Seroprevalence of severe fever with thrombocytopenia syndrome (SFTS) virus antibodies in humans and animals in Ehime prefecture,Japan, an endemic region of SFTS

Severe fever with thrombocytopenia syndrome (SFTS) was first identified as an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV) in China and has also been found to be endemic to Japan and South Korea, indicating that SFTS is of great concern in East Asia. The aim of the present study was to determine the seroprevalence of SFTSV antibodies in humans and animals in SFTS-endemic regions of Japan. One of 694 (0.14%) healthy persons over 50 years of age and 20 of 107 (18.7%) wild and domestic animals in Ehime prefecture of western Japan were determined to be seropositive for SFTSV antibodies by virus neutralization test and ELISA, respectively. The seropositive person, a healthy 74-year-old woman, was a resident of the southwest part of Ehime prefecture engaged in citriculture and field work. This woman's sample exhibited neutralizing activity against SFTSV although she had neither a clear experience with tick bites nor SFTS-like clinical illness. These findings indicate that most people living in the endemic regions are not infected with SFTSV and suggest that most of the SFTS patients reported so far do not reflect the tip of an iceberg of people infected with SFTSV, but at the same time, that SFTSV infection does not always induce severe SFTS-associated symptoms. These findings also suggested that SFTSV has been maintained in nature within animal species and ticks.     

A patient with severe fever with thrombocytopenia syndrome and hemophagocytic lymphohistiocytosis-associated involvement of the central nervous system

Severe fever with thrombocytopenia syndrome (SFTS), a severe infectious disease caused by novel bunyavirus, SFTS virus (SFTSV), is endemic to China, Korea, and Japan. Most SFTS patients show abnormalities in consciousness. Pathological findings in the central nervous system (CNS) of SFTS patients are not reported. A 53-year-old Japanese man was admitted to Uwajima City Hospital with an 8-day history of fever and diarrhea. Laboratory tests revealed leukopenia, thrombocytopenia, and liver enzyme elevation. He was diagnosed as having severe fever with thrombocytopenia syndrome (SFTS) following detection of the SFTSV genome in his blood. Bone marrow aspiration revealed hemophagocytic lymphohistiocytosis. He suffered progressive CNS disturbance and died on day 13 from onset of first symptoms. The SFTSV genome load in blood and levels of certain cytokines increased over the disease course. Necrotizing lymphadenitis with systemic lymphoid tissues positive for nucleocapsid protein (NP) of SFTSV was revealed by immunohistochemical (IHC) analysis. SFTSV-NP-positive immunoblasts were detected in all organs examined, including the CNS, and in the vascular lumina of each organ. Parenchymal cells of all organs examined were negative for SFTSV-NP on IHC analysis. Microscopic examination of the pons showed focal neuronal cell degeneration with hemosiderin-laden macrophages around extended microvessels with perivascular inflammatory cell infiltration and intravascular fibrin deposition. Autopsy confirmed this patient with SFTS was positive for systemic hemophagocytic lymphohistiocytosis including in the CNS. This patient's neurological abnormalities may have been caused by both functional and organic abnormalities. These novel findings provide important insights into the pathophysiology of SFTS.     

L-DOPA,a treatment for Parkinson's disease,and its enantiomer D-DOPA inhibit severe fever with thrombocytopenia syndrome virus infection in vitro

Severe fever with thrombocytopenia syndrome (SFTS) is a hemorrhagic fever. Patients mainly develop fever, thrombocytopenia, and leukopenia. A high case fatality rate of 16.2–47% has been reported. Vaccines and antivirals that are effective against SFTS virus (SFTSV) are not yet available in clinical practice. We previously showed that o-dihydroxybenzene is the important chemical core structure for anti-SFTSV activity. In this study, we evaluated the anti-SFTSV efficacy of 3-Hydroxy-L-tyrosine (L-DOPA), a treatment for Parkinson's disease and its enantiomer, 3-hydroxy-D-tyrosine (D-DOPA), both of which have an o-dihydroxybenzene backbone. SFTSV was preincubated with L- or D-DOPA and then inhibition of viral infection as well as viral attachment to host cells were evaluated by viral quantification. Both L- and D-DOPA inhibited SFTSV infection in a dose-dependent manner, mainly by blocking viral attachment to host cells. The half-maximal inhibitory concentration (IC₅₀) of L-DOPA was 4.46–5.09 μM. IC₅₀ of D-DOPA was 4.23–6.72 μM. IC₅₀ of L-DOPA is very close to its maximum blood concentration after oral administration as a therapy for Parkinson's disease. D-DOPA, which IC₅₀ was almost the same as that of L-DOPA, might not cause side effect. Thus, our present study demonstrated that L- and D-DOPA are potentially useful candidates for anti-SFTSV drugs.     

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.     

Caffeic acid,a coffee-related organic acid,inhibits infection by severe fever with thrombocytopenia syndrome virus in vitro

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) causes tick-borne hemorrhagic fever in East Asia. The disease is characterized by high morbidity and mortality. Here, we evaluated the effects of caffeic acid (CA), a coffee-related organic acid with antiviral effects, against SFTSV infection. CA dose-dependently inhibited SFTSV infection in permissive human hepatoma Huh7.5.1–8 cells when SFTSV was added into the culture medium with CA. However, quinic acid (QA), another coffee-related organic acid, did not inhibit SFTSV infection. The 50% inhibitory concentration (IC₅₀) of CA against SFTSV was 0.048 mM, whereas its 50% cytotoxic concentration was 7.6 mM. The selectivity index (SI) was 158. Pre-incubation of SFTSV with CA for 4 h resulted in a greater inhibition of SFTSV infection (IC₅₀ = 0.019 mM; SI = 400). The pre-incubation substantially decreased viral attachment to the cells. CA treatment of the SFTSV-infected cells also inhibited the infection, albeit less effectively. CA activity after cell infection with SFTSV was more pronounced at a low multiplicity of infection (MOI) of 0.01 per cell (IC₅₀ = 0.18 mM) than at a high MOI of 1 per cell (IC₅₀ > 1 mM). Thus, CA inhibited virus spread by acting directly on the virus rather than on the infected cells. In conclusion, CA acted on SFTSV and inhibited viral infection and spread, mainly by inhibiting the binding of SFTSV to the cells. We therefore demonstrated CA to be a potential anti-SFTSV drug for preventing and treating SFTS.     

Several catechins and flavonols from green tea inhibit severe fever with thrombocytopenia syndrome virus infection in vitro

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever caused by SFTS virus (SFTSV). The mortality rate of SFTS is pretty high, but no vaccines and antiviral drugs are currently available.MethodsThe antiviral effects of six green tea-related polyphenols, including four catechins and two flavonols, on SFTSV were evaluated to identify natural antiviral compounds.ResultsPretreatment with all polyphenols inhibited SFTSV infection in a concentration-dependent manner. The half-maximal inhibitory concentrations of (?)-epigallocatechin gallate (EGCg) and (?)-epigallocatechin (EGC) were 1.7–1.9 and 11–39 μM, respectively. The selectivity indices of EGCg and EGC were larger than those of the other polyphenols. Furthermore, pretreatment with EGCg and EGC dose-dependently decreased viral attachment to the host cells. Additionally, the treatment of infected cells with EGCg and EGC inhibited infection more significantly at a lower multiplicity of infection (MOI) than at a higher MOI, and this effect was less effective than that of pretreatment. Pyrogallol, a trihydroxybenzene that is the structural backbone of both EGCg and EGC, also inhibited SFTSV infection, as did gallic acid.ConclusionsOur study revealed that green tea-related polyphenols, especially EGCg and EGC, are useful as candidate anti-SFTSV drugs. Furthermore, the structural basis of their antiviral activity was identified, which should enable investigations of more active drugs in the future.     

Current treatment of Crimean–Congo hemorrhagic fever in children

Crimean–Congo hemorrhagic fever (CCHF) is a fatal viral hemorrhagic fever and is usually transmitted to humans by tick bite, or exposure to infected blood or tissues of infected livestock or humans. Although children can be infected with the CCHF virus, infection is unusual in the younger age group. Early diagnosis and treatment of CCHF infection is critical to the survival of patients and the control of the disease. In this article, we underline current therapeutic approaches to CCHF infection in children.     

Epidemiological and behavioral factors associated with Crimean–Congo hemorrhagic fever virus infections in humans

Crimean–Congo hemorrhagic fever (CCHF), a viral disease with high fatality rate, is endemic in many countries in Europe, the Middle East, Asia and Africa. It is transmitted to humans either by tick bite or by direct contact with blood or tissues of viremic patients or livestock. Aim of the present study was to review the main epidemiological characteristics of the disease worldwide, with special attempt to show the epidemiological and behavioral factors that play a role in acquisition of the infection. It is obvious that these factors differ among countries, and the knowledge and understanding of the transmission routes in each region facilitates the implementation of proper control measures, the awareness enhancement and the prevention of the disease.     

Retrospective study on the possibility of an SFTS outbreak associated with undiagnosed febrile illness in veterinary professionals and a family with sick dogs in 2003

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging tick-born disease and its animal-to-human transmission has come to attention recently. During our sero-survey of SFTS virus (SFTSV) among veterinary professionals in 2018, a veterinarian and his assistant working in an animal hospital were tested positive by enzyme-linked immunosorbent assay (ELISA). An additional survey implied a cluster of SFTS cases in which four more people, a family who brought two sick dogs to the animal hospital in 2003, were involved. This study aimed at assessing the possibility of animal-to-human transmission of SFTSV in this cluster.MethodsRetrospective interviews were performed with the owner family of the dogs and their clinical records were obtained from each hospital. SFTSV-IgG were tested by ELISA and virus neutralization test using the sera collected from them in 2018.ResultsThe interviews revealed that a total of six people, the two veterinary professionals and the owner family who took care of the sick dogs, suffered from SFTS-like symptoms in the same period of time in 2003. All patients did not have tick bite before the onset and all suspected causative agents were excluded by laboratory tests. The serological tests in this study revealed the four owner family members were all positive for SFTSV antibodies.ConclusionsConsidering the extremely low seroprevalence of SFTSV antibodies among inhabitants of the region, the existence of SFTSV antibodies in all these six people presents a possibility that they were involved in an SFTS outbreak originated in the sick dogs in 2003.     

Clinical aspects of viral hemorrhagic fever

Viral hemorrhagic fever (VHF) is defined as virus infections that usually cause pyrexia and hemorrhagic symptoms with multiple organ failure. VHF includes following viral infections: Ebola hemorrhagic fever (EHF), Marburg hemorrhagic fever (MHF), Crimean-Congo hemorrhagic fever (CCHF) and Lassa fever. In particular, the causative agents of EHF, MHF, CCHF, and Lassa fever are Ebola, Marburg, CCHF, Lassa viruses, respectively, and regarded as biosafety level-4 pathogens because of their high virulence to humans. Recently, relatively large outbreaks of EHF and MHF have occurred in Africa, and areas of EHF- and MHF-outbreaks seem to be expanding. Although outbreaks of VHF have not been reported in Japan, there is a possibility that the deadly hemorrhagic fever viruses would be introduced to Japan in future. Therefore, preparedness for possible future outbreaks of VHF is necessary in areas without VHF outbreaks.     

辽宁省发热伴血小板减少综合征监测与病原学分析

目的 对2012年辽宁省发热伴血小板减少综合征（SFTS）流行病学特征和病原学检测结果进行分析,为临床诊断和预防控制提供依据。方法 以实验室确诊SFTS患者为研究对象,描述三间分布、临床症状体征,并对分离到的病原进行核苷酸序列分析。结果 2012年辽宁省报告的185例疑似病例中,38例实验室确诊感染SFTSV,病死率为5.26%。病例多来自丘陵地区,以中老年、农民为主,无明显性别差异;发病时间为6-10月,部分病例发病前有明确的蜱叮咬史;临床表现主要为发热（100%）、头痛（73.68%）、恶心（65.76%）;血常规检查有血小板计数减少（97.37%）和白细胞计数减少（78.95%）。分离到的9株SFTSV的S、M片段核苷酸序列同源性达95%以上。结论 辽宁省是SFTS的流行地区,需提高SFTS的诊疗能力及加强对SFTS的预防控制。     

一株发热伴血小板减少综合征布尼亚病毒的分离鉴定及其生长特性研究

目的 探索疑似发热伴血小板减少综合征病例中病原体的分离鉴定,了解病毒生长特性。方法 利用非洲绿猴肾细胞Vero E6从患者抗凝血标本中分离发热伴血小板减少综合征布尼亚病毒（SFTSV）,并通过血清学、形态学等方法对病毒进行鉴定;将分离的病毒接种不同细胞,利用荧光定量PCR检测不同时间细胞上清中病毒载量的变化。结果 从患者抗凝血标本中分离出SFTSV;免疫荧光显示感染病毒的细胞培养物能与患者血清发生阳性反应;在透射电镜下能观察到布尼亚病毒样颗粒。SFTSV可感染Vero E6、Hep G2、THP-1等多种细胞,但病毒在不同细胞中的复制水平差异明显。其中Vero E6细胞对SFTSV较易感,病毒可增殖至4.89109 copy/ml。而Hep-2和HT29细胞不能被SFTSV感染。结论 从疑似发热伴血小板减少综合征病例血液标本中成功分离出SFTSV。该病毒具有较广泛的细胞嗜性,对肾来源的细胞更易感。这些研究将为后续研究SFTSV的相关基础研究提供重要的线索。     

发热伴血小板减少综合征的血象及骨髓象分析

目的研究发热伴血小板减少综合征(SFTS)患者的血象和骨髓象特点。方法回顾性总结分析30例SFTS确诊患者的资料。结果 SFTS布尼亚病毒(SFTSV)感染机体可导致外周血白细胞、血小板减少,网织红细胞减低,并出现异型淋巴细胞,在疾病极期-晚期骨髓增生减低,造血细胞明显受抑,并出现较多噬血细胞。结论外周血和骨髓检测对SFTS的诊断、预后判断有一定的临床意义。     

Respiratory lesions in Congo-Crimean hemorrhagic fever

AIM: To characterize pathogenesis, clinical, laboratory and x-ray features of respiratory disease in Congo-Crimean hemorrhagic fever (CCHF). MATERIAL AND METHODS: CCHF diagnosis was made in 283 patients basing on the detection in blood of specific antibodies by enzyme immunoassay (EIA) and virus RNA by polymerase chain reaction (PCR). Serum cytokines were measured with EIA. RESULTS: Pulmonary lesion in CCHF had characteristics of acute respiratory distress syndrome (ARDS). It manifested in the hemorrhagic period with blood spitting, pulmonary hemorrhage and bleeding into the pleural cavity. A high level of proinflammatory cytokines in the blood correlated with the disease severity. CONCLUSION: Respiratory affection in CCHF was seen at all the stages of the infectious process. ARDS occurs during hemorrhagic manifestations and is accompanied with systemic inflammatory reaction.     

Crimean-Congo hemorrhagic fever: A pediatric case responding to plasmapheresis treatment

Crimean-Congo hemorrhagic fever (CCHF) is a life-threatening tick-borne viral infection. The most important step in the treatment of CCHF is supportive therapy. Ribavirin is the recommended antiviral agent for infected patients. We present a case of a child who presented to our pediatric intensive care unit due to CCHF and was treated with plasmapheresis and ribavirin. A previously healthy seven-month-old male infant presented to the emergency room with a fever of 39.5 °C, nosebleed, cough, vomiting, and weakness. We decided to apply plasmapheresis treatment due to multiple organ failure associated with thrombocytopenia, acute liver failure, and a family history of death from the disease. Plasmapheresis was performed in three sessions. By the sixth day of his admission to the intensive care unit, the patient’s clinical condition had improved and his laboratory values had returned to normal, so he was transferred to the infectious diseases service in stable condition.     

Viral hemorrhagic fevers including hantavirus pulmonary syndrome in the Americas

The term viral hemorrhagic fever refers to an acute systemic illness with a propensity for bleeding and shock. The viral hemorrhagic fevers endemic in the Americas include yellow fever, dengue hemorrhagic fever, the South American hemorrhagic fevers, hantavirus pulmonary syndrome, and hemorrhagic fever with renal syndrome. Because these diseases are primarily zoonotic, the distribution of any given virus is generally restricted by the distribution of its natural reservoir or arthropod vector. A high index of suspicion, detailed investigation of the travel and exposure history of the patient, and a basic understanding of the incubation periods and distributions of the various reservoirs of hemorrhagic fever viruses are imperative, as are prompt notification and laboratory confirmation. Clinical management is largely supportive, with a special emphasis on safe nursing practices to prevent nosocomial transmission.     

The combination of levodopa with levodopa-metabolizing enzyme inhibitors prevents severe fever with thrombocytopenia syndrome virus infection in vitro more effectively than single levodopa

Severe fever with thrombocytopenia syndrome is a hemorrhagic fever caused by a tick-borne infection. The causative agent, Dabie bandavirus, is also called the severe fever with thrombocytopenia syndrome virus (SFTSV). Ogawa et al. (2022) reported that levodopa, an antiparkinsonian drug with an o-dihydroxybenzene backbone, which is important for anti-SFTSV activity, inhibited SFTSV infection. Levodopa is metabolized by dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) in vivo. We evaluated the anti-SFTSV efficacy of two DDC inhibitors, benserazide hydrochloride and carbidopa, and two COMT inhibitors, entacapone and nitecapone, which also have an o-dihydroxybenzene backbone. Only DDC inhibitors inhibited SFTSV infection with pretreatment of the virus (half-maximal inhibitory concentration [IC₅₀]: 9.0–23.6 μM), whereas all the drugs inhibited SFTSV infection when infected cells were treated (IC₅₀: 21.3–94.2 μM). Levodopa combined with carbidopa and/or entacapone inhibited SFTSV infection in both conditions: pretreatment of the virus (IC₅₀: 2.9–5.8 μM) and treatment of infected cells (IC₅₀: 10.7–15.4 μM). The IC₅₀ of levodopa in the above-mentioned study for pretreatment of the virus and treatment of infected cells were 4.5 and 21.4 μM, respectively. This suggests that a synergistic effect was observed, especially for treatment of infected cells, although the effect is unclear for pretreatment of the virus. This study demonstrates the anti-SFTSV efficacy of levodopa-metabolizing enzyme inhibitors in vitro. These drugs may increase the time for which the levodopa concentration is maintained in vivo. The combination of levodopa and levodopa-metabolizing enzyme inhibitors might be a candidate for drug repurposing.     

北京市发热伴血小板减少综合征监测和病原检测分析

目的 分析北京市发热伴血小板或白细胞减少综合征监测和严重发热伴血小板减少综合征病毒(SFTSV)感染情况.方法 对符合监测对象定义的病例(体温≥37.5℃伴血小板＜80×109/L或白细胞＜3.0×109/L)进行流行病学调查并采集乙二胺四乙酸抗凝和非抗凝血液标本分别检测嗜吞噬细胞无形体和SFTSV.结果 201...     

Double filtration plasmapheresis for a case of Crimean-Congo hemorrhagic fever

Crimean-Congo hemorrhagic fever (CCHF), is a fatal viral infection transmitted to humans through a tick bite or exposure to blood or tissues of viremic hosts. The clinical presentation is characterized by sudden onset high fever, headache, myalgia, abdominal pain and nausea–vomiting followed by gastrointestinal, urinary, respiratory tract and brain hemorrhage. Laboratory findings include leucopenia, thrombocytopenia, elevated liver enzymes, prolonged prothrombin time and activated partial thromboplastin time. We report a case of CCHF who was treated with a combination of DFPP and ribavirin therapy. As a result of this multimodal treatment, patient’s clinical symptoms and laboratory findings improved gradually.