Risk Factors for Mortality in Severe Fever with Thrombocytopenia Syndrome Patients with Central Nervous System Complications.

BACKGROUND Severe fever with thrombocytopenia syndrome (SFTS) is a zoonotic viral hemorrhagic fever caused by the SFTS virus (SFTSV), which is a newly identified tick-borne bunyavirus, recently named Dabie bandavirus. In rural China, SFTSV or Dabie bandavirus is commonly transmitted by Haemaphysalis longicornis, the Asian longhorned tick. In recent years, SFTS has been of great concern due to its high morbidity and mortality. The present study investigated the risk factors for mortality in patients with SFTS complicated by central nervous system involvement. MATERIAL AND METHODS We studied 69 SFTS patients hospitalized between 2013 and 2020. We analyzed the laboratory test results and clinical data through univariate and multivariate regression. RESULTS Neurological complications occurred in 59 patients in the survival group and 10 in the mortality group. No significant gender difference was found between the 2 groups. No significant difference was found in age, hospitalization duration, or occurrence of encephalitis between the 2 groups. The mean duration of hospitalization and course of the disease in the mortality group were significantly shorter than those in the survival group (P<0.01). The mean values of platelet count, potassium, and sodium in the mortality group were significantly lower, while the mean values of aspartate aminotransferase, lactic dehydrogenase, creatine kinase-MB (CK-MB) and procalcitonin were higher than those in the survival group. Low platelet count and high CK-MB were independent risk factors for mortality in patients. For each unit increase in platelet count, the risk of mortality decreased by 24.2%, and for each unit increase in CK-MB, the probability of mortality increased by 118.6%. CONCLUSIONS Decreased platelets and increased CK-MB were independent risk factors for mortality in encephalitis patients. SFTS patients with encephalitis should be monitored for changes in these 2 indicators.

[The epidemiology and pathogeny investigation of two clusters of severe fever with thrombocytopenia syndrome disease outbreaking in Henan Province, 2022].

To investigate two clusters of severe fever with thrombocytopenia syndrome virus (SFTSV) in Xinyang City, Henan Province, in 2022, and analyze their causes, transmission route, risk factors, and the characteristics of virus genetic variation. Case search and case investigation were carried out according to the case definition. Blood samples from cases, family members and neighbors and samples of biological vectors were collected for RT-PCR to detect SFTSV. The whole genome sequencing and bioinformatics analysis were performed on the collected positive samples. A total of two clustered outbreaks occurred, involving two initial cases and ten secondary cases, all of which were family recurrent cases. Among them, nine secondary cases had close contact with the blood of the initial case, and it was determined that close contact with blood was the main risk factor for the two clustered outbreaks. After genome sequencing analysis, we found that the SFTSV genotype in two cases was type A, which was closely related to previous endemic strains in Xinyang. The nucleotide sequence of the SFTSV in the case was highly homologous, with a total of nine amino acid mutation sites in the coding region. It was not ruled out that its mutation sites might have an impact on the outbreak of the epidemic.

Neurological disease caused by Oropouche virus in northern Brazil: should it be included in the scope of clinical neurological diseases?

We describe two neurological cases of Oropouche virus infection in northern Brazil, where the virus is endemic but neglected as a pathogen. This study reiterates the necessity of developing protocols for diagnosing infections and training medical personnel to recognize the pathogenicity of Oropouche virus in neurological infections.

Severe fever with thrombocytopenia syndrome (SFTS) treated with a novel antiviral medication, favipiravir (T-705).

BACKGROUND: Severe fever and thrombocytopenia syndrome (SFTS) is an acute illness with a high mortality (16.2-29.1%). Unfortunately, there is no specific cure or vaccine for SFTS. METHODS: In this open-label study, two patients with SFTS were treated with favipiravir, a new antiviral drug. RESULTS: Patients had a sustainable virologic, immunologic and symptomatic recovery. CONCLUSIONS: Favipiravir may be a prosiming drug for the treatment of SFTS.

Low incidence of Schmallenberg virus infection in natural cases of abortion in domestic ruminants in Hungary.

An epizootic caused by a new orthobunyavirus called Schmallenberg virus (SBV) was recognised in European ruminants in 2011 and 2012. The re-emergence of the infection was reported in several countries in the subsequent years. Although the main clinical sign of SBV infection is abortion, the impact of SBV in natural cases of abortion in domestic ruminants had not been systematically examined before this study. The aim of the study was to investigate the role of SBV infection and to compare it to the importance of other causes of abortion by examining 537 natural cases of abortion that had occurred between 2011 and 2017 in Hungary. The cause of abortion was determined in 165 (31%) cases. An infectious cause was proved in 88 (16%) cases. SBV infection was found only in a total of four cases (0.8%) using real-time polymerase chain reaction. Three of them proved to be inapparent SBV infection, and one case was attributed to SBV-induced abortion by detecting non-purulent encephalitis and SBV nucleoprotein by immunohistochemistry in a brain tissue sample. According to the results, SBV played a minor role in natural cases of domestic ruminant abortion in Hungary during the 7-year period following the first SBV outbreak in 2011.

Fulminant myocarditis associated with severe fever with thrombocytopenia syndrome: a case report.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral infectious disease with high mortality. It causes multiple organ dysfunction; however, myocarditis has never been reported as a complication with SFTS. CASE PRESENTATION: A 62-year-old previously healthy woman developed fever, fatigue, diarrhea, and a mild consciousness disorder. She visited a local clinic, and laboratory data showed leukocytopenia, thrombocytopenia, and elevation of the aspartate aminotransferase level. She was transferred to Kagoshima University Hospital and diagnosed as having SFTS by real-time reverse transcription polymerase chain reaction. Subsequently, her blood pressure gradually decreased despite fluid resuscitation and vasopressor administration. Based on elevated toroponin I levels in serum, a transient diffuse left ventricular hypokinesis and wall thickening in echocardiography, diffuse ST elevation in electrocardiography, and exclusion of other heart diseases, she was diagnosed as having fulminant myocarditis. After hemodynamic support with inotropic agents, she recovered near normal cardiac function. She was discharged to home on day 28. CONCLUSIONS: We report the first case of fulminant myocarditis associated with SFTS.

[Unilateral peromelia of the left pelvic limb in a Brown Swiss calf]. / Unilaterale Peromelie der linken Beckengliedmasse bei einem Brown Swiss Kalb.

INTRODUCTION: Congenital deformities of the limbs occur sporadically in various species, but the cause is often unclear. The clinically healthy female Brown Swiss calf presented here showed a congenital peromelia of the left hind limb. The affected limb is twisted, disproportional and the bones distally of the metatarsus are missing. Karyotyping and genome sequencing did not indicate on a genetic cause of the anomaly. An infection with the Schmallenberg virus could not be ruled out. Furthermore, there was no evidence of further adverse environmental effects during pregnancy.

INTRODUCTION: Des malformations congénitales des membres, dont la cause est souvent peu claire, surviennent sporadiquement chez diverses espèces. Le veau Brown Swiss femelle présenté ici, tout en étant cliniquement sain, présentait une péromélie congénitale du postérieur gauche. Le membre concerné été en rotation interne, disproportionné et les os distalement au métatarse étaient absents. La détermination du caryotype et le séquençage de l'ensemble du génome n'ont apporté aucun élément parlant pour une cause génétique de l'anomalie. Il n'a pas été possible d'exclure une infection par le virus de ­Schmallenberg. D'autre part il n'y avait aucun élément évoquant d'autres influences environnementales néfastes durant la gestation.

Association of Batai Virus Infection and Encephalitis in Harbor Seals, Germany, 2016.

We isolated Batai virus from the brain of a euthanized, 26-year-old, captive harbor seal with meningoencephalomyelitis in Germany. We provide evidence that this orthobunyavirus can naturally infect the central nervous system of a mammal. The full-genome sequence showed differences from a previously reported virus isolate from a mosquito in Germany.

Heartland Virus and Hemophagocytic Lymphohistiocytosis in Immunocompromised Patient, Missouri, USA.

Heartland virus is a suspected tickborne pathogen in the United States. We describe a case of hemophagocytic lymphohistiocytosis, then death, in an immunosuppressed elderly man in Missouri, USA, who was infected with Heartland virus.

Multiple organ involvement in severe fever with thrombocytopenia syndrome: an immunohistochemical finding in a fatal case.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by SFTS bunyavirus (SFTSV), a tick borne bunyavirus. However, Immunohistochemistry of SFTS patients are not well studied. METHODS: We obtained multiple of tissues from a fatal case with SFTS, including blood, lungs, kidneys, heart, and spleen. The blood samples were used to isolate the causative agent for detection of viral RNA and further expression of recombinant viral protein as primary antibody. Immunohistochemistry of the heart, lungs, spleen and kidneys was used to characterize the viral antigen in tissue sections. RESULTS: A 79-year-old man, together with his wife, was admitted because of fever. Both patients were diagnosed with SFTS by the positive SFTSV RNA in the blood. The gentleman died of multiple organ failure 8 days after hospitalization. However, his wife recovered and was discharged. Immunohistochemistry indicated that SFTSV antigens were present in all studied organs including the heart, kidney, lung and spleen, of which the spleen presented with the highest amount of SFTSV antigens. The kidney was next while the heart and lungs showed lower amount of SFTSV antigens. CONCLUSIONS: SFTSV can direct infect multiple organs, resulting in multiple organ failure and ultimately in an unfavorable outcome.

Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.

[Severe fever with thrombocytopenia syndrome: epidemiology, pathophysiology, and development of specific treatment and prevention measures].

Severe fever with thrombocytopenia syndrome (SFTS) was first reported in 2011 as an emerging virus infection caused by a novel Phlebovirus in the Bunyaviridae family [SFTS virus (SFTSV)]. In addition, it was reported to be endemic to Hubei, Henan, Shandong, and Heilongjiang provinces in China. The primary symptoms of SFTS are gastrointestinal symptoms such as fever, general fatigue, nausea, vomiting, and diarrhea. The total blood cell counts in patients with SFTS reveal thrombocytopenia and leukopenia. A woman in her 50s died due to multiorgan failure, intestinal hemorrhage, and hemophagocytosis in the autumn of 2012. She was retrospectively diagnosed with SFTS, suggesting that SFTS was endemic not only to China but also to Japan. Subsequently, SFTS was reported to be endemic to South Korea as well. Approximately 5 years have passed since the discovery of SFTS endemicity in Japan. To date, 40-100 patients with SFTS from the western part of Japan have been reported annually to the National Institute of Infectious Diseases. The case-fatality rate of SFTS is approximately 20%. This high case-fatality rate could be attributed to multiorgan failure, coagulopathy, and hemophagocytosis, which are induced in most patients with SFTS. Reportedly, an antiviral drug, favipiravir, was effective in treating SFTSV infection in an animal infection model. SFTSV has been found to circulate between wild animals and several species of ticks in nature, suggesting that we cannot escape the risk of infection with SFTSV and that SFTS will continue to occur in endemic areas. Hence, the development of specific treatment and preventive measures with SFTS vaccines is imperative.

Novel Clinical and Pathologic Findings in a Heartland Virus-Associated Death.

We describe an investigation into a Heartland virus (HRTV)-associated death in Tennessee with novel clinical and pathologic findings. HRTV can cause rapidly fatal, widely disseminated infection with multisystem organ failure in patients without substantial comorbidities. We identified viral antigen in multiple organ tissues where it was not detected previously.

Severe fever with thrombocytopenia syndrome with myocardial dysfunction and encephalopathy: A case report.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China, Korea and Japan caused by a novel bunyavirus, SFTS virus (SFTSV). Although central nervous system manifestations are common in SFTS patients, the pathogenesis has not been elucidated; and there are few reports of myocardial dysfunction. Here we report an elderly Japanese patient with reversible myocardial dysfunction and encephalopathy. A previously healthy 65-year-old male engaged in forestry got a tick bite and developed fever and fatigue in 3 days. Three days after onset, he presented to a local hospital where the diagnosis of SFTS with hemophagocytotic syndrome was made. The blood test showed leukopenia and thrombocytopenia as well as elevated levels of alanine aminotransferase and aspartate aminotransferase. Marked hemophagocytosis was found on bone marrow smear. Peripheral blood was positive for SFTSV gene by reverse-transcription polymerase chain reaction. On day 7, the patient was transferred to our hospital. We observed disturbance of consciousness, Kernig sign and myoclonus to face and limbs. Decreased blood flow of whole cerebral cortex was detected by single photon emission computed tomography (SPECT). Chest X-ray revealed cardiomegaly and electrocardiography (ECG) showed abnormal T waves. These data suggested acute encephalopathy and myocardial dysfunction. We treated him with corticosteroid and blood transfusion, which resulted in the complete recovery of the above abnormal symptoms and laboratory data including the findings in SPECT and ECG in about a month. This case demonstrated transient myocardial dysfunction and encephalopathy can occur in addition to typical clinical manifestation of SFTS.

Fever with thrombocytopenia associated with a novel bunyavirus in China.

BACKGROUND: Heightened surveillance of acute febrile illness in China since 2009 has led to the identification of a severe fever with thrombocytopenia syndrome (SFTS) with an unknown cause. Infection with Anaplasma phagocytophilum has been suggested as a cause, but the pathogen has not been detected in most patients on laboratory testing. METHODS: We obtained blood samples from patients with the case definition of SFTS in six provinces in China. The blood samples were used to isolate the causal pathogen by inoculation of cell culture and for detection of viral RNA on polymerase-chain-reaction assay. The pathogen was characterized on electron microscopy and nucleic acid sequencing. We used enzyme-linked immunosorbent assay, indirect immunofluorescence assay, and neutralization testing to analyze the level of virus-specific antibody in patients' serum samples. RESULTS: We isolated a novel virus, designated SFTS bunyavirus, from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA sequence analysis revealed that the virus was a newly identified member of the genus phlebovirus in the Bunyaviridae family. Electron-microscopical examination revealed virions with the morphologic characteristics of a bunyavirus. The presence of the virus was confirmed in 171 patients with SFTS from six provinces by detection of viral RNA, specific antibodies to the virus in blood, or both. Serologic assays showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness. CONCLUSIONS: A novel phlebovirus was identified in patients with a life-threatening illness associated with fever and thrombocytopenia in China. (Funded by the China Mega-Project for Infectious Diseases and others.).

Discovery of severe fever with thrombocytopenia syndrome bunyavirus strains originating from intragenic recombination.

This study analyzes available severe fever with thrombocytopenia syndrome virus (SFTSV) genomes and reports that a sublineage of lineage I bears a unique M segment recombined from two of three prevailing SFTSV lineages. Through recombination, the sublineage has acquired nearly complete G1 associated with protective epitopes from lineage III, suggesting that this recombination has the capacity to induce antigenic shift of the virus. Therefore, this study provides some valuable implications for the vaccine design of SFTSV.

A reported death case of a novel bunyavirus in Shanghai, China.

This paper describes the first case of infection with a recently described novel bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), in Shanghai, China. The case is originally from Chizhou City, Anhui province within an endemic area for SFTSV. We describe the etiology, epidemiological characteristics, clinical diagnosis and treatment of this fatal case. This case is unique because major cause of death was renal failure, whereas other reported cases have been due to hemorrhage. The investigation and response to this case provides meaningful insight for the early and rapid diagnosis, treatment, prevention and control of severe fever with thrombocytopenia syndrome virus in non-endemic regions in China and globally.

Severe fever with thrombocytopenia syndrome virus replicates in platelets and enhances platelet activation.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection causes an emerging hemorrhagic fever in East Asia with a high mortality rate. Thrombocytopenia is a consistent feature of SFTS illness, but the mechanism remains elusive. OBJECTIVES: We aimed to better understand the role of platelets in the pathophysiology of SFTSV infection, including the development of thrombocytopenia. METHODS: Using platelets from healthy volunteers and patients with SFTS, we evaluated the functional changes in platelets against SFTSV infection. We investigated the direct effect of glycoprotein VI on platelet-SFTSV interaction by quantitative real-time PCR, molecular docking, surface plasmon resonance spectrometry, flow cytometry, western blot, and platelet functional studies in vitro. Interactions of SFTSV and platelet-SFTSV complexes with macrophages were also determined by scanning electron microscope, quantitative real-time PCR, and flow cytometry. RESULTS: This study is the first to demonstrate that platelets are capable of harboring and producing SFTSV particles. Structural and functional studies found that SFTSVs bind platelet glycoprotein VI to potentiate platelet activation, including platelet aggregation, adenosine triphosphate release, spreading, clot retraction, coagulation, phosphatidylserine exposure, thrombus formation, and adherence. In vitro mechanistic studies highlighted that the interaction of platelets with human THP-1 cells promoted SFTSV clearance and suppressed cytokine production in macrophages. However, unwanted SFTSV replication in macrophages reciprocally aggravated SFTSV persistence in the circulation, which may contribute to thrombocytopenia and other complications during SFTSV infection. CONCLUSION: These findings together highlighted the pathophysiological role of platelets in initial intrinsic defense against SFTSV infections, as well as intertwined processes with host immunity, which can also lead to thrombocytopenia and poor prognosis.

The pathogenic and clinical characteristics of severe fever with thrombocytopenia syndrome patients with co-infections.

Objective: The study aimed to comprehensively describe and evaluate the pathogenic and clinical characteristics of severe fever with thrombocytopenia syndrome (SFTS) patients with co-infections. Methods: We retrospectively collected clinical data and laboratory indicators of the SFTS patients at Tongji Hospital from October 2021 to July 2023. Results: A total of 157 patients with SFTS virus (SFTSV) infection were involved in the analysis, including 43 co-infection and 114 non-co-infection patients. The pathogens responsible for co-infection were primarily isolated from respiratory specimens. Fungal infections, primarily Aspergillus fumigatus, were observed in 22 cases. Bacterial infections, with Klebsiella pneumoniae and carbapenem-resistant Acinetobacter baumannii as the main pathogens, were identified in 20 cases. SFTS patients with co-infection exhibited higher mortality (P=0.011) compared to non-co-infection patients. Among SFTS patients co-infected with both bacteria and fungi (8 cases) or specific drug-resistant strains (11 cases), the mortality rate was as high as 70% (14/19). In comparison with the non-co-infection group, SFTS patients with co-infection displayed significant alteration in inflammatory markers, coagulation function, and liver function indicators. Conclusion: The mortality rate of SFTS patients with co-infection is relatively high, underscoring the need for enhanced monitoring and timely, appropriate treatment to minimize the mortality rate.

Epizootic of ovine congenital malformations associated with Schmallenberg virus infection.

Epizootic outbreaks of congenital malformations in sheep are rare and have, to the best of our knowledge, never been reported before in Europe. This paper describes relevant preliminary findings from the first epizootic outbreak of ovine congenital malformations in the Netherlands. Between 25 November and 20 December 2011, congenital malformations in newborn lambs on sheep farms throughout the country were reported to the Animal Health Service in Deventer. Subsequently, small ruminant veterinary specialists visited these farms and collected relevant information from farmers by means of questionnaires. The deformities varied from mild to severe, and ewes were reported to have given birth to both normal and deformed lambs; both male and female lambs were affected. Most of the affected lambs were delivered at term. Besides malformed and normal lambs, dummy lambs, unable to suckle, were born also on these farms. None of the ewes had shown clinical signs during gestation or at parturition. Dystocia was common, because of the lambs' deformities. Lambs were submitted for post-mortem examination, and samples of brain tissue were collected for virus detection. The main macroscopic findings included arthrogryposis, torticollis, scoliosis and kyphosis, brachygnathia inferior, and mild-to-marked hypoplasia of the cerebrum, cerebellum and spinal cord. Preliminary data from the first ten affected farms suggest that nutritional deficiencies, intoxication, and genetic factors are not likely to have caused the malformations. Preliminary diagnostic analyses of precolostral serum samples excluded border disease virus, bovine viral diarrhoea virus, and bluetongue virus. In December 2011, samples of brain tissue from 54 lambs were sent to the Central Veterinary Institute of Wageningen University Research, Lelystad. Real-time PCR detected the presence of a virus, provisionally named the Schmallenberg virus, in brain tissue from 22 of the 54 lambs, which originated from seven of eight farms that had submitted lambs for post-mortem examination. This Schmallenberg virus was first reported in Germany and seems to be related to the Shamonda, Aino, and Akabane viruses, all of which belong to the Simbu serogroup of the genus Orthobunyavirus of the family Bunyaviridae. These preliminary findings suggest that the Schmallenberg virus is the most likely cause of this epizootic of ovine congenital malformations, which is the first such outbreak reported in Europe.