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Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus infection with a high lethality rate. The purpose of this study was to investigate the changes in coagulation parameters in patients with SFTS, aiming to provide clinical evidence for early diagnosis, treatment, and disease analysis. Methods: A total of 40 patients with SFTS attended from April 1, 2020 to May 21, 2022 in Nanjing Drum Tower Hospital were selected and grouped according to the duration of the disease, mild and severe disease, cure and death, with 50 healthy physical examiners as controls, and the risk of severe and death disease was predicted using ROC curves. Results: Comparison between the healthy, mild and severe groups revealed that PT, INR, APTT, TT, D-D and vWF levels were higher than those in the healthy control group, and FII, FIX, FX, FXI, FXII, PC and PS levels were lower than those in the healthy control group, the differences were statistically significant (p < 0.05). Comparing the results of SFTS patients with different course times, the results of Fib, FV, FVII, FVIII, FIX, FX, FXI were statistically significant (p < 0.05). Among the survived and deceased patients, the PT, INR, DD and PS results of the deceased patients were higher than those of the survived patients, and the FVIII, FIX, FXI, FXII and PC were lower than those of the survived patients. The area under the ROC curve showed that D-D had higher predictive ability for the risk of severe disease (AUROC 0.93, sensitivity and specificity at a Cut-off value of 1.50 mg/L were 90.0 and 86.5%, respectively) and the risk of death occurring (AUROC 0.84, sensitivity and specificity at a Cut-off value of 3.39 mg/L were 87.5 and 80.0%, respectively). Discussion: The monitoring of the coagulation parameters in patients with SFTS is great significance for identifying the severity and death of the patient's condition, and it is of great clinical value to provide early attention, timely intervention and maximum reduction of the mortality rate for patients at risk of severe disease. [ABSTRACT FROM AUTHOR]

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is a fatal viral disease characterized by high fever, thrombocytopenia, leukopenia, and multi-organ haemorrhage. Disruption of the humoral immune response and decreased lymphocyte numbers are thought to contribute to the disease severity. These findings have been obtained through the analysis of peripheral blood leukocytes in human patients, whereas analysis of lymph nodes has been limited. Thus, in this study, we characterized the germinal centre response and apoptosis in the lymph nodes of cats with fatal SFTS, because SFTS in cats well mimics the pathology of human SFTS.MethodsLymph node tissue sections collected during necropsy from seven fatal SFTS patients and five non-SFTS cases were used for histopathological analysis. Additionally, lymph node tissue sections collected from cats with experimental infection of SFTS virus (SFTSV) were also analysed.ResultsIn the lymphoid follicles of cats with SFTS, a drastic decrease in Bcl6- and Ki67-positive germinal centre B cells was observed. Together, the number of T cells in the follicles was also decreased in SFTS cases. In the paracortex, a marked increase in cleaved-caspase3 positivity was observed in T cells. These changes were independent of the number of local SFTS virus-positive cell. Furthermore, the analysis of cats with experimental SFTSV infection revealed that the intrafollicular Bcl6- and CD3-positive cell numbers in cats with low anti-SFTSV antibody production were significantly lower than those in cats with high anti-SFTSV antibody production.DiscussionThese results suggest that dysfunction of the humoral response in severe SFTS was caused by the loss of germinal centre formation and massive apoptosis of T cells in the lymph nodes due to systemically circulating viruses.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonosis caused by a novel bunyavirus. Until recently, the SFTS related acute kidney injury (AKI) was largely unexplored. This study aimed to investigate the clinical characteristics and outcomes of AKI in patients with SFTS. Methods: The non-AKI and AKI groups were compared in terms of general characteristics, clinical features, laboratory parameters and cumulative survival rate. The independent risk factors for in-hospital mortality in patients with SFTS were analyzed by multivariate logistic regression to identify the population with poor prognosis. Results: A total of 208 consecutive patients diagnosed with SFTS were enrolled, including 153 (73.6%) patients in the non-AKI group and 55 (26.4%) patients in the AKI group. Compared with patients without AKI, patients with AKI were older and had a higher frequency of diabetes. Among these laboratory parameters, platelet count, albumin and fibrinogen levels of patients with AKI were identified to be significantly lower than those of patients without AKI, while ALT, AST, ALP, triglyceride, LDH, BUN, uric acid, creatine, Cys-C, ß2-MG, potassium, AMY, lipase, CK-MB, TnI, BNP, APTT, thrombin time, D-dimer, CRP, IL-6, PCT and ESR levels were significantly higher in patients with AKI. A higher SFTS viral load was also detected in the AKI patients than in the non-AKI patients. The cumulative survival rates of patients at AKI stage 2 or 3 were significantly lower than those of patients without AKI or at AKI stage 1. However, there was no significant difference in the cumulative survival rates between patients without AKI and those with stage 1 AKI. Univariate and multivariate binary logistic regression analyses demonstrated that stage 2 or 3 AKI was an independent risk factor for in-hospital mortality in patients with SFTS. Conclusion: AKI is associated with poor outcomes in patients with SFTS, especially patients at AKI stage 2 or 3, who generally have high mortality. Our findings support the importance of early identification and timely treatment of AKI in patients with SFTS. [ABSTRACT FROM AUTHOR]

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by a novel bunyavirus, characterized by high fever, thrombocytopenia, and multiple organ damage. Disturbances in lipid metabolism often occur during viral infections, but the changes and clinical significance of lipid profiles in SFTS patients remain unclear. This study aimed to investigate the alterations in lipid profiles and their clinical significance in SFTS patients. Methods: A total of 157 SFTS patients and 157 healthy controls were enrolled in this study. Serum lipid levels were collected and analyzed among different groups and prognosis categories. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of lipid levels in distinguishing between severe and mild cases, as well as surviving and non-surviving patients. Pearson correlation analysis was used to examine the associations between lipid levels and clinical laboratory parameters. Results: SFTS patients exhibited significantly lower levels of HDL-c, LDL-c, cholesterol, APoAI, and ApoB compared to healthy controls, while triglyceride levels were significantly higher. Serum HDL-c and ApoAI demonstrated good performance as indicators for distinguishing between survivors and non-survivors (AUC of 0.87 and 0.85, respectively). Multivariate regression analysis indicated that HDL-c independently acts as a protective factor in patients with SFTS. HDL-c levels showed decline in non-survivors but recovered in survivors. Moreover, HDL-c exhibited significant correlations with various clinical laboratory parameters (IL-6, CRP, AST, TT, APTT, PLT, ALB, and CD4). Conclusion: This study identified abnormalities in serum lipid metabolism among SFTS patients. HDL-c and ApoAI levels hold potential as biomarkers for distinguishing survivors from non-survivors. Additionally, HDL-c and ApoAI may serve as therapeutic targets for the management of SFTS patients. [ABSTRACT FROM AUTHOR]

Background: Conducting an up-to-date analysis on the genomic diversity and evolution patterns of severe fever with thrombocytopenia syndrome virus (SFTSV) is crucial for elucidating the underlying mechanisms of its emergency and pathogenicity, as well as assessing the extent of its threat to public health. Methods: Complete genome sequences of SFTSV were obtained from GenBank until December 19, 2022. A thorough phylogenetic analysis was conducted using comprehensive bioinformatics methods to estimate the genomic diversity and evolution. Results: The phylogenetic classification of SFTSV strains yielded seven lineages (AG) for each genome segment. SFTSV displayed notable variations in evolutionary patterns among different regions and segments, without a linear accumulation of nucleotide substitutions within segments and regions. The comprehensive analysis revealed 54 recombination events and 17 reassortment strains, including the first discovery of recombination events involving sea-crossing and speciescrossing. Selection analysis identified three positive sites (2, 671, 1353) in RNAdependent RNA polymerase, three positive sites (22, 298, 404) in glycoprotein, and two positive sites (9, 289) in nonstructural protein. No positive selection sites were found in nucleoprotein. Conclusion: Our study unveiled the existence of multiple evolutionary forces influencing SFTSV, contributing to its increasing genetic diversity, which had the potential to modify its antigenicity and pathogenicity. Furthermore, our study highlights the importance of tracking the spread of SFTSV across regions and species. [ABSTRACT FROM AUTHOR]

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays amajor role in the pathogenesis of SFTS has not yet been investigated. Methods: TRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR-/- SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3OE THP-1 cells and peritoneal macrophages extracted from TRIM3-/- mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection usingWestern blot. Flowcytometry was used to verify TLR3 expression on peripheral bloodmonocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot. Results: Compared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR-/- SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1b, IL-6, and TNF-a, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination. Conclusion: TRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS. [ABSTRACT FROM AUTHOR]

Objectives: Invasive pulmonary aspergillosis (IPA) is common in immuno-compromised people, and a high incidence of IPA has been found in patients with severe fever with thrombocytopenia syndrome (SFTS). Our study aimed to determine the independent risk factors for IPA and the relationship between smoking status and the risk of IPA in SFTS patients. Methods: A retrospective analysis of SFTS patients in the First Affiliated Hospital of Nanjing Medical University from May 2011 to December 2021 was reviewed. The patients were divided into two groups: IPA and non-IPA groups. We compared demographic characteristics, clinical manifestation, laboratory parameters, treatment, and prognosis, and explored the risk factors of IPA using logistic regression and ROC curve. The dose-dependent effect of smoking on the risk of IPA was further estimated, including the age of smoking initiation, daily smoking amount, smoking duration, and pack-years of smoking. Results: In total, 189 individuals were included. Compared with the non-IPA group, the IPA group had higher levels of smoking, drinking, cough, dyspnea, aCCI scores, Dabie bandavirus (DBV) RNA load, ferritin, PCT, IL-6, APTT, LDH, BUN, creatinine, and lower levels of FT4 and TSH. The incidences ofMODS, admission to ICU, ventilation, and broad-spectrumantibiotic treatment were significantly higher in the IPA group than in the non-IPA group. Multivariable logistic analysis showed that smoking history, cough, creatinine, admission to ICU, broad-spectrum, and corticosteroid therapies were the independent risk factors for IPA in SFTS patients. We further confirmed that the age of smoking initiation<30 years, smoking at least one pack per day, smoking for at least 40 years, and having at least 40 pack-years of smoking exposure were the independent risk factors for IPA among smokers. Conclusion: The prognosis of SFTS patients in the IPA group is worse than that of the non-IPA group. Attention should be paid to SFTS patients with a smoking history, cough, creatinine, admission to ICU, and broad-spectrum and corticosteroid therapies. There is a strong dose-dependent association between smoking and IPA development in SFTS patients. Prophylactic antifungal therapy should be considered for SFTS patients with these risk factors, but further studies are necessary to determine if it is beneficial for the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. The pathophysiology of SFTS remains unclear. Hence, the identification of inflammatory biomarkers for SFTS is crucial for the timely management and prevention of disease severity. Methods: A total of 256 patients with SFTS were divided into a survivor group and a non-survivor group. Classical inflammatory biomarkers such as ferritin, procalcitonin (PCT), C-reactive protein (CRP), and white blood cells were investigated for their association with viral load and the clinical significance for predicting the mortality of patients with SFTS. Results: Serum ferritin and PCT showed a positive association with viral load. Ferritin and PCT levels in non-survivors were significantly higher than those in survivors at 7-9 days from symptom onset. The area under the receiver operating characteristic curve (AUC) values of ferritin and PCT for predicting the fatal outcome of SFTS were 0.9057 and 0.8058, respectively. However, the CRP levels and WBC counts exhibited a weak association with viral load. The AUC value of CRP for predicting mortality was more than 0.7 at 13-15 days from symptom onset. Discussion: Ferritin and PCT levels, especially ferritin, could be potential inflammatory biomarkers for predicting the prognosis of patients with SFTS in its early stages. [ABSTRACT FROM AUTHOR]

Objective: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality rate, especially SFTS combined with central neurological complications. The purpose of this study was to explore risk factors of central neurological complications in SFTS patients. Methods: In this retrospective study, SFTS patients admitted to the First Affiliated Hospital of Nanjing Medical University between January 2017 and December 2021 were enrolled. Based on the presence or absence of central neurological complications, SFTS patients were divided into case group and control group. The patients’ laboratory parameters and clinical data were collected for statistical analysis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy of independent risk factors in identifying SFTS patients with central neurological complications. Results: In total, 198 hospitalized SFTS patients with complete medical records, clear etiological diagnosis and clinical outcomes were enrolled in this study. Of these, 74 (37.4%) cases were diagnosed with SFTS with central neurological complications, 29 (39.2%) cases died, and no death occurred in the control group. Multivariate logistic regression analysis revealed pulmonary rales, atrial fibrillation, and high serum SFTSV RNA, lactate dehydrogenase level during the fever stage as independent risk factors for the development of central neurological complications in SFTS patients. ROC curve analysis showed that the area under the ROC curve (AUC) of serum SFTSV RNA and lactate dehydrogenase levels were 0.748 (95%CI: 0.673–0.823, p < 0.001) and 0.864 (95%CI: 0.815–0.914, p < 0.001), respectively, in central neurological complications predicted in SFTS patients. Conclusion: Severe fever with thrombocytopenia syndrome (SFTS) combined with central neurological complications has high morbidity and mortality and diverse clinical manifestations. Early monitoring of lung signs, electrocardiogram, blood SFTSV RNA, and lactate dehydrogenase levels in SFTS patients may be useful in predicting the occurrence of central neurological complications. [ABSTRACT FROM AUTHOR]

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) has become a global threat to public health since its first report in China in 2009. However, the pathogenesis of SFTS virus (SFTSV) in humans remains unclear. Also, there are no effective therapeutics for SFTS. Cyclophilin A (CyPA) regulates protein folding and trafficking involved in various viral infectious diseases, but its role in SFTSV infection has not been elucidated.MethodsWe detected plasma CyPA levels in 29 healthy subjects and 30 SFTS patients by ELISA. In THP-1 cells and normal human peripheral blood mononuclear cells (PBMCs), SFTSV-induced extracellular CyPA (eCyPA) was also detected by ELISA. In THP-1, the effects of CyPA on Mitogen-activated protein kinase (MAPK) pathway and NF-κB were determined by Western blot. We validated the interaction between CypA and CD147 by human recombinant CyPA (hrCyPA) and the CD147 inhibitor. Effects of CyPA inhibitor Cyclosporine A (CsA) on cytokines and SFTSV replication in THP-1 cells was also detected. 8-week-old Interferon-α/β Receptor (IFNAR) knockout (IFNAR-/-) C57BL/6 mice were divided into mock group, 106TCID50 SFTSV (Untreated) group and 106TCID50 SFTSV+CsA (CsA-treated) group. The changes of body weight, animal behavior and survival time of each group were recorded. Blood samples were collected from tail vein regularly. After death, the liver, spleen, lung, kidney and brain were collected for pathological HE staining and SFTSV-NP immunohistochemical staining.ResultsCompared to healthy subjects and SFTS patients in the febrile phase of the disease, plasma CyPA levels in SFTS patients at the multi-organ dysfunction (MOD) phase showed significantly elevated (P < 0.01). Extracellular CyPA activates the MAPK pathway by binding to CD147 in THP-1 infected with SFTSV. CsA inhibits the pro-inflammatory and promoting replication effects of CyPA after SFTSV infection in vitro. In vivo, CsA can prolong the survival time and delay the weight loss of SFTSV mice. CsA reduces multi-organ dysfunction in IFNAR−/− mice infected with SFTSV.DiscussionOur results indicate that CyPA is associated with SFTSV-induced cytokine storm, which can be a potential target for SFTS therapy.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality. Methods: A retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified. Results: A total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan–Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be <3 days. Conclusion: The SFTSV viral load and NLR showed great efficacy in predicting the fatal outcome of patients with SFTS, and NLR is a convenient and efficient early-warning biomarker that helps healthcare workers focus on patients with high risks of fatal outcomes. The efficacy of gamma-globulin provided a new idea for the treatment of SFTS, which needs further analysis in future studies. [ABSTRACT FROM AUTHOR]

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality.MethodsA retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified.ResultsA total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan–Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus infection with a high lethality rate. The purpose of this study was to investigate the changes in coagulation parameters in patients with SFTS, aiming to provide clinical evidence for early diagnosis, treatment, and disease analysis., Methods: A total of 40 patients with SFTS attended from April 1, 2020 to May 21, 2022 in Nanjing Drum Tower Hospital were selected and grouped according to the duration of the disease, mild and severe disease, cure and death, with 50 healthy physical examiners as controls, and the risk of severe and death disease was predicted using ROC curves., Results: Comparison between the healthy, mild and severe groups revealed that PT, INR, APTT, TT, D-D and vWF levels were higher than those in the healthy control group, and FII, FIX, FX, FXI, FXII, PC and PS levels were lower than those in the healthy control group, the differences were statistically significant ( p < 0.05). Comparing the results of SFTS patients with different course times, the results of Fib, FV, FVII, FVIII, FIX, FX, FXI were statistically significant ( p < 0.05). Among the survived and deceased patients, the PT, INR, DD and PS results of the deceased patients were higher than those of the survived patients, and the FVIII, FIX, FXI, FXII and PC were lower than those of the survived patients. The area under the ROC curve showed that D-D had higher predictive ability for the risk of severe disease (AUROC 0.93, sensitivity and specificity at a Cut-off value of 1.50 mg/L were 90.0 and 86.5%, respectively) and the risk of death occurring (AUROC 0.84, sensitivity and specificity at a Cut-off value of 3.39 mg/L were 87.5 and 80.0%, respectively)., Discussion: The monitoring of the coagulation parameters in patients with SFTS is great significance for identifying the severity and death of the patient's condition, and it is of great clinical value to provide early attention, timely intervention and maximum reduction of the mortality rate for patients at risk of severe disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xia, Jia, Chen, Wang and Xu.)

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is a fatal viral disease characterized by high fever, thrombocytopenia, leukopenia, and multi-organ haemorrhage. Disruption of the humoral immune response and decreased lymphocyte numbers are thought to contribute to the disease severity. These findings have been obtained through the analysis of peripheral blood leukocytes in human patients, whereas analysis of lymph nodes has been limited. Thus, in this study, we characterized the germinal centre response and apoptosis in the lymph nodes of cats with fatal SFTS, because SFTS in cats well mimics the pathology of human SFTS., Methods: Lymph node tissue sections collected during necropsy from seven fatal SFTS patients and five non-SFTS cases were used for histopathological analysis. Additionally, lymph node tissue sections collected from cats with experimental infection of SFTS virus (SFTSV) were also analysed., Results: In the lymphoid follicles of cats with SFTS, a drastic decrease in Bcl6- and Ki67-positive germinal centre B cells was observed. Together, the number of T cells in the follicles was also decreased in SFTS cases. In the paracortex, a marked increase in cleaved-caspase3 positivity was observed in T cells. These changes were independent of the number of local SFTS virus-positive cell. Furthermore, the analysis of cats with experimental SFTSV infection revealed that the intrafollicular Bcl6- and CD3-positive cell numbers in cats with low anti-SFTSV antibody production were significantly lower than those in cats with high anti-SFTSV antibody production., Discussion: These results suggest that dysfunction of the humoral response in severe SFTS was caused by the loss of germinal centre formation and massive apoptosis of T cells in the lymph nodes due to systemically circulating viruses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sakai, Mura, Kuwabara, Kagimoto, Sakurai, Morimoto, Park, Shimojima, Nagata, Ami, Yoshikawa, Iwata-Yoshikawa, Fukushi, Watanabe, Kurosu, Okutani, Kimura, Imaoka, Saijo, Morikawa, Suzuki and Maeda.)

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6–30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo, with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load 5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by SFTS virus (SFTSV), which is a novel bunyavirus. SFTSV was first isolated from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction in China. Subsequently, it was found to be widely distributed in Southeast Asia (Korea, Japan, and Vietnam). SFTSV can be transmitted not only from ticks but also from domestic animals, companion animals, and humans. Because the case fatality rate of SFTS is high (6–30%), development of specific and effective treatment for SFTS is required. Studies of potential antiviral drugs for SFTS-specific therapy have been conducted on existing or newly discovered agents in vitro and in vivo , with ribavirin and favipiravir being the most promising candidates. While animal experiments and retrospective studies have demonstrated the limited efficacy of ribavirin, it was also speculated that ribavirin would be effective in patients with a viral load <1 × 106 copies/mL. Favipiravir showed higher efficacy than ribavirin against SFTSV in in vitro assays and greater efficacy in animal models, even administrated 3 days after the virus inoculation. Although clinical trials evaluating the efficacy of favipiravir in SFTS patients in Japan are underway, this has yet to be confirmed. Other drugs, including hexachlorophene, calcium channel blockers, 2′-fluoro-2′-deoxycytidine, caffeic acid, amodiaquine, and interferons, have also been evaluated for their inhibitory efficacy against SFTSV. Among them, calcium channel blockers are promising because in addition to their efficacy in vitro and in vivo , retrospective clinical data have indicated that nifedipine, one of the calcium channel blockers, reduced the case fatality rate by >5-fold. Although further research is necessary to develop SFTS-specific therapy, considerable progress has been achieved in this area. Here we summarize and discuss recent advances in antiviral drugs against SFTSV. [ABSTRACT FROM AUTHOR]

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonosis caused by a novel bunyavirus. Until recently, the SFTS related acute kidney injury (AKI) was largely unexplored. This study aimed to investigate the clinical characteristics and outcomes of AKI in patients with SFTS., Methods: The non-AKI and AKI groups were compared in terms of general characteristics, clinical features, laboratory parameters and cumulative survival rate. The independent risk factors for in-hospital mortality in patients with SFTS were analyzed by multivariate logistic regression to identify the population with poor prognosis., Results: A total of 208 consecutive patients diagnosed with SFTS were enrolled, including 153 (73.6%) patients in the non-AKI group and 55 (26.4%) patients in the AKI group. Compared with patients without AKI, patients with AKI were older and had a higher frequency of diabetes. Among these laboratory parameters, platelet count, albumin and fibrinogen levels of patients with AKI were identified to be significantly lower than those of patients without AKI, while ALT, AST, ALP, triglyceride, LDH, BUN, uric acid, creatine, Cys-C, β2-MG, potassium, AMY, lipase, CK-MB, TnI, BNP, APTT, thrombin time, D-dimer, CRP, IL-6, PCT and ESR levels were significantly higher in patients with AKI. A higher SFTS viral load was also detected in the AKI patients than in the non-AKI patients. The cumulative survival rates of patients at AKI stage 2 or 3 were significantly lower than those of patients without AKI or at AKI stage 1. However, there was no significant difference in the cumulative survival rates between patients without AKI and those with stage 1 AKI. Univariate and multivariate binary logistic regression analyses demonstrated that stage 2 or 3 AKI was an independent risk factor for in-hospital mortality in patients with SFTS., Conclusion: AKI is associated with poor outcomes in patients with SFTS, especially patients at AKI stage 2 or 3, who generally have high mortality. Our findings support the importance of early identification and timely treatment of AKI in patients with SFTS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Hu, Jiang, Hu, Li, Deng and Xiong.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an acute infectious disease caused by a novel bunyavirus, characterized by high fever, thrombocytopenia, and multiple organ damage. Disturbances in lipid metabolism often occur during viral infections, but the changes and clinical significance of lipid profiles in SFTS patients remain unclear. This study aimed to investigate the alterations in lipid profiles and their clinical significance in SFTS patients., Methods: A total of 157 SFTS patients and 157 healthy controls were enrolled in this study. Serum lipid levels were collected and analyzed among different groups and prognosis categories. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of lipid levels in distinguishing between severe and mild cases, as well as surviving and non-surviving patients. Pearson correlation analysis was used to examine the associations between lipid levels and clinical laboratory parameters., Results: SFTS patients exhibited significantly lower levels of HDL-c, LDL-c, cholesterol, APoAI, and ApoB compared to healthy controls, while triglyceride levels were significantly higher. Serum HDL-c and ApoAI demonstrated good performance as indicators for distinguishing between survivors and non-survivors (AUC of 0.87 and 0.85, respectively). Multivariate regression analysis indicated that HDL-c independently acts as a protective factor in patients with SFTS. HDL-c levels showed decline in non-survivors but recovered in survivors. Moreover, HDL-c exhibited significant correlations with various clinical laboratory parameters (IL-6, CRP, AST, TT, APTT, PLT, ALB, and CD4)., Conclusion: This study identified abnormalities in serum lipid metabolism among SFTS patients. HDL-c and ApoAI levels hold potential as biomarkers for distinguishing survivors from non-survivors. Additionally, HDL-c and ApoAI may serve as therapeutic targets for the management of SFTS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Fan, Xia, Xu, Chen, Ye, Chen and Wang.)

Background: Conducting an up-to-date analysis on the genomic diversity and evolution patterns of severe fever with thrombocytopenia syndrome virus (SFTSV) is crucial for elucidating the underlying mechanisms of its emergency and pathogenicity, as well as assessing the extent of its threat to public health., Methods: Complete genome sequences of SFTSV were obtained from GenBank until December 19, 2022. A thorough phylogenetic analysis was conducted using comprehensive bioinformatics methods to estimate the genomic diversity and evolution., Results: The phylogenetic classification of SFTSV strains yielded seven lineages (A-G) for each genome segment. SFTSV displayed notable variations in evolutionary patterns among different regions and segments, without a linear accumulation of nucleotide substitutions within segments and regions. The comprehensive analysis revealed 54 recombination events and 17 reassortment strains, including the first discovery of recombination events involving sea-crossing and species-crossing. Selection analysis identified three positive sites (2, 671, 1353) in RNA-dependent RNA polymerase, three positive sites (22, 298, 404) in glycoprotein, and two positive sites (9, 289) in nonstructural protein. No positive selection sites were found in nucleoprotein., Conclusion: Our study unveiled the existence of multiple evolutionary forces influencing SFTSV, contributing to its increasing genetic diversity, which had the potential to modify its antigenicity and pathogenicity. Furthermore, our study highlights the importance of tracking the spread of SFTSV across regions and species., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Pang, Wang, Tian, Xu, Chong, Liang, Ma, Kou and Wen.)

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by the Dabie bandavirus (DBV), and it has become a global public health threat. Cytokine storm is considered to be an important pathogenesis of critical SFTS. Tripartite motif-containing 3 (TRIM3), as a member of the TRIM protein family, may contribute to the regulation of the immune and inflammatory responses after viral infection. However, whether TRIM3 plays a major role in the pathogenesis of SFTS has not yet been investigated., Methods: TRIM3 mRNA levels were detected in PBMCs between 29 SFTS patients and 29 healthy controls by qRT-PCR. We established the pathogenic IFNAR -/- SFTS mouse model successfully by inoculating subcutaneously with DBV and testing the expression levels of TRIM3 mRNA and protein by qRT-PCR and immunofluorescence in the livers, spleens, lungs, and kidneys. TRIM3 OE THP-1 cells and peritoneal macrophages extracted from TRIM3 -/- mice were infected with DBV. The effect of TRIM3 on cytokines was detected by qRT-PCR and ELISA. Then we examined Toll-like receptor 3 (TLR3) and protein phosphorylation in the MAPK pathway after DBV infection using Western blot. Flow cytometry was used to verify TLR3 expression on peripheral blood monocytes in SFTS patients. We further explored the interaction between TRIM3 and TLR3 using CO-IP and Western blot., Results: Compared to healthy controls, TRIM3 mRNA expression in PBMCs is decreased in SFTS patients, especially in severe cases. TRIM3 mRNA and protein were synchronously reduced in the livers, spleens, lungs, and kidney tissues of the IFNAR -/- SFTS mice model. In the DBV-infected cell model, TRIM3 overexpression can inhibit the DBV-induced release of IL-1β, IL-6, and TNF-α, the expression of TLR3, and protein phosphorylation in the MAPK pathway, which plays an anti-inflammatory role, while TRIM3 deficiency exacerbates the pro-inflammatory effects. We further found that TRIM3 can promote TLR3 degradation through K48-linked ubiquitination., Conclusion: TRIM3 can inhibit the production of cytokines by regulating the degradation of TLR3 through K48-linked ubiquitination, which can be a therapeutic target for improving the prognosis of SFTS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jin, Dai, Ouyang, Huang, Jiang, Yang, Zhou, Lin, Wang, Wang, Sun, Lu, Liu, Hu, Zhu, Zhu and Li.)

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease affecting hundreds of people in China each year. To better understand the epidemiological characteristics and environmental risk factors associated with the incidence of SFTS in Hubei Province, China, we conducted a retrospective epidemiological study and risk assessment of SFTS from 2011 to 2016. Although, the incidence and epidemic areas of SFTS are increasing, the fatality rate has decreased. Elderly farmers are the population most commonly infected with SFTS virus between May and July in the northeast Hubei Province, which seems to be consistent with local agricultural activities and the seasonal abundance of ticks. Spatial scanning showed that regions bordering with Xinyang City, Henan Province accounted for most of the SFTS cases in Hubei Province, and there was a significant association of SFTS incidence with temporal changes in the climate within these clusters. Multivariate modeling analysis identified density of cattle, rain-fed cropland, built-up land, temperature, and relative humidity as independent risk factors for the distribution of SFTS. Future epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local SFTS disease and to optimize interventions. [ABSTRACT FROM AUTHOR]

Objectives: Invasive pulmonary aspergillosis (IPA) is common in immuno-compromised people, and a high incidence of IPA has been found in patients with severe fever with thrombocytopenia syndrome (SFTS). Our study aimed to determine the independent risk factors for IPA and the relationship between smoking status and the risk of IPA in SFTS patients., Methods: A retrospective analysis of SFTS patients in the First Affiliated Hospital of Nanjing Medical University from May 2011 to December 2021 was reviewed. The patients were divided into two groups: IPA and non-IPA groups. We compared demographic characteristics, clinical manifestation, laboratory parameters, treatment, and prognosis, and explored the risk factors of IPA using logistic regression and ROC curve. The dose-dependent effect of smoking on the risk of IPA was further estimated, including the age of smoking initiation, daily smoking amount, smoking duration, and pack-years of smoking., Results: In total, 189 individuals were included. Compared with the non-IPA group, the IPA group had higher levels of smoking, drinking, cough, dyspnea, aCCI scores, Dabie bandavirus (DBV) RNA load, ferritin, PCT, IL-6, APTT, LDH, BUN, creatinine, and lower levels of FT4 and TSH. The incidences of MODS, admission to ICU, ventilation, and broad-spectrum antibiotic treatment were significantly higher in the IPA group than in the non-IPA group. Multivariable logistic analysis showed that smoking history, cough, creatinine, admission to ICU, broad-spectrum, and corticosteroid therapies were the independent risk factors for IPA in SFTS patients. We further confirmed that the age of smoking initiation <30 years, smoking at least one pack per day, smoking for at least 40 years, and having at least 40 pack-years of smoking exposure were the independent risk factors for IPA among smokers., Conclusion: The prognosis of SFTS patients in the IPA group is worse than that of the non-IPA group. Attention should be paid to SFTS patients with a smoking history, cough, creatinine, admission to ICU, and broad-spectrum and corticosteroid therapies. There is a strong dose-dependent association between smoking and IPA development in SFTS patients. Prophylactic antifungal therapy should be considered for SFTS patients with these risk factors, but further studies are necessary to determine if it is beneficial for the prognosis of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dai, Pu, Hu, Zhu, Han, Shi, Li and Jin.)

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. The pathophysiology of SFTS remains unclear. Hence, the identification of inflammatory biomarkers for SFTS is crucial for the timely management and prevention of disease severity., Methods: A total of 256 patients with SFTS were divided into a survivor group and a non-survivor group. Classical inflammatory biomarkers such as ferritin, procalcitonin (PCT), C-reactive protein (CRP), and white blood cells were investigated for their association with viral load and the clinical significance for predicting the mortality of patients with SFTS., Results: Serum ferritin and PCT showed a positive association with viral load. Ferritin and PCT levels in non-survivors were significantly higher than those in survivors at 7-9 days from symptom onset. The area under the receiver operating characteristic curve (AUC) values of ferritin and PCT for predicting the fatal outcome of SFTS were 0.9057 and 0.8058, respectively. However, the CRP levels and WBC counts exhibited a weak association with viral load. The AUC value of CRP for predicting mortality was more than 0.7 at 13-15 days from symptom onset., Discussion: Ferritin and PCT levels, especially ferritin, could be potential inflammatory biomarkers for predicting the prognosis of patients with SFTS in its early stages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Sun, Geng, Yang, Shan and Chen.)

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) has become a global threat to public health since its first report in China in 2009. However, the pathogenesis of SFTS virus (SFTSV) in humans remains unclear. Also, there are no effective therapeutics for SFTS. Cyclophilin A (CyPA) regulates protein folding and trafficking involved in various viral infectious diseases, but its role in SFTSV infection has not been elucidated., Methods: We detected plasma CyPA levels in 29 healthy subjects and 30 SFTS patients by ELISA. In THP-1 cells and normal human peripheral blood mononuclear cells (PBMCs), SFTSV-induced extracellular CyPA (eCyPA) was also detected by ELISA. In THP-1, the effects of CyPA on Mitogen-activated protein kinase (MAPK) pathway and NF-κB were determined by Western blot. We validated the interaction between CypA and CD147 by human recombinant CyPA (hrCyPA) and the CD147 inhibitor. Effects of CyPA inhibitor Cyclosporine A (CsA) on cytokines and SFTSV replication in THP-1 cells was also detected. 8-week-old Interferon-α/β Receptor (IFNAR) knockout (IFNAR-/-) C57BL/6 mice were divided into mock group, 10 6 TCID 50 SFTSV (Untreated) group and 10 6 TCID 50 SFTSV+CsA (CsA-treated) group. The changes of body weight, animal behavior and survival time of each group were recorded. Blood samples were collected from tail vein regularly. After death, the liver, spleen, lung, kidney and brain were collected for pathological HE staining and SFTSV-NP immunohistochemical staining., Results: Compared to healthy subjects and SFTS patients in the febrile phase of the disease, plasma CyPA levels in SFTS patients at the multi-organ dysfunction (MOD) phase showed significantly elevated ( P < 0.01). Extracellular CyPA activates the MAPK pathway by binding to CD147 in THP-1 infected with SFTSV. CsA inhibits the pro-inflammatory and promoting replication effects of CyPA after SFTSV infection in vitro. In vivo, CsA can prolong the survival time and delay the weight loss of SFTSV mice. CsA reduces multi-organ dysfunction in IFNAR-/- mice infected with SFTSV., Discussion: Our results indicate that CyPA is associated with SFTSV-induced cytokine storm, which can be a potential target for SFTS therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Jin, Ouyang, Jiang, Yang, Hu, Dai, Zhang, Zhang, Han, Zhao, Lin, Wang, Wang, Sun, Lu, Zhu and Li.)

Objective: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality rate, especially SFTS combined with central neurological complications. The purpose of this study was to explore risk factors of central neurological complications in SFTS patients., Methods: In this retrospective study, SFTS patients admitted to the First Affiliated Hospital of Nanjing Medical University between January 2017 and December 2021 were enrolled. Based on the presence or absence of central neurological complications, SFTS patients were divided into case group and control group. The patients' laboratory parameters and clinical data were collected for statistical analysis. Receiver operating characteristic (ROC) curve analysis was used to evaluate the prediction accuracy of independent risk factors in identifying SFTS patients with central neurological complications., Results: In total, 198 hospitalized SFTS patients with complete medical records, clear etiological diagnosis and clinical outcomes were enrolled in this study. Of these, 74 (37.4%) cases were diagnosed with SFTS with central neurological complications, 29 (39.2%) cases died, and no death occurred in the control group. Multivariate logistic regression analysis revealed pulmonary rales, atrial fibrillation, and high serum SFTSV RNA, lactate dehydrogenase level during the fever stage as independent risk factors for the development of central neurological complications in SFTS patients. ROC curve analysis showed that the area under the ROC curve (AUC) of serum SFTSV RNA and lactate dehydrogenase levels were 0.748 (95% CI : 0.673-0.823, p  < 0.001) and 0.864 (95% CI : 0.815-0.914, p  < 0.001), respectively, in central neurological complications predicted in SFTS patients., Conclusion: Severe fever with thrombocytopenia syndrome (SFTS) combined with central neurological complications has high morbidity and mortality and diverse clinical manifestations. Early monitoring of lung signs, electrocardiogram, blood SFTSV RNA, and lactate dehydrogenase levels in SFTS patients may be useful in predicting the occurrence of central neurological complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Huang, Liu, Tan, Chen, Zeng, Zhu, Shao, Xue, Li and Yue.)

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease affecting hundreds of people in China each year. To better understand the epidemiological characteristics and environmental risk factors associated with the incidence of SFTS in Hubei Province, China, we conducted a retrospective epidemiological study and risk assessment of SFTS from 2011 to 2016. Although, the incidence and epidemic areas of SFTS are increasing, the fatality rate has decreased. Elderly farmers are the population most commonly infected with SFTS virus between May and July in the northeast Hubei Province, which seems to be consistent with local agricultural activities and the seasonal abundance of ticks. Spatial scanning showed that regions bordering with Xinyang City, Henan Province accounted for most of the SFTS cases in Hubei Province, and there was a significant association of SFTS incidence with temporal changes in the climate within these clusters. Multivariate modeling analysis identified density of cattle, rain-fed cropland, built-up land, temperature, and relative humidity as independent risk factors for the distribution of SFTS. Future epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local SFTS disease and to optimize interventions.