Acute pancreatitis in patients with severe fever with thrombocytopenia syndrome virus infection

BackgroundSevere fever with thrombocytopenia syndrome (SFTS), a novel tick-borne disease caused by SFTS virus (SFTSV), has been reported in China, Japan, South Korea, and Vietnam since 2009. SFTSV infection can cause multiple organ damage, including acute pancreatitis (AP). We summarize the clinical features, treatment and outcome of AP associated with SFTSV.MethodsWe retrospectively review the clinical manifestations, laboratory tests, treatment, and outcome of AP associated with SFTSV infection from January 2009 to December 2018 in Liaoning Province, China.ResultsA total of 418 SFTS patients were reviewed. Fifteen (3.6%) of 418 met the criteria for AP associated with SFTSV infection. The first reported symptom for all SFTS-AP patients was fever. All the SFTS-AP patients presented with thrombocytopenia, and 13 (86.7%) of them presented with leukopenia on admission. Thirteen (86.7%) of 15 SFTS-AP patients were severe SFTS patients, and 9 (60.0%) patients were diagnosed with multiple organ dysfunction syndrome. One SFTS-AP patient died of multiple organ failure. Six (40%) of 15 SFTS-AP patients were not confirmed with SFTSV infection when AP was diagnosed, and the median delay between SFTSV infection and AP diagnosis was 5 days (range, 2–7 days).ConclusionsAP is not a frequent complication of SFTS, and is more frequently seen in severe SFTS patients. Most patients with SFTS-AP have mild or moderate disease, and can recover with conservative management; however, severe SFTS-AP can be fatal. In SFTS endemic areas, clinicians should be alert to the possibility of SFTS when AP patients with tick exposure, thrombocytopenia, and leukopenia have a fever before abdominal pain.     

Clinical progress and risk factors for death in severe Fever with thrombocytopenia syndrome patients

Background.?Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV) with an average fatality rate of 12%. The clinical factors for death in SFTS patients remain unclear. Methods.?Clinical features and laboratory parameters were dynamically collected for 11 fatal and 48 non-fatal SFTS cases. Univariate logistic regression was used to evaluate the risk factors associated with death. Results.?Dynamic tracking of laboratory parameters revealed that during the initial fever stage, the viral load was comparable for the patients who survived as well as the ones that died. Then in the second stage when multi-organ dysfunction occurred, from 7-13 days after disease onset, the viral load decreased in survivors but it remained high in the patients that died. The key risk factors that contributed to patient death were elevated serum aspartate aminotransferase, lactate dehydrogenase, creatine kinase, and creatine kinase fraction, as well as the appearance of CNS (central nervous system) symptoms, hemorrhagic manifestation, disseminated intravascular coagulation, and multi-organ failure. All clinical markers reverted to normal in the convalescent stage for SFTS patients who survived. Conclusions.?We identified a period of 7-13 days after the onset of illness as the critical stage in SFTS progression. A sustained serum viral load may indicate that disease conditions will worsen and lead to death.     

Plasma Exchange Did Not Reduce Viral Load in a Recovered Case of Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). There is no specific treatment for SFTS, although several reports have indicated that plasma exchange (PE) can be an effective therapy for severe SFTS. However, whether or not PE can reduce the viral load is unclear. We herein report a woman with SFTS who had her SFTSV viral load measured just before and after PE. While the patient recovered, there was no significant difference in the SFTSV viral load after PE. Our results confirmed that PE itself does not reduce the SFTSV viral load.     

发热伴血小板减少综合征流行病学研究进展

发热伴血小板减少综合征（Severe fever with thrombocytopenia syndrome,SFTS）是近几年来新发现的一种以发热伴血小板减少为主要临床表现的传染性疾病,新布尼亚病毒是引起该病的病原体.蜱叮咬是主要的传播途径,可通过人-人接触传播.该病发病急,病情进展快,部分患者可因多脏器功能衰竭而死亡,病死率约10％.本文对该病病原学、病例分布特点及其传染源、传播途径和易感人群三个流行环节方面的最新研究进展作一综述.     

Pathological Characteristics of a Patient with Severe Fever with Thrombocytopenia Syndrome (SFTS) Infected with SFTS Virus through a Sick Cat’s Bite

A woman in her fifties showed symptoms of fever, loss of appetite, vomiting, and general fatigue 2 days after she was bitten by a sick cat, which had later died, in Yamaguchi prefecture, western Japan, in June 2016. She subsequently died of multiorgan failure, and an autopsy was performed to determine the cause of death. However, the etiological pathogens were not quickly identified. The pathological features of the patient were retrospectively re-examined, and the pathology of the regional lymph node at the site of the cat bite was found to show necrotizing lymphadenitis with hemophagocytosis. The pathological features were noted to be similar to those of patients reported to have severe fever with thrombocytopenia syndrome (SFTS). Therefore, the lymph node section was retrospectively tested immunohistochemically, revealing the presence of the SFTS virus (SFTSV) antigen. The sick cat showed similar symptoms and laboratory findings similar to those shown in human SFTS cases. The patient had no history of tick bites, and did not have skin lesions suggestive of these. She had not undertaken any outdoor activities. It is highly possible that the patient was infected with SFTSV through the sick cat’s bite. If a patient gets sick in an SFTS-endemic region after being bitten by a cat, SFTS should be considered in the differential diagnosis.     

Person-to-person transmission of severe fever with thrombocytopenia syndrome virus

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a newly discovered bunyavirus, SFTS virus (SFTSV), and causes high fatality (12% on average and as high as 30%). The objective of this study was to determine whether SFTSV could be transmitted from person to person. We analyzed sera of 13 patients from two clusters of unknown infectious diseases that occurred between September and November of 2006 in Anhui Province of China for SFTSV antibody by indirect immunofluorescence assay and for SFTSV RNA by RT-PCR. We found that all patients (n=14) had typical clinical symptoms of SFTS including fever, thrombocytopenia, and leukopenia and all secondary patients in both clusters got sick at 6-13 days after contacting or exposing to blood of index patients. We demonstrated that all patients in cluster 1 including the index patient and nine secondary patients and all three secondary patients in cluster 2 had seroconversion or fourfold increases in antibody titer to SFTSV and/or by RT-PCR amplification of SFTSV RNA from the acute serum. The index patient in cluster 2 was not analyzed because of lack of serum. No person who contacted the index patient during the same period, but were not exposed to the index patient blood, had got illness. We concluded that SFTSV can be transmitted from person to person through contacting patient's blood.     

Clinical Update of Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an acute febrile illness characterized by fever, leukopenia, thrombocytopenia, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting resulting from infection with the SFTS virus (SFTSV). The SFTSV is transmitted to humans by tick bites, primarily from Haemaphysalis longicornis, Amblyomma testudinarium, Ixodes nipponensis, and Rhipicephalus microplus. Human-to-human transmission has also been reported. Since the first report of an SFTS patient in China, the number of patients has also been increasing. The mortality rate of patients with SFTS remains high because the disease can quickly lead to death through multiple organ failure. In particular, an average fatality rate of approximately 20% has been reported for SFTS patients, and no treatment strategy has been established. Therefore, effective antiviral agents and vaccines are required. Here, we aim to review the epidemiology, clinical manifestations, laboratory diagnosis, and various specific treatments (i.e., antiviral agents, steroids, intravenous immunoglobulin, and plasma exchange) that have been tested to help to cope with the disease.     

Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model

The discovery of an emerging viral disease, severe fever with thrombocytopenia syndrome (SFTS), caused by SFTS virus (SFTSV), has prompted the need to understand pathogenesis of SFTSV. We are unique in establishing an infectious model of SFTS in C57/BL6 mice, resulting in hallmark symptoms of thrombocytopenia and leukocytopenia. Viral RNA and histopathological changes were identified in the spleen, liver, and kidney. However, viral replication was only found in the spleen, which suggested the spleen to be the principle target organ of SFTSV. Moreover, the number of macrophages and platelets were largely increased in the spleen, and SFTSV colocalized with platelets in cytoplasm of macrophages in the red pulp of the spleen. In vitro cellular assays further revealed that SFTSV adhered to mouse platelets and facilitated the phagocytosis of platelets by mouse primary macrophages, which in combination with in vivo findings, suggests that SFTSV-induced thrombocytopenia is caused by clearance of circulating virus-bound platelets by splenic macrophages. Thus, this study has elucidated the pathogenic mechanisms of thrombocytopenia in a mouse model resembling human SFTS disease.     

Residual and Late Onset Symptoms Appeared in a Patient with Severe Fever with Thrombocytopenia in a Convalescence Stage

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by Dabie bandavirus (formerly SFTS virus, SFTSV). Its manifestations during the convalescent phase have not been widely described. We report a patient presenting with hematospermia, fatigue, myalgia, alopecia, insomnia, and depression during the recovery phase of SFTS. Since these symptoms are widely observed in patients with viral hemorrhagic fevers, there might be common mechanisms between SFTS and other viral hemorrhagic fevers. Close monitoring may be required during the recovery phase of SFTS.     

Loperamide Inhibits Replication of Severe Fever with Thrombocytopenia Syndrome Virus

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). SFTS is mainly prevalent in East Asia. It has a mortality rate of up to 30%, and there is no approved treatment against the disease. In this study, we evaluated the effect of loperamide, an antidiarrheal and antihyperalgesic agent, on the propagation of SFTSV in a cell culture system. Methods: SFTSV-infected human cell lines were exposed to loperamide, and viral titers were evaluated. To clarify the mode of action of loperamide, several chemical compounds having shared targets with loperamide were used. Calcium imaging was also performed to understand whether loperamide treatment affected calcium influx. Results: Loperamide inhibited SFTSV propagation in several cell lines. It inhibited SFTSV in the post-entry step and restricted calcium influx into the cell. Furthermore, nifedipine, a calcium channel inhibitor, also blocked post-entry step of SFTSV infection. Conclusions: Loperamide inhibits SFTSV propagation mainly by restraining calcium influx into the cytoplasm. This indicates that loperamide, a Food and Drug Administration (FDA)-approved drug, has the potential for being used as a treatment option against SFTS.     

Clinical and Epidemiological Study on Severe Fever with Thrombocytopenia Syndrome in Yiyuan County,Shandong Province,China

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China. Polymerase chain reaction and enzyme-linked immunosorbent assay were used to detect SFTS virus (SFTSV) and Anaplasma phagocytophilum in previous clinically diagnosed human anaplasmosis patients and SFTS patients. A serosurvey for SFTSV infection was also conducted on healthy persons and animals in Yiyuan County in Shandong Province of China. Among 21 patients SFTSV was detected in 17 (81%) however A. phagocytophilum was not detected in any of the patients. The seroprevalence rate of IgG antibody to SFTSV antigens was 1.3% (1 of 78) in healthy persons, 95% (19 of 20) in goats, 50% (1 of 2) in dogs, 0% in cattle (0 of 21), and rats (Rattus norvegicus) (0 of 35). The conclusion of this study was that co-infection of SFTSV and A. phagocytophilum are rare in SFTS patients and goats might play an important role in transmission of SFTSV.     

Host cytokine storm is associated with disease severity of severe Fever with thrombocytopenia syndrome

Background.?Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease in China, caused by SFTS virus (SFTSV). Severe SFTS patients can quickly proceed to multiorgan dysfunction and death; however, underlying pathogenic mechanisms remain unclear. Methods.?Serum samples from 15 fatal and 44 nonfatal SFTS cases were subjected to multiplex-microbead immunoassays to detect a broad spectrum of cytokines. The viral load and virus-specific IgG titers were also tested by real-time PCR and ELISA, respectively. Results.?Cytokines IL-1RA, IL-6, IL-10, G-CSF, IP-10, and MCP-1 were elevated in SFTS patients and produced at robust levels in fatal cases. In contrast, cytokines PDGF-BB and RANTES decreased in SFTS patients. These cytokines reverted to normal ranges during the convalescent phase of SFTSV infection. Cytokines IL-1β, IL-8, MIP-1α, and MIP-1β showed a unique pattern of elevation in fatal cases but not in nonfatal cases. However, these cytokines increased in the convalescent phase of nonfatal SFTS cases. Our regression analysis revealed that the serum viral load correlated with these cytokines. Moreover, levels of these cytokines correlated with various clinical parameters and virus-specific IgG titers. Conclusion.?The study demonstrates that SFTSV infection induces a cytokine storm with abnormally expressed cytokine profiles, which are associated with the disease severity.     

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

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

新布尼亚病毒感染致发热伴血小板减少综合征的危险因素分析

目的探讨新布尼亚病毒感染致发热伴血小板减少综合征发病的危险因素。方法采用1∶2配对的病例-对照研究,对40例病例和80例对照进行问卷调查,同时采集患者血清标本,应用荧光RT-PCR和IgM、IgG抗体试剂盒检测新布尼亚病毒核酸及抗体。采用条件Logistic回归分析发病的危险因素。结果病例组农民占90.00%(36/40),显著高于对照组62.50%(50/80)(P<0.01)。病例组暴露于养狗、养猫、养牛、家禽养殖、生活区周围有蜱、病前1月被蜱叮咬、从事田间作业、工作区及住宅周围有杂草灌木的风险显著高于对照组(OR值均大于1,P值均小于0.05)。多因素分析表明,在调整了性别、年龄、民族和职业因素后,生活区周围有蜱(OR=5.44, P<0.01)是新布尼亚病毒感染致发热伴血小板减少综合征发病的危险因素。结论不同形式的蜱暴露为新布尼亚病毒感染致发热伴血小板减少综合征的危险因素。     

Seroprevalence and Risk Factors for Severe Fever with Thrombocytopenia Syndrome Virus Infection in Jiangsu Province,China, 2011

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by a novel bunyavirus, is an emerging infectious disease in China. In 2011, this new virus was designated as severe fever with thrombocytopenia syndrome virus (SFTSV). The aim of the present study was to determine the seroprevalence and risk factors of SFTSV infection. The investigation was conducted among the general population in Jiangsu Province, China in 2011. A total of 2,510 serum samples were collected. Testing by enzyme-linked immunosorbent assay was conducted to determine the seroprevalence of SFTSV infection. Result showed that the overall seroprevalence of SFTSV infection was 0.44% (11 of 2,510) in seven counties in Jiangsu Province. Multiple variable logistic regression analysis showed that raising goats, farming, and grazing were risk factors for SFTSV infection. Raising goats, farming, and grazing might be important risk factors for virus exposure, and appropriate health education could be useful in preventing infections.     

Epidemiological Survey of Severe Fever with Thrombocytopenia Syndrome Virus in Ticks in Nagasaki,Japan

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease endemic in East Asia. Transmitted to other organisms by infected ticks, the SFTS virus (SFTSV) and is endemic to Nagasaki in western Japan. However, epidemiological information regarding SFTSV in Nagasaki ticks has not been available to date. In this study, we began by examining the sensitivities of SFTSV gene detection by real-time RT-PCR and virus isolation in cultured cells and mice. These methods could detect SFTSV in the samples containing more than 4 × 10⁰ ffu. Next, we attempted to isolate SFTSV and to detect viral gene in 2,222 nymph and adult ticks collected from May to August 2013 among seven regions of Nagasaki. However, neither virus isolation nor viral gene detection were confirmed in the tick pools. SFTSV positivity rates are considered to be very low in ticks, and viral loads are also very limited. Further investigations increasing the number of ticks and including larval samples as well as improved detection methods, may be required to find SFTSV-positive ticks in this region.     

Severe Fever with Thrombocytopenia Syndrome in Cats and Its Prevalence among Veterinarian Staff Members in Nagasaki,Japan

In this study, we investigated severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) infection in cats in Nagasaki, Japan. In total, 44 of 133 (33.1%) cats with suspected SFTS were confirmed to be infected with SFTSV. Phylogenetic analyses of SFTSV isolates from cats indicated that the main genotype in Nagasaki was J1 and that unique reassortant strains with J2 (S segment) and unclassified genotypes (M and L segments) were also present. There were no significant differences in virus growth in cell cultures or fatality in SFTSV-infected mice between the SFTSV strains that were isolated from recovered and fatal cat cases. Remarkably, SFTSV RNAs were detected in the swabs from cats, indicating that the body fluids contain SFTSV. To evaluate the risk of SFTSV infection when providing animal care, we further examined the seroprevalence of SFTSV infection in veterinarian staff members; 3 of 71 (4.2%) were seropositive for SFTSV-specific antibodies. Our results provide useful information on the possibility of using cats as sentinel animals and raised concerns of the zoonotic risk of catching SFTSV from animals.     

Kinetics of Glycoprotein-Specific Antibody Response in Patients with Severe Fever with Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne disease in East Asia that is causing high mortality. The Gn glycoprotein of the SFTS virus (SFTSV) has been considered to be an essential target for virus neutralization. However, data on anti-Gn glycoprotein antibody kinetics are limited. Therefore, we investigated the kinetics of Gn-specific antibodies compared to those of nucleocapsid protein (NP)-specific antibodies. A multicenter prospective study was performed in South Korea from January 2018 to September 2021. Adult patients with SFTS were enrolled. Anti-Gn-specific IgM and IgG were measured using an enzyme-linked immunosorbent assay. A total of 111 samples from 34 patients with confirmed SFTS were analyzed. Anti-Gn-specific IgM was detected at days 5–9 and peaked at day 15–19 from symptom onset, whereas the anti-NP-specific IgM titers peaked at days 5–9. Median seroconversion times of both anti-Gn- and NP-specific IgG were 7.0 days. High anti-Gn-specific IgG titers were maintained until 35–39 months after symptom onset. Only one patient lost their anti-Gn-specific antibodies at 41 days after symptom onset. Our data suggested that the anti-Gn-specific IgM titer peaked later than anti-NP-specific IgM, and that anti-Gn-specific IgG remain for at least 3 years from symptom onset.     

Phylogenetic Analysis of Severe Fever with Thrombocytopenia Syndrome Virus in South Korea and Migratory Bird Routes between China,South Korea,and Japan

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease. The SFTS virus (SFTSV) has been detected in the Haemaphysalis longicornis, which acts as a transmission host between animals and humans. SFTSV was first confirmed in China in 2009 and has also been circulating in Japan and South Korea. However, it is not known if a genetic connection exists between the viruses in these regions and, if so, how SFTSV is transmitted across China, South Korea, and Japan. We therefore hypothesize that the SFTSV in South Korea share common phylogenetic origins with samples from China and Japan. Further, we postulate that migratory birds, well-known carriers of the tick H. longicornis, are a potential source of SFTSV transmission across countries. Our phylogenetic analysis results show that the SFTSV isolates in South Korea were similar to isolates from Japan and China. We connect this with previous work showing that SFTSV-infected H. longicornis were found in China, South Korea, and Japan. In addition, H. longicornis were found on migratory birds. The migratory bird routes and the distribution of H. longicornis are concurrent with the occurrence of SFTSV. Therefore, we suggest that migratory birds play an important role in dispersing H. longicornis-borne SFTSV.