A nomogram to predict mortality in patients with severe fever with thrombocytopenia syndrome at the early stage-A multicenter study in China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) caused by the SFTS virus is an emerging infectious disease that was first identified in the rural areas of China in 2011. Severe cases often result in death due to multiple organ failure. To date, there are still numerous problems remain unresolved in SFTS, including unclear pathogenesis, lack of specific treatment, and no effective vaccines available. AIM: To analyze the clinical information of patients with early-stage SFTS and to establish a nomogram for the mortality risk. METHODS: Between April 2011 and December 2018, data on consecutive patients who were diagnosed with SFTS were prospectively collected from five medical centers distributed in central and northeastern China. Multivariable Cox analyses were used to identify the factors independently associated with mortality. A nomogram for mortality was established using those factors. RESULTS: During the study period, 429 consecutive patients were diagnosed with SFTS at the early stage of the disease (within 7 days of fever), among whom 69 (16.1%) died within 28 days. The multivariable Cox proportional hazard regression analysis showed that low lymphocyte percentage, early-stage encephalopathy, and elevated concentration of serum LDH and BUN were independent risk factors for fatal outcomes. Received-operating characteristic curves for 7-, 14-, and 28-days survival had AUCs of 0.944 (95% CI: 0.920-0.968), 0.924 (95% CI: 0.896-0.953), and 0.924 (95% CI: 0.895-0.952), respectively. Among low-risk patients, 6 patients died (2.2%). Among moderate-risk patients, 25 patients died (24.0%, hazard ratio (HR) = 11.957). Among high-risk patients, the mortality rate was 69.1% (HR = 57.768). CONCLUSION: We established a simple and practical clinical scoring system, through which we can identify critically ill patients and provide intensive medical intervention for patients as soon as possible to reduce mortality.

Nucleocapsid protein-specific IgM antibody responses in the disease progression of severe fever with thrombocytopenia syndrome.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that is caused by the SFTS virus (SFTSV) and has a high fatality rate. SFTSV-specific antibody profiles among patients with different clinical outcomes are yet to be described. The nucleocapsid protein (NP) is the most immunogenic viral antigen of the SFTSV. This study, therefore, sought to determine NP-specific antibody responses among SFTS patients with different disease progressions. METHODS: In the present study, 43 patients with confirmed SFTS were enrolled in our cohort, and 9 of them deceased. The clinical presentations and key laboratory parameters associated with SFTS fatality were also recorded. Serum samples from each patient were collected every 2 days during their hospitalization. NP-specific IgM and IgG responses as well as Gn or Gc-specific IgM responses were examined by enzyme-linked immunosorbent assay (ELISA), whereas, the dynamic viral loads of SFTSV RNA were quantified via real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: First, 77% of patients generated positive NP-specific IgM antibody responses within two weeks since illness onset, defined as 'N-specific IgM-positive patients', while the rest of the patients were termed as 'N-specific IgM-delayed patients'. Only 17% of the patients generated NP-specific IgG responses. The absence of NP-specific humoral responses was strongly associated with a high risk of fatality and severity of SFTS. IgM-positive patients had significantly lower levels of viral loads, less disturbed coagulopathy, and hepatic and cardiac damage compared to IgM-delayed patients. Moreover, compared to severe or fatal SFTS patients, mild SFTS patients had significantly higher magnitudes of NP-specific IgM responses, but not NP-specific IgG, Gn-specific IgM, or Gc-specific IgM responses. The abundance of NP-specific IgM responses negatively correlated with viral loads, coagulation disturbances, and hepatic injuries among SFTS patients. CONCLUSIONS: Our data highlight distinct humoral profiles of NP-specific IgM responses among SFTS patients with different disease progressions and clinical outcomes.

Survey to determine the farm-level impact of Schmallenberg virus during the 2016-2017 United Kingdom lambing season.

Schmallenberg virus (SBV) causes abortions, stillbirths and fetal malformations in naïve ruminants. The impact of the initial outbreak (2011/2012) on British sheep farms has been previously investigated, with higher farmer perceived impacts and increased lamb and ewe mortality reported on SBV-affected farms. After several years of low, or no, circulation the UK sheep flock once again became vulnerable to SBV infection. Re-emergence was confirmed in autumn 2016. This study reports the analysis of a questionnaire designed to determine the farm-level impact of SBV on the 2016/2017 UK lambing period. Higher neonatal lamb mortality, dystocia and associated ewe deaths, and higher perceived impacts on sheep welfare, flock financial performance and farmer emotional wellness were reported on SBV confirmed (n=59) and SBV suspected (n=82), than SBV not suspected (n=74) farms. Additionally, although few farmers (20.4 per cent) reported previously vaccinating against SBV, the majority (78.3 per cent) stated they would vaccinate if purchasing at less than £1 per dose. These results are largely comparable to the findings reported for the 2011/2012 outbreak, highlighting the ongoing impact of SBV on sheep farms. If SBV continues to re-emerge cyclically, the economic and animal welfare costs to the UK sheep farming industry will continue.

Vascular endothelial injury in severe fever with thrombocytopenia syndrome caused by the novel bunyavirus.

Severe fever with thrombocytopenia syndrome virus (SFTSV) infection typically causes acute fever, thrombocytopenia and leucopenia, presenting with a high case fatality rate. The pathogenesis of SFTSV infection, however, is not well described. It was hypothesized that endothelial dysfunction might play part in the disease process. In current study, we retrospectively analyzed the clinical manifestations among a large group of confirmed SFTS cases and found evidence of plasma leakage and vascular endothelial injury. Then we established a SFTSV infection cell model and determined the infectivity and stimulation of SFTSV on vascular endothelial cells in vitro. The hyperpermeability of endothelial cells directly induced by SFTSV was confirmed by electrical resistance and dextran diffusion assay. The virus induced alterations of cell junctions and cytoskeleton was also revealed. It's suggested that vascular endothelial cell injury and barrier function damage were induced after SFTSV infection, which is a vital but neglected pathogenesis of SFTS.

Dynamic changes in the immunological characteristics of T lymphocytes in surviving patients with severe fever with thrombocytopenia syndrome (SFTS).

OBJECTIVE: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality. T cell deficiency has recently been described, but the changes in T cell functionality during acute SFTS virus (SFTSV) infection and the mechanisms leading to T lymphocyte death remain largely unknown. This study was conducted to evaluate T cell functionality and the expression of apoptotic/proliferation and activation/inhibition markers during acute SFTSV infection. METHODS: Twenty-eight surviving SFTS patients were sequentially sampled during their entire hospital stay. SFTSV RNA copies were investigated using real-time RT-PCR. The expression levels of apoptotic markers (annexin V and CD95) and proliferation and activation markers (Ki-67, HLA-DR, and CD25) and the expression levels of programmed cell death-1 (PD-1), interferon gamma (IFN-γ), and granzyme B in T cells were evaluated by flow cytometry for the SFTS patients. RESULTS: In parallel with T cell depletion, higher annexin V and CD95 expression was observed in SFTS patients. Additionally, the expression levels of Ki-67, HLA-DR, CD25, and PD-1 and the levels of IFN-γ and granzyme B in T lymphocytes were markedly increased in the SFTS patients. CONCLUSIONS: T cell proliferation, activation, and functional enhancement were apparent despite the observation of T cell apoptosis, suggesting that these processes are involved in the complex protective response to SFTSV infection.

Isolation and characterization of Kabuto Mountain virus, a new tick-borne phlebovirus from Haemaphysalis flava ticks in Japan.

In Japan, indigenous tick-borne phleboviruses (TBPVs) and their associated diseases first became evident in 2013 by reported human cases of severe fever with thrombocytopenia syndrome (SFTS). In this study, we report a novel member of the genus Phlebovirus designated as Kabuto Mountain virus (KAMV), which was isolated from the ixodid tick Haemaphysalis flava in Hyogo, Japan. A complete viral genome sequencing and phylogenetic analyses showed that KAMV is a novel member of TBPVs, which is closely related to the Uukuniemi and Kaisodi group viruses. However, unlike the Uukuniemi group viruses, the 165-nt intergenic region (IGR) in the KAMV S segment was highly C-rich in the genomic sense and not predicted to form a secondary structure, which are rather similar to those of the Kaisodi group viruses and most mosquito/sandfly-borne phleboviruses. Furthermore, the NSs protein of KAMV was highly divergent from those of other TBPVs. These results provided further insights into the genetic diversity and evolutionary relationships of TBPVs. KAMV could infect and replicate in some rodent and primate cell lines. We evaluated the infectivity and pathogenicity of KAMV in suckling mice, where we obtained a virulent strain after two passages via intracerebral inoculation. This is the first report showing the existence of a previously unrecognized TBPV in Japan, other than the SFTS virus.

Fetopathic effects of experimental Schmallenberg virus infection in pregnant goats.

Schmallenberg virus (SBV) is an emerging virus responsible for congenital malformations in the offspring of domestic ruminants. It is speculated that infection of pregnant dams may also lead to a significant number of unrecognized fetal losses during the early period of gestation. To assess the pathogenic effects of SBV infection of goats in early pregnancy, we inoculated dams at day 28 or 42 of gestation and followed the animals until day 55 of gestation. Viremia in the absence of clinical signs was detected in all virus-inoculated goats. Fetal deaths were observed in several goats infected at day 28 or 42 of gestation and were invariably associated with the presence of viral genomic RNA in the affected fetuses. Among the viable fetuses, two displayed lesions in the central nervous system (porencephaly) in the presence of viral genome and antigen. All fetuses from goats infected at day 42 and the majority of fetuses from goats infected at day 28 of gestation contained viral genomic RNA. Viral genome was widely distributed in these fetuses and their respective placentas, and infectious virus could be isolated from several organs and placentomes of the viable fetuses. Our results show that fetuses of pregnant goats are susceptible to vertical SBV infection during early pregnancy spanning at least the period between day 28 and 42 of gestation. The outcomes of experimental SBV infection assessed at day 55 of gestation include fetal mortalities, viable fetuses displaying lesions of the central nervous system, as well as viable fetuses without any detectable lesion.

Score risk model for predicting severe fever with thrombocytopenia syndrome mortality.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging epidemic infectious disease with high mortality in East Aisa, especially in China. To predict the prognosis of SFTS precisely is important in clinical practice. METHODS: From May 2013 to November 2015, 233 suspected SFTS patients were tested for SFTS virus using RT-PCR. Cox regression model was utilized to comfirm independent risk factors for mortality. A risk score model for mortality was constructed based on regression coefficient of risk factors. Log-rank test was used to evaluate the significance of this model. RESULTS: One hundred seventy-four patients were confirmed with SFTS, of which 40 patients died (23%). Baseline age, serum aspartate aminotransferase (AST) and serum creatinine (sCr) level were independent risk factors of mortality. The area under ROC curve (AUCs) of these parameters for predicting death were 0.771, 0.797 and 0.764, respectively. And hazard ratio (HR) were 1.128, 1.002 and 1.013, respectively. The cutoff value of the risk model was 10. AUC of the model for predicting mortality was 0.892, with sensitivity and specificity of 82.5 and 86.6%, respectively. Log-rank test indicated strong statistical significance (×2 = 88.35, p < 0.001). CONCLUSIONS: This risk score model may be helpful to predicting the prognosis of SFTS patients.

Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease endemic in parts of Asia. The etiologic agent, SFTS virus (SFTSV; family Bunyaviridae, genus Phlebovirus) has caused significant morbidity and mortality in China, South Korea, and Japan, with key features of disease being intense fever, thrombocytopenia, and leukopenia. Case fatality rates are estimated to be in the 30% range, and no antivirals or vaccines are approved for use for treatment and prevention of SFTS. There is evidence that in human cells, SFTSV sequesters STAT proteins in replication complexes, thereby inhibiting type I interferon signaling. Here, we demonstrate that hamsters devoid of functional STAT2 are highly susceptible to as few as 10 PFU of SFTSV, with animals generally succumbing within 5 to 6 days after subcutaneous challenge. The disease included marked thrombocytopenia and inflammatory disease characteristic of the condition in humans. Infectious virus titers were present in the blood and most tissues 3 days after virus challenge, and severe inflammatory lesions were found in the spleen and liver samples of SFTSV-infected hamsters. We also show that SFTSV infection in STAT2 knockout (KO) hamsters is responsive to favipiravir treatment, which protected all animals from lethal disease and reduced serum and tissue viral loads by 3 to 6 orders of magnitude. Taken together, our results provide additional insights into the pathogenesis of SFTSV infection and support the use of the newly described STAT2 KO hamster model for evaluation of promising antiviral therapies. IMPORTANCE: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral disease for which there are currently no therapeutic options or available vaccines. The causative agent, SFTS virus (SFTSV), is present in China, South Korea, and Japan, and infections requiring medical attention result in death in as many as 30% of the cases. Here, we describe a novel model of SFTS in hamsters genetically engineered to be deficient in a protein that helps protect humans and animals against viral infections. These hamsters were found to be susceptible to SFTSV and share disease features associated with the disease in humans. Importantly, we also show that SFTSV infection in hamsters can be effectively treated with a broad-spectrum antiviral drug approved for use in Japan. Our findings suggest that the new SFTS model will be an excellent resource to better understand SFTSV infection and disease as well as a valuable tool for evaluating promising antiviral drugs.

A simple and practical score model for predicting the mortality of severe fever with thrombocytopenia syndrome patients.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging disease with a high fatality rate. The risk factors for death are not clearly identified, and there is no clinical score model to predict the prognosis. We retrospectively collected the clinical information of clinical symptoms and laboratory parameters of SFTS patients on admission. After analyzing the clinical characteristics of 179 SFTS patients, we found that an elevated level of neurologic symptoms, respiratory symptoms, viral load, and a lower level of monocyte percentage were the critical risk factors for mortality. We used the 4 variables to assemble a score formula named the SFTS index [SFTSI = 5 × Neurologic symptoms-level + 4 × Respiratory symptoms-level + 3 × LG10 Viral load - 2 × LN Monocyte% - 7]. The AURC of this model was 0.964, which was higher than the AURC 0.913 of the viral load especially among the patients with higher viral loads (0.936 vs 0.821). We identified that the neurologic symptoms, respiratory symptoms, viral load, and monocyte percentage were the critical risk factors for SFTS mortality. The clinical score model of SFTSI provides a practical method for clinicians to stratify patients with SFTS and to adopt prompt effective treatment strategies.

Tofla virus: A newly identified Nairovirus of the Crimean-Congo hemorrhagic fever group isolated from ticks in Japan.

Ixodid ticks transmit several important viral pathogens. We isolated a new virus (Tofla virus: TFLV) from Heamaphysalis flava and Heamaphysalis formsensis in Japan. The full-genome sequences revealed that TFLV belonged to the genus Nairovirus, family Bunyaviridae. Phylogenetic analyses and neutralization tests suggested that TFLV is closely related to the Hazara virus and that it is classified into the Crimean-Congo hemorrhagic fever group. TFLV caused lethal infection in IFNAR KO mice. The TFLV-infected mice exhibited a gastrointestinal disorder, and positron emission tomography-computed tomography images showed a significant uptake of (18)F-fluorodeoxyglucose in the intestinal tract. TFLV was able to infect and propagate in cultured cells of African green monkey-derived Vero E6 cells and human-derived SK-N-SH, T98-G and HEK-293 cells. Although TFLV infections in humans and animals are currently unknown, our findings may provide clues to understand the potential infectivity and to develop of pre-emptive countermeasures against this new tick-borne Nairovirus.

Epidemiological and clinical characteristics of severe fever with thrombocytopenia syndrome (SFTS) in China: an integrated data analysis.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was caused by a novel bunyavirus, SFTSV. The study aimed to disclose the epidemiological and clinical characteristics of SFTSV infection in China so far. An integrated clinical database comprising 1920 SFTS patients was constructed by combining first-hand clinical information collected from SFTS sentinel hospitals (n = 1159) and extracted data (n = 761) from published literature. The considered variables comprised clinical manifestations, routine laboratory tests of acute infection, hospitalization duration and disease outcome. SFTSV-IgG data from 19 119 healthy subjects were extracted from the published papers. The key clinical variables, case-fatality rate (CFR) and seroprevalence were estimated by meta-analysis. The most commonly seen clinical manifestations of SFTSV infection were fever, anorexia, myalgia, chill and lymphadenopathy. The major laboratory findings were elevated lactate dehydrogenase, aminotransferase, followed by thrombocytopenia, lymphocytopenia, elevated alanine transaminase and creatine kinase. A CFR of 12·2% was estimated, significantly higher than that obtained from national reporting data, but showing no geographical difference. In our paper, the mortality rate was about 1·9 parts per million. Older age and longer delay to hospitalization were significantly associated with fatal outcome. A pooled seroprevalence of 3·0% was obtained, which increased with age, while comparable for gender. This study represents a clinical characterization on the largest group of SFTS patients up to now. A higher than expected CFR was obtained. A wider spectrum of clinical index was suggested to be used to identify SFTSV infection, while the useful predictor for fatal outcome was found to be restricted.

Characteristics and Factors Associated with Death among Patients Hospitalized for Severe Fever with Thrombocytopenia Syndrome, South Korea, 2013.

In South Korea, nationwide surveillance for severe fever with thrombocytopenia syndrome (SFTS) began during 2013. Among 301 surveillance cases, 35 hospitalized case-patients in 25 areas were confirmed by using virologic testing, and 16 (46%) case-patients subsequently died. The SFTS cases occurred during May-November and peaked during June (9 cases, 26%). The incidence of SFTS was higher in the southern regions of South Korea. Age and neurologic symptoms, including decreased level of consciousness and slurred speech, were heavily associated with death; neurologic symptoms during the first week after disease onset were also associated with death. Although melena was common among patients who died, no other hemorrhagic manifestations were substantively more common among those who died. No effective treatments, including ribavirin, were identified. Expansion of SFTS surveillance to include the outpatient sector and development of an antibody test would enhance completeness of SFTS detection in South Korea.

Genetic Susceptibility Is One of the Determinants for Severe Fever with Thrombocytopenia Syndrome Virus Infection and Fatal Outcome: An Epidemiological Investigation.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China and case-fatality rate of SFTS is very high (approximately 10%). However, genetic susceptibility for SFTS virus (SFTSV) infection and fatal outcome of SFTSV infection in humans are unclear. In this study, we investigated the clinical, laboratory and epidemiological features of SFTS in a cluster of three sisters who died of SFTSV infection between late April and mid-May 2014. Before disease onset, two of the sisters (Case A and case B) had common exposure history for ticks by working together in a field to pick tea leaves from April 8 to April 12. The third sister (Case C) did not live or work together with case A and B, but had ticks in her living environment. SFTSV RNA sequences were amplified from three cases were not identical, suggesting that the three sisters were most likely infected with SFTSV through tick bite rather than through person-to-person transmission of SFTSV. The sequence of SFTSV from case C was identical to SFTSV sequences from 3 groups of ticks collected around the residential area of case C. Seroprevalence of SFTSV IgG antibody among healthy population in the area where the patients resided was 4.05% (3/74). The majority of SFTSV infections were mild cases and all three sisters died of SFTSV infection suggested that they were highly susceptible to SFTSV. Our findings indicated that genetic susceptibility was a risk factor for SFTSV infection and fatal outcome.

Age is a critical risk factor for severe fever with thrombocytopenia syndrome.

BACKGROUND: Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease in East Asia. SFTS is a tick borne hemorrhagic fever caused by SFTSV, a new bunyavirus named after the syndrome. We investigated the epidemiology of SFTS in Laizhou County, Shandong Province, China. METHODS: We collected serum specimens of all patients who were clinically diagnosed as suspected SFTS cases in 2010 and 2011 in Laizhou County. The patients' serum specimens were tested for SFTSV by real time fluorescence quantitative PCR (RT-qPCR). We collected 1,060 serum specimens from healthy human volunteers by random sampling in Laizhou County in 2011. Healthy persons' serum specimens were tested for specific SFTSV IgG antibody by ELISA. RESULTS: 71 SFTS cases were diagnosed in Laizhou County in 2010 and 2011, which resulted in the incidence rate of 4.1/100,000 annually. The patients ranged from 15 years old to 87 years old and the median age of the patients were 59 years old. The incidence rate of SFTS was significantly higher in patients over 40 years old and fatal cases only occurred in patients over 50 years old. 3.3% (35/1,060) of healthy people were positive to SFTSV IgG antibody. The SFTSV antibody positive rate was not significantly different among people at different age groups. CONCLUSION: Our results revealed that seroprevalence of SFTSV in healthy people in Laizhou County was not significantly different among age groups, but SFTS patients were mainly elderly people, suggesting that age is the critical risk factor or determinant for SFTS morbidity and mortality.

Risk factors for malformations and impact on reproductive performance and mortality rates of Schmallenberg virus in sheep flocks in the Netherlands.

In Northwestern Europe, an epizootic outbreak of congenital malformations in newborn lambs due to infection with Schmallenberg virus (SBV) started at the end of 2011. The objectives of this study were to describe clinical symptoms of SBV infection, the effect of infection on mortality rates, and reproductive performance in sheep, as well as to identify and quantify flock level risk factors for SBV infections resulting in malformations in newborn lambs. A case-control study design was used, with 93 case flocks that had notified malformed lambs and 84 control flocks with no such lambs. Overall animal seroprevalence in case flocks was estimated at 82.0% (95% CI: 74.3-87.8), and was not significantly different from the prevalence in control flocks being 76.4% (95% CI: 67.2-83.6). The percentages of stillborn lambs or lambs that died before weaning, repeat breeders, and lambs with abnormal suckling behaviour were significantly higher in case flocks compared to control flocks. However, effect of SBV infection on mortality rates and reproductive performance seemed to be limited. Multivariable analysis showed that sheep flocks with an early start of the mating season, i.e. before August 2011 (OR = 33.1; 95% CI: 10.0-109.8) and in August 2011 (OR = 8.2; 95% CI: 2.7-24.6) had increased odds of malformations in newborn lambs caused by SBV compared to sheep flocks with a start of the mating season in October 2011. Other flock-level risk factors for malformations in newborn lambs were purchase of silage (OR 5.0; 95% CI: 1.7-15.0) and flocks with one or more dogs (OR = 3.3; 95% CI: 1.3-8.3). Delaying mating until October could be a potential preventive measure for naïve animals to reduce SBV induced losses. As duration of immunity after infection with SBV is expected to last for several years, future SBV induced congenital malformations are mainly expected in offspring of early mated seronegative animals.

Schmallenberg virus epidemic: impact on milk production, reproductive performance and mortality in dairy cattle in the Netherlands and Kleve district, Germany.

Schmallenberg virus (SBV), a novel orthobunyavirus that rapidly spread throughout north-western Europe in 2011, caused congenital malformations in lambs and goat kids (Van den Brom et al., 2012) and newborn calves (Hoffmann et al., 2012). The impact of the SBV epidemic seemed limited however, in terms of the number of affected herds with malformed offspring (European Food Safety Authority, 2012b). Nevertheless, little is known with regard to the overall within-herd impact of SBV infection. The objective of the current study was to quantify the impact of the 2011 SBV epidemic on the productivity of dairy cattle in the Netherlands and the district of Kleve, Germany. For the Netherlands, several multilevel multivariable statistical models were applied on eight productivity parameters regarding milk production, reproductive performance and mortality. All four fertility parameters analysed were slightly but significantly reduced between August 1st and November 1st 2011 compared to the reference period in 2009-2010. Between August 15th and September 19th 2011, the average loss in milk production per cow was -0.26kg (95% CI: -0.30; -0.22) per day in dairy herds, compared to the reference period (p<0.001). The total loss per cow in a subgroup of dairy herds that notified malformations in newborn calves during the mandatory notification period in the Netherlands was -0.43kg (95% CI: -0.59; -0.28) per day (p<0.001). For Germany, a study was carried out in the district of Kleve, situated in the state of North Rhine-Westphalia near the Dutch border. Data on milk yield, two fertility parameters and the number of rendered calves in this specific region were analysed. There was a small but significant increase in the number of secondary and third inseminations between August 1st and November 1st 2011, indicating reduced fertility. No significant change in calf mortality was observed in the assumed SBV period. Milk production at district level did not seem to be affected by SBV in August and September 2011. SBV had no or limited impact on mortality rates, which was as expected given the relatively mild expression of SBV in adult cows and the low incidence of notified malformations in newborn calves. Our results indicate that SBV had a limited impact on productivity of dairy cattle. However, the total economic impact of SBV on the ruminant industry not only consists of productivity caused losses; it is expected that international trade restrictions formed a larger part of the total economic impact.

The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR(-/-)) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10(6) focus-forming units of SFTSV. Histologic examination of tissues of IFNAR(-/-) mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.

Preliminary survey on the impact of Schmallenberg virus on sheep flocks in South of Belgium.

Between late February and May 2012, a preliminary anonym survey was conducted among sheep farmers in south of Belgium in order to contribute to future estimations of the economic losses caused by Schmallenberg virus (SBV). Based on clinical signs consistent with SBV infection, this survey involved 13 meat sheep flocks considered as positive flocks with subsequent SBV detection by RT-qPCR [SBV-positive flocks (PF); total of 961 animals], and 13 meat sheep flocks considered as negative flocks (NF; total of 331 animals). These preliminary results indicated several significant characteristics that were more present in PF than in NF. These include an increased rate of abortions (6.7% in PF versus 3.2% in NF), of lambs born at term but presenting malformations (10.1% in PF versus 2.0% in NF) and of dystocia (10.1% in PF versus 3.4% in NF). Lamb mortality during the first week of life was reported more frequently in PF (8 of 13 PF, 61.5%) than in NF (1 of 13 NF, 7.7%). In PF, the observed prolificacy rate was 2-fold lower (93%) than expected (186%). The implementation of a survey at larger scale, including a high number of breeders, is necessary to allow a more detailed analysis of the SBV impact in the sheep sector.

Clinical progression and predictors of death in patients with severe fever with thrombocytopenia syndrome in China.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease of which the clinical progression and factors related to death are still unclear. OBJECTIVE: To identify the clinical progression of SFTS and explore predictors of fatal outcome throughout the disease progress. STUDY DESIGN: A prospective study was performed in a general hospital located in Xinyang city during 2011-2013. Confirmed SFTS patients were recruited and laboratory parameters that were commonly evaluated in clinical practice were collected. The clinical progression was determined based on analysis of dynamic profiles and Friedman's test. At each clinical stage, the laboratory features that could be used to predict fatal outcome of SFTS patients were identified by stepwise discriminant analysis. RESULTS: Totally 257 survivors and 54 deceased SFTS patients were recruited and the data of 11 clinical and laboratory parameters along their entire disease course were consecutively collected. Three clinical stages (day 1-5 post onset, day 6-11 post onset and day 12 to hospital discharge) were determined based on distinct clinical parameters evaluations. Multivariate discriminant analysis at each clinical stage disclosed the indicators of the fatal outcome as decreased platelet counts at early stage, older age and increased AST level at middle stage, and decreased lymphocyte percentage and increased LDH level at late stage. CONCLUSIONS: The significant indicators at three clinical stages could be used to assist identifying the patients with high risk of death. This knowledge might help to perform supportive treatment and avoid fatality.