Severe fever with thrombocytopenia syndrome: a systematic review and meta-analysis of epidemiology, clinical signs, routine laboratory diagnosis, risk factors, and outcomes.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with the high case-fatality rate, and lack of vaccines. We aimed to systematically analysed the epidemiological characteristics, clinical signs, routine laboratory diagnosis, risk factors, and outcomes. METHODS: Documents on SFTS were collected by searching the Chinese National Knowledge Infrastructure, Wan Fang Data, PubMed, Embase, and Web of Science databases from 2011 to 2018. Meta-analysis was performed by using Review Manager and Stata software. RESULTS: Twenty-five articles involving 4143 cases were included. Diarrhea (odds ratio (OR) =1.60, 95% confidence interval (CI): 1.06 to 2.42, P = 0.02), and vomiting (OR = 1.56, 95% CI: 1.01 to 2.39, P = 0.04) on admission were associated with the fatal outcomes of SFTS. Compared to patients with mild symptoms, patients with severe symptoms had significantly elevated levels of lactic acid dehydrogenase (standard mean difference (SMD) =1.27, 95% CI: 0.59 to 1.94), alanine aminotransferase (SMD = 0.55, 95% CI: 0.24 to 0.85), aspirate aminotransferase (SMD = 1.01, 95% CI: 0.69 to 1.32), and creatine kinase (SMD = 1.04, 95% CI: 0.74 to 1.33) but had reduced platelet counts (SMD = -0.87, 95% CI: - 1.16 to - 0.58) and albumin levels (SMD = -1.00, 95% CI: - 1.32 to - 0.68). The risk factors for poor prognosis included age (mean difference (MD) =6.88, 95% CI: 5.41 to 8.35) and farming (OR = 2.01, 95% CI: 1.06 to 3.80). For the risk factors of contracting SFTS, the incidence of SFTS related to tick bites was 24% [95% CI: 0.18 to 0.31]. The pooled case-fatality rate of SFTS patients was 18% [95% CI: 0.16 to 0.21]. CONCLUSIONS: China is the country with the highest incidence of SFTS. May to July was the peak of the epidemic, and farmers were a high-risk group. The risk factor for SFTS included age (poor prognosis) and tick bites (contracting SFTS). Patients with severe diarrhea and vomiting symptoms on admission should be noted. Clinicians could use routine laboratory parameters and clinical symptoms as references for clinically suspected cases, classification of SFTS, and timely treatment, especially in basic hospitals.

Predictive risk score model for severe fever with thrombocytopenia syndrome mortality based on qSOFA and SIRS scoring system.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is a severe systemic virus infectious disease usually having multi-organ dysfunction which resembles sepsis. METHODS: Data of 321 patients with laboratory-confirmed SFTS from May 2013 to July 2017 were retrospectively analyzed. Demographic and clinical characteristics, calculated quick sequential organ failure assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria for survivors and nonsurvivors were compared. Independent risk factors associated with in-hospital mortality were obtained using multivariable logistic regression analysis. Risk score models containing different risk factors for mortality in stratified patients were established whose predictive values were evaluated using the area under ROC curve (AUC). RESULTS: Of 321 patients, 87 died (27.1%). Age (p < 0.001) and percentage numbers of patients with qSOFA≥2 and SIRS≥2 (p < 0.0001) were profoundly greater in nonsurvivors than in survivors. Age, qSOFA score, SIRS score and aspartate aminotransferase (AST) were independent risk factors for mortality for all patients. qSOFA score was the only common risk factor in all patients, those age ≥ 60 years and those enrolled in the intensive care unit (ICU). A risk score model containing all these risk factors (Model1) has high predictive value for in-hospital mortality in these three groups with AUCs (95% CI): 0.919 (0.883-0.946), 0.929 (0.862-0.944) and 0.815 (0.710-0.894), respectively. A model only including age and qSOFA also has high predictive value for mortality in these groups with AUCs (95% CI): 0.872 (0.830-0.906), 0.885(0.801-0.900) and 0.865 (0.767-0.932), respectively. CONCLUSIONS: Risk models containing qSOFA have high predictive validity for SFTS mortality.

Severe Fever With Thrombocytopenia Syndrome Virus-Induced Macrophage Differentiation Is Regulated by miR-146.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever with a high mortality rate in humans, which is caused by SFTS virus (SFTSV), a novel phlebovirus in the Bunyaviridae family, is tick borne and endemic in Eastern Asia. Previous study found that SFTSV can infect and replicate in macrophages in vivo and in vitro. However, the role of macrophages in virus replication and the potential pathogenic mechanisms of SFTSV in macrophage remain unclear. In this study, we provided evidence that the SFTSV infection drove macrophage differentiation skewed to M2 phenotype, facilitated virus shedding, and resulted in viral spread. We showed evidence that miR-146a and b were significantly upregulated in macrophages during the SFTSV infection, driving the differentiation of macrophages into M2 cells by targeting STAT1. Further analysis revealed that the elevated miR-146b but not miR-146a was responsible for IL-10 stimulation. We also found that SFTSV increased endogenous miR-146b-induced differentiation of macrophages into M2 cells mediated by viral non-structural protein (NSs). The M2 skewed differentiation of macrophages may have important implication to the pathogenesis of SFTS.

Severe fever with thrombocytopenia syndrome can masquerade as hemorrhagic fever with renal syndrome.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with a high fatality rate and high frequency of person-to-person transmission and is caused by SFTSV, a tick-borne Phlebovirus. Because SFTS has similar clinical manifestations and epidemic characters (such as spatial and temporal distributions) with hemorrhagic fever with renal syndrome (HFRS) in China, we reason that SFTS patients might be misdiagnosed as HFRS. METHODOLOGY/PRINCIPAL FINDINGS: Acute-phase sera of 128 clinically diagnosed HFRS patients were retrospectively analyzed for Hantavirus IgM antibodies with ELISA. Hantavirus-negative patients' sera were further analyzed for SFTSV IgM antibodies with ELISA. ELISA showed that 73 of 128 (57.0%) of clinically diagnosed HFRS patients were IgM antibody positive to Hantaviruses. Among the 55 Hantavirus-IgM negative patients, four (7.3%) were IgM antibody positive to SFTSV. The results indicated that the four SFTS patients were misdiagnosed as HFRS. The misdiagnosed SFTS patients had clinical manifestations common to HFRS and were unable to be differentiated from HFRS clinically. CONCLUSIONS: Our study showed that SFTS patients could be clinically misdiagnosed as HFRS. The misdiagnosis of SFTS as HFRS causes particular concern because it may increase the risk of death of SFTS patients and person-to-person transmission of SFTSV without proper care for and isolation of SFTS patients.

Correlations between clinical features and death in patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging high-fatality infectious disease caused by a novel phlebovirus belonging to the Bunyaviridae family. Thus, the independent predictors of death in this disease must be identified to improve the survival of affected patients.A total of 25 hospitalized patients with SFTS virus infection were enrolled in our study, and their medical records and laboratory data were reviewed. The risk factors for death were examined by binary logistic regression.The patient age was significantly higher in the deceased cases than in those who recovered (P = .020). Moreover, the occurrence of shock, respiratory failure, hemorrhagic manifestations, kidney dysfunction, and arrhythmia was significantly more common in the deceased cases than in the recovered cases (P = .016, P = .004, P = .005, P = .002, P = .038). Univariate binary logistic regression showed that shock, arrhythmia, and hemorrhage, as well as PCT, serum creatinine (Scr), and blood urea nitrogen (BUN) elevations, were the risk factors for death (odds ratio, OR 28.5, P = .015; OR 13.5, P = .027; OR 36, P = .008; OR 28.5, P = .015; OR 36, P = .008; and OR 76.0, P = .004). However, the BUN increase was the only independent risk factor for death indicated by multivariate logistic regression (OR 76.0, P = .004).SFTS presents with a high fatality rate. When patients with SFTS manifest shock, arrhythmia, hemorrhage, PCT increase, and Scr and BUN elevations, especially BUN > 8.2 µmol/L, health care providers should be alerted and must administer early intervention to prevent the progress to death.

Analysis of clinical features and early warning indicators of death from severe fever with thrombocytopenia syndrome.

OBJECTIVE: To determine the clinical features of confirmed cases of severe fever with thrombocytopenia syndrome (SFTS) and to explore the early warning indicators of death from SFTS. METHODS: A retrospective case-control study was performed at a single medical institution in Yantai. A total of 20 SFTS patients who died (death group) during January 2014 to December 2015 and another 40 age- and sex-matched SFTS patients who survived (survivor group) were identified from the case records. The differences in demographic characteristics, clinical signs and symptoms, and laboratory parameters in the early stage of disease were compared between the two groups. Conditional logistic regression was used to identify the independent risk factors for mortality in SFTS patients. RESULTS: Univariate logistic regression analysis showed that a disturbance of consciousness, pulse-temperature deficit, neurological signs, hemorrhagic manifestations, pulmonary infection, decreased lymphocyte percentage, high lactate dehydrogenase and creatine kinase levels, increased serum creatinine, blood urea nitrogen, and C-reactive protein (CRP), hyponatremia, and prolonged activated partial thromboplastin time (APPT) and prothrombin time were associated with mortality. On multivariate logistic regression analysis, the independent predictors of death were neurological signs (odds ratio (OR) 31.247, 95% confidence interval (CI) 4.813-202.853), hemorrhagic manifestations (OR 20.251, 95% CI 2.056-199.443), disturbance of consciousness (OR 15.359, 95% CI 2.139-110.268), hyponatremia (OR 5.280, 95% CI 1.235-22.575), increased CRP (OR 2.641, 95% CI 1.090-6.396), increased serum creatinine (OR 6.776, 95% CI 1.047-43.840), and prolonged APTT (OR 6.018, 95% CI 1.450-24.975). CONCLUSIONS: Neurological signs, hemorrhagic manifestations, disturbance of consciousness, hyponatremia, prolonged APTT, and increased CRP and serum creatinine are risk factors for death in SFTS.

Clinical features of fatal severe fever with thrombocytopenia syndrome that is complicated by invasive pulmonary aspergillosis.

INTRODUCTION: Severe fever with thrombocytopenia syndrome (SFTS) has been prevalent in parts of Asia during recent years. However, SFTS with invasive pulmonary aspergillosis (IPA) is rare, and it is important to understand its clinical features. MATERIALS AND METHODS: Total four cases of SFTS with IPA are reviewed and detailing the disease progression, treatment options, and prognosis were summarized and analyzed. RESULTS: The patients with SFTS-associated IPA first presented with fever, gastrointestinal symptoms, thrombocytopenia, leukopenia, and multiple organ failure. After 1-2 weeks, the patients developed mild polypnea and wheezing rales, and quickly developed dyspnea and respiratory failure. Tracheal intubation was usually performed, but did not relieve the intractable airway spasm and pulmonary ventilation failure. Bronchoscopy confirmed that the antifungal treatment was ineffective and the aspergillosis had worsened. All patients died of type 2 respiratory failure caused by continued airway obstruction and spasticity. CONCLUSIONS: Given the high mortality rate in this series, there is a need for increased awareness of SFTS-associated IPA. Additional examinations should be performed in these cases, and early-stage antifungal treatment with organ support may be helpful.

Severe fever with thrombocytopenia syndrome-associated encephalopathy/encephalitis.

OBJECTIVES: Severe fever with thrombocytopenia syndrome (SFTS) virus has a variety of central nervous system (CNS) manifestations. However, there are limited data regarding SFTS-associated encephalopathy/encephalitis (SFTSAE) and its mechanism. METHODS: All patients with confirmed SFTS who underwent cerebrospinal fluid (CSF) examination due to suspected acute encephalopathy were enrolled in three referral hospitals between January 2013 and October 2016. Real-time RT-PCR for SFTS virus and chemokine/cytokines levels from blood and CSF were analysed. RESULTS: Of 41 patients with confirmed SFTS by RT-PCR for SFTS virus using blood samples, 14 (34%) underwent CSF examination due to suspected SFTSAE. All 14 patients with SFTSE revealed normal protein and glucose levels in CSF, and CSF pleocytosis was uncommon (29%, 4/14). Of the eight patients whose CSF was available for further analysis, six (75%) yielded positive results for SFTS virus. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) level in CSF were significantly higher than those in serum (geometric mean 1889 pg/mL in CSF versus 264 pg/mL in serum for MCP-1, p = 0.01, and geometric mean 340 pg/mL in CSF versus 71 pg/mL in serum for IL-8, p = 0.004). CONCLUSIONS: The CNS manifestation of SFTS as acute encephalopathy/encephalitis is a common complication of SFTS. Although meningeal inflammation was infrequent in patients with SFTSAE, SFTS virus was frequently detected in CSF with elevated MCP-1 and IL-8. These findings indicate that possible direct invasion of the CNS by SFTS virus with the associated elevated cytokine levels in CSF may play an important role in the pathogenesis of SFTSAE.

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.

A Pediatric Case of Severe Fever with Thrombocytopenia Syndrome in Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease and elderly people living in rural areas have the greatest risk of infection. We report the first pediatric case of SFTS in Korea and the clinical characteristics and disease progression in children. A 10-year-old child from Chonnam province visited the hospital with myalgia and a history of fever over the previous 8 days. Her father noticed a tick on her head and removed it before fever developed. Because the symptoms continued, her father consulted the community health center and SFTS virus was detected both from the tick (Haemaphysalis longicornis) and the patient's blood. On hospitalization, fever and severe myalgia were improved and no gastrointestinal and hemorrhagic symptoms were observed. The patient was successfully treated with a combination of steroids, IVIG, and ribavirin. In this report, a pediatric case of SFTS presents a mild clinical course but close attention must be paid to the screening of children with mild symptoms consisting of SFTS.

[A Fatal Case of Severe Fever with Thrombocytopenia Syndrome Complicated by Hemophagocytic Lymphohistiocytosis].

Severe fever with thrombocytopenia syndrome (SFTS) is a recently identified emerging viral infectious disease in China that is caused by a novel phlebovirus in the family Bunyaviridae, SFTS virus, with an average case fatality rate of 12-30%. A cytokine storm with abnormally expressed cytokine profiles is associated with the disease severity. Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and lifethreatening syndrome associated with excessive immune activation. We report herein on a fatal case of SFTS complicated by HLH. Consecutive plasma exchange and immunomodulatory therapy was ineffective in our case. The pathognomonic histological feature was necrotizing lymphadenitis with massive hemophagocytosis of systemic lymphoid tissues with SFTS viruses and SFTS-RNA copies. No specific treatment of SFTS is available, and an effective treatment strategy for patients with rapidly progressing SFTS has not been established. Appropriate immunomodulatory therapy is necessary for SFTS patients complicated by HLH.

Severe fever with thrombocytopenia syndrome bunyavirus-related human encephalitis.

BACKGROUND: Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus. Until recently, SFTSV-associated encephalitis remained largely uninvestigated. METHODS: We made clinical investigation on SFTS patients who experienced encephalitis in one reference hospital in Henan Province from 2011 to 2013 to identify the risk factors for encephalitis occurrence and their fatal outcome development. RESULTS: Altogether 538 SFTS patients were included and 19.1% of them developed encephalitis. Fatal outcome occurred in 44.7% of the encephalitis patients. The risk factors associated with encephalitis occurrence and death included older age, longer delay between disease onset and hospital admission, pre-existing diabetes and myalgias, as well as the laboratory evaluations of higher virus load on admission, decreased WBC, PLT count, lymphocyte percentage and ALB, elevated neutrophils percentage, AST, ALT, LDH, CK, ALP, GGT, BUN and CREA. These parameters could be used as potential predictors referring to severe SFTS cases. One SFTSV strain was isolated from cerebrospinal fluid sample. Cytokine/chemokine assay revealed that blood EOTAXIN, IFN-γ, IL-15, IL-6, IP-10, TNF-α were remarkably elevated before clinical deterioration in the confirmed encephalitis patient. CONCLUSIONS: SFTSV is capable of infecting the central nervous system and screening for SFTSV in encephalitis of unknown reason should be performed in SFTS endemic regions. The encephalitis occurrence and fatal outcome could be potentially predicted by clinical and laboratory evaluations.

[Acute Toscana virus infection in an anti-HIV positive patient]. / Anti-HIV pozitif bir hastada saptanan akut Toskana virus enfeksiyonu.

Sandfly fever is an infectious disease transmitted to people through sandfly bites. It usually takes three days and causes chills, high fever, headache, nausea-vomiting and myalgia. The causative agent, namely sandfly fever virus (SFV), is a member of the Bunyaviridae family, Phlebovirus genus. Toscana virus (TOSV) is a serotype of SFV, as so Sicilian and Naples viruses. Seroprevalence studies have demonstrated that SFV infections which have mild symptoms or asymptomatic, can be overcome. Studies concerning TOSV infections in Turkey are limited to a small number of regional seroprevalence surveys, blood-donor screening studies and detection of viral RNA in previously collected cerebrospinal fluid samples of suspected meningoencephalitis patients in whom no causative agents were identified. In this report from Turkey, the first acute case of TOSV infection diagnosed in a patient with HIV seropositivity, was presented. A 42-year-old male patient was admitted to Numune Research and Training Hospital Adana, Turkey with high fever, headache and malaise. The patient who lived in an area near to a forest in Istanbul, had no contact history with ticks, mosquitoes and other animals. He stated that he had had the symptoms before arriving to Adana. The patient was hospitalized due to leucopenia, anemia, and thrombocytopenia accompanying high fever. Serum samples were sent to National Arbovirus and Viral Zoonotic Diseases Unit of the Turkish Public Health Institute, for the detection of Crimean-Congo haemorrhagic fever (CCHF) virus and SFV. Western Blot test was run to confirm the presence of anti-HIV antibodies detected twice with ELISA. In the following days, the patient's fever and symptoms decreased, and thrombocyte levels increased. Although CCHF virus PCR and ELISA IgM tests as well as SFV IgM and IgG immunofluorescence antibody (IFA) tests were negative, real time reverse transcriptase PCR test yielded a positive result for TOSV. SFV IgG antibodies against Toscana and Naples viruses were found to be positive in the serum sample collected at the end of a three-week follow-up. Even though TOSV infection is usually known to have an asymptomatic clinical course, it may rarely lead to serious manifestations like meningoencephalitis. In our country where SFV is endemic, TOSV should be considered in the differential diagnosis of patients presenting with high fever and meningoencephalitis symptoms.

[Retrospective study of viral causes of central nervous system infections in Tunisia (2003-2009)]. / Étude rétrospective des étiologies virales des infections neuroméningées en Tunisie (2003-2009)

OBJECTIVES: To determine the role of enteroviruses, Herpesviridae, West Nile virus and Sandfly Toscana virus in central nervous system (CNS) infections in Tunisia. METHODOLOGY: 847 cerebrospinal fluid (CSF) samples, 427 serum samples and 23 stool samples were collected from 1071 patients hospitalized for CNS viral infections from January 2003 through December 2009. All CSF samples were first tested by PCR to detect enteroviruses and Herpesviridae. In specific epidemic contexts in patients negative for these viruses, arbovirus infection was tested by ELISA. RESULTS: Virological testing was positive in 17.5% of cases. West Nile virus and enteroviruses accounted for 58% of them, enteroviruses 23.5%, Herpesviridae 8.5%, and Toscana virus 10%. West Nile virus infection was observed only in 2003, during an outbreak in coastal regions. Toscana virus circulated regularly throughout the study period. Enteroviruses were responsible for grouped cases of aseptic meningitis in both 2003 and 2005. Arboviruses and enteroviruses were detected mainly in summer and autumn. Herpesviridae were associated with sporadic cases of meningoencephalitis. CONCLUSION: This report on viral causes of CNS infections in Tunisia shows that West Nile virus and enteroviruses appear to circulate mainly during epidemics, while the circulation of Toscana virus seems continuous. Negative virus findings may be due, at least in part, to late sampling, inappropriate sample collection and transportation to the virology lab, or failure to test for the right virus. It is essential to promote collaboration between clinicians and biologists to maximize the likelihood of diagnosis.

Histological description of the lymphadenopathy related to Toscana virus infection. Report of a case.

Toscana virus (TOSV) infection is a frequent cause of meningitis in central Italy during summer. The disease generally has a benign course. Rarely, the infection produces a severe disease, with encephalitis and signs of systemic involvement, including lymphadenopathy. Since there is no clinical necessity of performing lymph node biopsy in such cases, the histopathological feature of TOSV-related lymphadenitis is not known. We herein present a case in which lymphadenopathy preceded the onset of meningitis. The excised lymph node showed a non-specific mixed-type lymphoid hyperplasia, with follicular hyperplasia, sinusal expansion and paracortical involvement. We also demonstrated the presence of viral protein and viral RNA in the lymph node tissue.

Virus Toscana, West Nile y de la coriomeningitis linfocitaria como causantes de meningitis aséptica en España / Toscana virus, West Nile virus and lymphocoriomeningitis virus as causing agents of aseptic meningitis in Spain

Fundamento y objetivo: La mayoría de los casos de meningitis aséptica (MA) están causados por enterovirus (EV), virus del grupo herpes y de parotiditis (VP). Sin embargo, un porcentaje importante de casos de MA permanecen sin diagnóstico etiológico. Material y método: Se estudiaron los casos de MA recibidos en el Centro Nacional de Microbiología entre 2000 y 2005, negativos a EV, virus del grupo herpes y VP, de los que se dispuso de suero (341 casos, 382 sueros); se determinaron la inmunoglobulina G (IgG) y M (IgM) frente a virus Toscana (VTOS) y virus West Nile (VWN) por enzimoinmunoanálisis (Diesse, Italia, y Focus, EE. UU., respectivamente), y virus de la coriomeningitis linfocitaria (VCML) por inmunofluorescencia indirecta. Resultados: Se diagnosticaron 19 (5,6%) casos con infección reciente por VTOS con positividad de IgG e IgM. La prevalencia de la infección fue del 10, el 5,2, el 9,6, el 10,7, el 1,2 y el 1,6%, respectivamente, desde 2000 hasta 2005. Los casos se produjeron de mayo a octubre y han ocurrido en Madrid, costa de Levante y Andalucía. En relación con el VCML, se obtuvieron 4 (1,2%) casos positivos, por presencia de IgG e IgM (3 casos), o por seroconversión de IgG. Todos los casos fueron en verano y ocurrieron en Málaga, Badajoz, Madrid y Huelva. No se ha diagnosticado ningún caso por VWN. Conclusiones: Se confirma que el VTOS es un importante agente productor de MA en España, así como la presencia de infecciones por VCML. Se debe considerar la inclusión de ambos virus en el algoritmo diagnóstico de la MA (AU)

Background and objective: Cases of aseptic meningitis (AM) are mostly due to enterovirus (EV), herpesvirus, and mumps virus (MV). An important number of cases remains without an etiologic diagnosis. Material and method: Cases received at the National Center for Microbiology between 2000 and 2005, with negative results for EV, herpesviruses and MP, in which serum samples were available, were included in the study (341 cases, 382 serum samples). All the samples were tested for IgG and IgM to Toscana virus (TOSV), West Nile virus (WNV) by ELISA (from Diesse, Italy, and Focus, USA, respectively), and lymphocoriomeningitis virus (LCMV) by indirect immunofluorescence. Results: Nineteen cases (5,6%) showed IgG and IgM to TOSV, which was diagnosed as a recent infection. The prevalence of the infection was 10%, 5,2%, 9,6%, 10,7%, 1,2% and 1,6%, from 2000 up to 2005, respectively. Cases occurred from May to October, appearing in Madrid, Coast of Levante and Andalucía. In relation to LCMV, 4 positive cases were detected, either by presence of IgG and IgM (3 cases) or by IgG seroconversion. All cases occurred in Summer and were seen in Málaga, Badajoz, and Madrid. No recent infections due to WNV were detected. Conclusions: TOSV is confirmed as an important etiologic agent of AM in Spain. Infections due to LCMV were detected as well. Both viruses should be included in the AM diagnostic algorithm (AU)

Sandfly - Pappataci fever in Bosnia and Herzegovina: the new-old disease.

Sandfly fever viruses (SFV) are endemic in the Mediterranean, Middle East, northern African and western Asian countries. Toscana virus (TOSV), serotype of Sandfly fever Naples virus, is among of the three most prevalent viruses associated with meningitis during the warm seasons in northern Mediterranean countries. The historical data of the sandfly fever (Pappataci fever) indicates its origin in Bosnia and Herzegovina at the end of 19th century. There is a long period of time for which there are no data on research related to the SFV in Bosnia and Herzegovina. The purpose of the study was to investigate the presence of sandfly fever in Bosnia and Herzegovina in recent years. The 68 of serum samples were obtained from February 2006 until September 2008 from a group of patients with febrile illness of unknown etiology. The sera were tested on the presence of IgG and IgM antibodies against TOSV by specific serology test- recomLine Bunyavirus IgG/IgM immuno-line assay. The recent TOSV-infection was confirmed in the patients in each year during the study: 10,71% (3/28) in 2008; 9,38% (3/32) in 2007 and 12,50% (1/8) in 2006. The presence of specific antibodies to TOSV in the sera of the patients in recent years indicates re-emerging character of the disease in this region. It would be necessary to make biological, epidemiological and clinical research on the TOSV and related phleboviruses to elucidate the problem of SFV in Bosnia and Herzegovina.