSs) protein was suggested to mediate the pathogenesis by inhibiting antiviral interferon signaling in the host. However, whether SFTSV NSs protein mediates the induction of a fatal cytokine storm remains unaddressed. We demonstrated that SFTSV NSs promotes the hyperinduction of cytokine/chemokine genes in vitro, reminiscent of a cytokine storm. Using gene deletion and pharmacological intervention, we found that the induced cytokine storm is driven by the transcription factor NF-κB. Our investigation revealed that TANK-binding kinase 1 (TBK1) suppresses NF-κB signaling and cytokine/chemokine induction in a kinase activity-dependent manner and that NSs sequesters TBK1 to prevent it from suppressing NF-κB, thereby promoting the activation of NF-κB and its target cytokine/chemokine genes. Of note, NF-κB inhibition suppressed the induction of proinflammatory cytokines in SFTSV-infected type I interferon (IFN-I) receptor 1-deficient (Ifnar1-/-) mice. These findings establish the essential role of NSs in SFTS pathogenesis and suggest NF-κB as a possible therapeutic target.

Invasive pulmonary aspergillosis is a frequent complication in patients with severe fever with thrombocytopenia syndrome: A retrospective study

ObjectivesInvasive pulmonary aspergillosis (IPA) usually occurs in immunocompromised hosts. It has recently been reported that patients with severe fever with thrombocytopenia syndrome (SFTS) can also develop IPA. The aim of this study was to determine the incidence of IPA in SFTS patients and to investigate the relevant clinical, imaging, and laboratory characteristics. MethodsA retrospective review was conducted of all patients with SFTS admitted to Nanjing Drum Tower Hospital, a tertiary hospital in Nanjing City, China, between January 2016 and December 2019. The patients were divided into two groups according to whether they had IPA: the IPA group and the non-IPA group. Data on clinical manifestations, laboratory findings, imaging characteristics, treatments, and outcomes were collected and analysed. ResultsA total of 91 SFTS patients were included, of whom 29 (31.9%) developed IPA. In-hospital mortality (22.0%) was higher in the IPA group than in the non-IPA group. Univariate logistic regression showed that diabetes, cough, wheezing, amylase level, vasopressor use, encephalopathy, and intensive care unit transfer were risk factors for the development of IPA. Multivariate logistic regression analysis identified wheezing as an independent predictor of IPA in SFTS patients. ConclusionsSFTS combined with IPA is associated with high morbidity and mortality. It is necessary to strengthen screening for fungal infections after admission in SFTS patients. However, whether early antifungal prophylaxis should be administered needs further investigation.

A multicenter non-randomized, uncontrolled single arm trial for evaluation of the efficacy and the safety of the treatment with favipiravir for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a bunyavirus infection with high mortality. Favipiravir has shown effectiveness in preventing and treating SFTS virus (SFTSV) infection in animal models. A multicenter non-randomized, uncontrolled single arm trial was conducted to collect data on the safety and the effectiveness of favipiravir in treatment of SFTS patients. All participants received favipiravir orally (first-day loading dose of 1800 mg twice a day followed by 800 mg twice a day for 7–14 days in total). SFTSV RT-PCR and biochemistry tests were performed at designated time points. Outcomes were 28-day mortality, clinical improvement, viral load evolution, and adverse events (AEs). Twenty-six patients were enrolled, of whom 23 were analyzed. Four of these 23 patients died of multi-organ failure within one week (28-day mortality rate: 17.3%). Oral favipiravir was well tolerated in the surviving patients. AEs (abnormal hepatic function and insomnia) occurred in about 20% of the patients. Clinical symptoms improved in all patients who survived from a median of day 2 to day10. SFTSV RNA levels in the patients who died were significantly higher than those in the survivors (p = 0.0029). No viral genomes were detectable in the surviving patients a median of 8 days after favipiravir administration. The 28-day mortality rate in this study was lower than those of the previous studies in Japan. The high frequency of hepatic dysfunction as an AE was observed. However, it was unclear whether this was merely a side effect of favipiravir, because liver disorders are commonly seen in SFTS patients. The results of this trial support the effectiveness of favipiravir for patients with SFTS.

Clinical Progress and Risk Factors for Death from Severe Fever with Thrombocytopenia Syndrome: A Multihospital Retrospective Investigation in Anhui, China

Knowledge of the clinical progress of severe fever with thrombocytopenia syndrome (SFTS) and the associated predictors of mortality is important for providing appropriate treatment in severe cases. A multihospital retrospective study was conducted in three SFTS-endemic cities, in 2018. Of the 208 SFTS-confirmed cases, there were 189 survivors and 19 deaths. The median age was 64 years; 104 (50.0%) patients were men, and 188 (90.4%) were farmers. Furthermore, 203 (97.6%) patients reported fever and 70 (33.7%) reported fatigue. Most fatal cases had complications including multiple-organ failure, central nervous syndrome (CNS) abnormalities, and disseminated intravascular coagulation. During the fever phase, alanine transaminase, aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, D-dimer, glucose, hydroxybutyrate dehydrogenase, lactate dehydrogenase (LDH), procalcitonin, prothrombin time, and uric acid levels were higher in fatal than in nonfatal cases (P < 0.05). Creatine kinase (CK), CK-MB (CKMB), AST, and LDH levels were significantly lower in nonfatal than in fatal cases (P < 0.05). Central nervous syndrome abnormalities (odds ratio [OR] = 20.9, 95% CI: 4.3, 100), body temperature ≥ 38.5°C (OR = 23.2, 95% CI: 3.4, 158), BUN levels ≥ 6.4 mmol/L (OR = 9.9, 95% CI: 2.2, 44), CKMB levels ≥ 100 U/L (OR = 33.2, 95% CI: 5.8, 192), and LDH levels ≥ 1,000 U/L (OR = 8.3, 95% CI: 1.9, 37) were predictors of mortality. Our findings reveal that the presence of specific complications and laboratory parameters may serve as predictors of mortality and aid in early identification of severe SFTS cases in clinical practice.

Isolation of Severe Fever with Thrombocytopenia Syndrome Virus from Various Tick Species in Area with Human Severe Fever with Thrombocytopenia Syndrome Cases.

Severe fever with thrombocytopenia syndrome (SFTS), caused by Dabie bandavirus, generally called SFTS virus (SFTSV), is an emerging zoonosis in East Asia. In Japan, 50-100 cases of SFTS have been reported each year since the first case was reported in 2013. SFTS is a tick-borne infectious disease, and SFTSV has been isolated from ticks in China and South Korea. Haemaphysalis longicornis and Amblyomma testudinarium are considered the primary vectors in Japan. However, the other tick species seldom feeding on humans might also play an important role in maintaining the virus in nature. In this study, we collected ticks on vegetation around the location where two SFTS patients were estimated to have been infected in Miyazaki Prefecture, Japan, isolated live SFTSV, and performed a phylogenetic analysis. A total of 257 ticks were collected, and SFTSV RNA was detected in 19.5% (9/46) of tick pools. A total of 10 infectious SFTSVs were successfully isolated from A. testudinarium, Haemaphysalis flava, Haemaphysalis formosensis, Haemaphysalis hystricis, and Haemaphysalis megaspinosa. Furthermore, the whole viral sequences isolated from ticks were highly homologous to sequences isolated from SFTS patients in the same sampling area in the past. These results suggest that SFTSVs are maintained in these tick species in the sampling area and sporadically transmitted to humans. Surveillance of SFTSV in ticks provides important information about the risk of incidental transmission to humans.

A highly attenuated vaccinia virus strain LC16m8-based vaccine for severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) caused by a species Dabie bandavirus (formerly SFTS virus [SFTSV]) is an emerging hemorrhagic infectious disease with a high case-fatality rate. One of the best strategies for preventing SFTS is to develop a vaccine, which is expected to induce both humoral and cellular immunity. We applied a highly attenuated but still immunogenic vaccinia virus strain LC16m8 (m8) as a recombinant vaccine for SFTS. Recombinant m8s expressing SFTSV nucleoprotein (m8-N), envelope glycoprotein precursor (m8-GPC), and both N and GPC (m8-N+GPC) in the infected cells were generated. Both m8-GPC- and m8-N+GPC-infected cells were confirmed to produce SFTSV-like-particles (VLP) in vitro, and the N was incorporated in the VLP produced by the infection of cells with m8-N+GPC. Specific antibodies to SFTSV were induced in mice inoculated with each of the recombinant m8s, and the mice were fully protected from lethal challenge with SFTSV at both 103 TCID50 and 105 TCID50. In mice that had been immunized with vaccinia virus strain Lister in advance of m8-based SFTSV vaccine inoculation, protective immunity against the SFTSV challenge was also conferred. The pathological analysis revealed that mice immunized with m8-GPC or m8-N+GPC did not show any histopathological changes without any viral antigen-positive cells, whereas the control mice showed focal necrosis with inflammatory infiltration with SFTSV antigen-positive cells in tissues after SFTSV challenge. The passive serum transfer experiments revealed that sera collected from mice inoculated with m8-GPC or m8-N+GPC but not with m8-N conferred protective immunity against lethal SFTSV challenge in naïve mice. On the other hand, the depletion of CD8-positive cells in vivo did not abrogate the protective immunity conferred by m8-based SFTSV vaccines. Based on these results, the recombinant m8-GPC and m8-N+GPC were considered promising vaccine candidates for SFTS.

The predictive effect of the platelet-to-lymphocyte ratio (PLR) and the neutrophil-to-lymphocyte ratio (NLR) on the risk of death in patients with severe fever with thrombocytopenia syndrome (SFTS): a multi-center study in China.

BackgroundSevere fever with thrombocytopenia syndrome is caused by infection with the severe fever with thrombocytopenia syndrome virus.MethodsBetween April 2011 and December 2019, data on consecutive patients who were diagnosed with severe fever with thrombocytopenia syndrome were prospectively collected from five medical centers in China. The score of the death risk model was correlated with the platelet-to-lymphocyte ratio and the neutrophil-to-lymphocyte ratio. Multivariable Cox analyses were used to identify the independent factors associated with mortality.ResultsDuring the study period, 763 patients were diagnosed with severe fever with thrombocytopenia syndrome; 415 of these patients were enrolled in our study. We found that the neutrophil-to-lymphocyte ratio of the group that died was significantly higher on admission (P=0.007) than that of the group that survived, and the neutrophil-to-lymphocyte ratio showed a positive correlation with the score of the death risk model. Multivariate Cox regression suggested that a neutrophil-to-lymphocyte ratio greater than 5.4 was an independent risk factor for survival time (HR=6.767, P=0.011). Platelet-to-lymphocyte ratio did not show a special role in this study.ConclusionsA neutrophil-to-lymphocyte ratio greater than 5.4 can increase the risk of death and decrease the survival time of patients. In summary, the neutrophil-to-lymphocyte ratio provides a supplementary means for effectively managing severe fever with thrombocytopenia syndrome (SFTS).

Two Different Strains of Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) in North and South Osaka by Phylogenetic Analysis of Evolutionary Lineage: Evidence for Independent SFTSV Transmission

Severe fever with thrombocytopenia syndrome (SFTS) is a novel tick-borne infectious disease, therefore, the information on the whole genome of the SFTS virus (SFTSV) is still limited. This study demonstrates a nearly whole genome of the SFTSV identified in Osaka in 2017 and 2018 by next-generation sequencing (NGS). The evolutionary lineage of two genotypes, C5 and J1, was identified in Osaka. The first case in Osaka belongs to suspect reassortment (L:C5, M:C5, S:C4), the other is genotype J1 (L: J1, M: J1, S: J1) according to the classification by a Japanese group. C5 was identified in China, indicating that C5 identified in this study may be transmitted by birds between China and Japan. This study revealed that different SFTSV genotypes were distributed in two local areas, suggesting the separate or focal transmission patterns in Osaka.