Risk factors for neurological complications in children with Flavivirus infection.

This study aims to characterize the acute neurological manifestations caused by DENV, ZIKV, and YFV during hospitalization; identify the risk factors associated with persistent neurological complications after discharge; and evaluate the time to resolution during clinical follow-up. A prospective study evaluated 505 children, between March 2014 and July 2019, hospitalized with neurological manifestations and that doctors suspected infection of the central nervous system (CNS). Viral infection of collected cerebrospinal fluid (CSF) was confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). Patients were clinically followed up after hospital discharge. Analysis of predictive factors and survival curves was performed. This study identified clinical symptoms and changes in the CSF laboratory, electroencephalogram (EEG), and CNS image as predictors of complications in children with confirmed infection in the CNS by DENV, ZIKV, or YFV. No statistical difference was found (p value 0.574) in the time to the resolution of complications in children after hospital discharge between the three types of flaviviruses. Children with YFV, detected in CSF samples, had a 53% higher risk of developing neurological complications. Performing etiological diagnosis by RT-PCR of CSF samples of children with neurological manifestations, especially during Flavivirus outbreaks, is an essential tool for improving the prognosis and clinical follow-up of these patients.

Human Usutu Virus Infection with Atypical Neurologic Presentation, Montpellier, France, 2016.

Infection with Usutu virus (USUV) has been recently associated with neurologic disorders, such as encephalitis or meningoencephalitis, in humans. These findings indicate that USUV is a potential health threat. We report an acute human infection with USUV in France putatively associated with a clinical diagnosis of idiopathic facial paralysis.

Outbreak of West Nile virus infection among humans in Serbia, August to October 2012.

We describe the first reported outbreak of West Nile virus (WNV) infection in humans in Serbia in August to October 2012 and examine the association of various variables with encephalitis and fatal outcome. Enzyme-linked immunosorbent assay (ELISA) was used for detection of WNV-specific IgM and IgG antibodies in sera and cerebrospinal fluid. A total of 58 patients (mean age: 61 years; standard deviation: 15) were analysed: 44 were from Belgrade and its suburbs; 52 had neuroinvasive disease, of whom 8 had meningitis, while 44 had encephalitis. Acute flaccid paralysis developed in 13 of the patients with encephalitis. Age over 60 years and immunosuppression (including diabetes) were independently associated with the development of encephalitis in a multivariate analysis: odds ratio (OR): 44.8 (95% confidence interval (CI): 4.93­408.59); p=0.001 (age over 60 years); OR: 10.76 (95% CI: 1.06­109.65); p=0.045 (immunosuppression including diabetes). Respiratory failure requiring mechanical ventilation developed in 13 patients with encephalitis. A total of 35 patients had completely recovered by the time they were discharged; nine patients died. The presence of acute flaccid paralysis, consciousness impairment, respiratory failure and immunosuppression (without diabetes) were found to be associated with death in hospital in a univariate analysis (p<0.001, p=0.007, p<0.001 and p=0.010, respectively).

Hepatic Manifestations of Nonhepatotropic Infectious Agents Including Severe Acute Respiratory Syndrome Coronavirus-2, Adenovirus, Herpes Simplex Virus, and Coxiella burnetii.

Nonhepatotropic viruses such as adenovirus, herpes simplex virus, flaviviruses, filoviruses, and human herpes virus, and bacteria such as Coxiella burnetii, can cause liver injury mimicking acute hepatitis. Most of these organisms cause a self-limited infection. However, in immunocompromised patients, they can cause severe hepatitis or in some cases fulminant hepatic failure requiring an urgent liver transplant. Hepatic dysfunction is also commonly seen in patients with severe acute respiratory syndrome coronavirus-2 infection. Patients with preexisting liver diseases are likely at risk for severe coronavirus disease 2019 (COVID-19) and may be associated with poor outcomes.

The continued threat of emerging flaviviruses.

Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge.

Selective involvement of temporal regions in a case of flavivirus encephalitis.

Clinical manifestations of flavivirus infection may be various, from unapparent to severe meningoencephalitis. Our patient, 2 weeks after returning home from a holiday at Elba Island, developed biphasic fever, later associated with nausea and vomiting and followed by incoming seizures responsive to thiopental sodium only. Brain MRI showed bilateral hyperintensity (T2) in amygdale, hippocampus, left insular and temporal inferior cortex. Standard and microbiological CSF examination was normal, but microbiological serum analysis showed seroconversion for flavivirus. The patient came to our observation 6 months after disease onset and at that time he was affected by frequent seizures and severe cognitive impairment with behavioural disturbances; the patient also showed distal weakness with footstepping. EEG showed bitemporal epileptic foci. During the following months, seizures greatly decreased and cognitive status improved in response to a complex antiepileptic therapy. Flavivirus encephalitis should be taken into account in the differential diagnosis of encephalitis selectively involving temporal lobes.

First human case of Usutu virus neuroinvasive infection, Italy, August-September 2009.

We report the first worldwide case of Usutu virus (USUV) neuroinvasive infection in a patient with diffuse large B cell lymphoma who presented with fever and neurological symptoms and was diagnosed with meningoencephalitits. The cerebrospinal fluid was positive for USUV, and USUV was also demonstrated in serum and plasma samples by RT-PCR and sequencing. Partial sequences of the premembrane and NS5 regions of the viral genome were similar to the USUV Vienna and Budapest isolates.

Viral testing of 18 consecutive cases of equine serum hepatitis: A prospective study (2014-2018).

BACKGROUND: Three flaviviruses (equine pegivirus [EPgV]; Theiler's disease-associated virus [TDAV]; non-primate hepacivirus [NPHV]) and equine parvovirus (EqPV-H) are present in equine blood products; the TDAV, NPHV, and EqPV-H have been suggested as potential causes of serum hepatitis. OBJECTIVE: To determine the prevalence of these viruses in horses with equine serum hepatitis. ANIMALS: Eighteen horses diagnosed with serum hepatitis, enrolled from US referral hospitals. METHODS: In the prospective case study, liver, serum, or both samples were tested for EPgV, TDAV, NPHV, and EqPV-H by PCR. RESULTS: Both liver tissue and serum were tested for 6 cases, serum only for 8 cases, and liver only for 4 cases. Twelve horses received tetanus antitoxin (TAT) 4-12.7 weeks (median = 8 weeks), 3 horses received commercial equine plasma 6-8.6 weeks, and 3 horses received allogenic stem cells 6.4-7.6 weeks before the onset of hepatic failure. All samples were TDAV negative. Two of 14 serum samples were NPHV-positive. Six of 14 serum samples were EPgV-positive. All liver samples were NPHV-negative and EPgV-negative. EqPV-H was detected in the serum (N = 8), liver (N = 4), or both samples (N = 6) of all 18 cases. The TAT of the same lot number was available for virologic testing in 10 of 12 TAT-associated cases, and all 10 samples were EqPV-H positive. CONCLUSIONS AND CLINICAL IMPORTANCE: We demonstrated EqPV-H in 18 consecutive cases of serum hepatitis. EPgV, TDAV, and NPHV were not consistently present. This information should encourage blood product manufacturers to test for EqPV-H and eliminate EqPV-H-infected horses from their donor herds.

Zika virus-related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice.

Although Zika virus (ZIKV) infection in pregnant women can cause placental damage, intrauterine growth restriction, microcephaly, and fetal demise, these disease manifestations only became apparent in the context of a large epidemic in the Americas. We hypothesized that ZIKV is not unique among arboviruses in its ability to cause congenital infection. To evaluate this, we tested the capacity of four emerging arboviruses [West Nile virus (WNV), Powassan virus (POWV), chikungunya virus (CHIKV), and Mayaro virus (MAYV)] from related (flavivirus) and unrelated (alphavirus) genera to infect the placenta and fetus in immunocompetent, wild-type mice. Although all four viruses caused placental infection, only infection with the neurotropic flaviviruses (WNV and POWV) resulted in fetal demise. WNV and POWV also replicated efficiently in second-trimester human maternal (decidua) and fetal (chorionic villi and fetal membrane) explants, whereas CHIKV and MAYV replicated less efficiently. In mice, RNA in situ hybridization and histopathological analysis revealed that WNV infected the placenta and fetal central nervous system, causing injury to the developing brain. In comparison, CHIKV and MAYV did not cause substantive placental or fetal damage despite evidence of vertical transmission. On the basis of the susceptibility of human maternal and fetal tissue explants and pathogenesis experiments in immunocompetent mice, other emerging neurotropic flaviviruses may share with ZIKV the capacity for transplacental transmission, as well as subsequent infection and injury to the developing fetus.

[Usutu virus: the phantom menace]. / Le virus Usutu : la menace fantôme.

Usutu virus, an arbovirus discovered in Africa in 1959, has spread over a large part of Europe over the last twenty years causing significant bird mortality as reported in France since 2015. The zoonotic risk, associated with this succession of avian epizootics in Europe, deserves to be taken into account even if human cases remain rare to date. Human infections are most often asymptomatic or present a benign clinical expression. However, neurological complications such as encephalitis or meningoencephalitis have been described. In addition, the recent description of an atypical case of facial paralysis in France suggests that the clinical spectrum of infections caused by Usutu virus is not fully characterized. Finally, the recent history of other arboviral outbreaks invites the scientific community to be extremely vigilant.

Usutu Virus Epizootic and Plasmodium Coinfection in Eurasian Blackbirds ( Turdus merula) in Flanders, Belgium.

At the end of the summer of 2016, unusually high levels of mortality were detected in Passeriformes and Strigiformes in Flanders, Belgium, mainly in Eurasian Blackbirds ( Turdus merula). A passive surveillance program demonstrated a widespread Usutu virus outbreak and revealed a coinfection with Plasmodium in 99% of the dead passerine birds that were necropsied.

The Impact of Prior Flavivirus Infections on the Development of Type 2 Diabetes Among the Indigenous Australians.

It is estimated that 5% of Australians over the age of 18 have diabetes, with the number of new cases increasing every year. Type 2 diabetes (T2D) also represents a significant disease burden in the Australian indigenous population, where prevalence is three times greater than that of non-indigenous Australians. Prevalence of T2D has been found to be higher in rural and remote indigenous Australian populations compared with urban indigenous Australian populations. Several studies have also found that body mass index and waist circumference are not appropriate for the prediction of T2D risk in indigenous Australians. Regional and remote areas of Australia are endemic for a variety of mosquito-borne flaviviruses. Studies that have investigated seroprevalence of flaviviruses in remote aboriginal communities have found high proportions of seroconversion. The family Flaviviridae comprises several genera of viruses with non-segmented single-stranded positive sense RNA genomes, and includes the flaviviruses and hepaciviruses. Hepatitis C virus (HCV) has been shown to be associated with insulin resistance and subsequent development of T2D. Flaviviruses and HCV possess conserved proteins and subgenomic RNA structures that may play similar roles in the development of insulin resistance. Although dietary and lifestyle factors are associated with increased risk of developing T2D, the impact of infectious diseases such as arboviruses has not been assessed. Flaviviruses circulating in indigenous Australian communities may play a significant role in inducing glucose intolerance and exacerbating T2D.

Hippocampal involvement in dengue fever.

Flaviviruses are among the most important emerging viruses known to man. Dengue is the most common flavivirus infection in Singapore, and is transmitted between humans by the Aedes mosquito. We report a 25-year-old man with dengue fever complicated by selective hippocampal involvement manifesting as amnesia. This has not been described in the literature previously. Dengue polymerase chain reaction and serology were positive. Magnetic resonance imaging of the brain showed bilateral hippocampal involvement.

Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses.

Using a recently described hamster model of severe yellow fever (YF), we examined the hypothesis that prior infection with heterologous flaviviruses protects against severe or fatal YF. Hamsters were singly or sequentially infected with Japanese encephalitis, St. Louis encephalitis, West Nile, and/or dengue-1 viruses, and then challenged with a virulent strain of yellow fever virus (YFV). In contrast to control (naive) hamsters, many of which appeared clinically ill or died after YFV infection, the flavivirus-immune animals remained asymptomatic. The flavivirus-immune hamsters also had a reduced viremia and lower serum levels of alanine aminotransferase and total bilirubin, compared with naive hamsters, following YFV infection. Histologically, livers of animals in the flavivirus-immune and control groups showed comparable levels of multifocal necrapoptosis. However, steatosis was not observed in the flavivirus-immune animals, whereas naive hamsters developed extensive microvesicular steatosis in the liver following YFV infection. These findings suggest that hepatocytic steatosis is an adverse microscopic feature associated with severe disease in YFV infection. Our experimental results support earlier anecdotal reports that prior exposure of humans to heterologous flaviviruses reduces subsequent risk of fatal YFV infection.

Dengue infection presenting with central nervous system manifestation.

The objective of this study was to investigate the possibility of dengue virus infection causing an abnormal neurologic presentation. Between 1996 and 1998, all pediatric patients with clinical manifestations of encephalitis-like illness who were admitted to the Department of Pediatrics, Siriraj Hospital were prospectively studied for any evidence of dengue virus infection. The diagnosis of dengue virus infection was based on mosquito viral isolation and serologic and polymerase chain reaction (PCR) evidence. Of 44 patients with the preliminary diagnosis of acute viral encephalitis, 8 were diagnosed with dengue infection. All of these 8 patients were diagnosed by serology. In addition to the serologic diagnosis, four also had positive PCR, one had positive viral isolation, and one had both positive PCR and viral isolation. Only two patients were diagnosed by serologic evidence alone. All except one had clinical courses and laboratory findings compatible with typical dengue infection. All had obvious encephalitic clinical manifestations with normal cerebrospinal fluid findings except one patient, who had mildly increased cerebrospinal fluid protein. All of these patients recovered completely and had benign clinical courses except one patient, who developed leakage symptoms. None had liver failure. Dengue virus can cause acute encephalopathy with fever. It can masquerade as other types of acute viral encephalitis. However, its clinical course and prognosis are usually favorable.

A mídia em meio às ‘emergências’ do vírus Zika: questões para o campo da comunicação e saúde / The media among the Zika virus ‘emergencies’: issues for thecommunication and health field / /Los medios de comunicación entre las ‘emergencias’ del virus Zika:preguntas para el campo de la comunicación y salud

Típico caso de um vírus emergente, o Zika havia circulado de forma restrita quando chegou ao Brasil, onde acabaria por se tornar parte de uma emergência em saúde pública e um tema com fortíssima presença nos meios de comunicação em 2015. Este artigo baseia-se em um trabalho realizado no contexto do Observatório Saúde na Mídia, no qual traçamos uma linha do tempo com os principais pontos da escalada de atenção sobre o vírus Zika na mídia brasileira em 2015, incluindo a cobertura midiática e os anúncios oficiais. Confrontamos essa linha do tempo com uma análise de capas de nove jornais impressos publicados nos meses de novembro e dezembro de 2015, período em que o Ministério da Saúde admitiu a possível correlação do vírus com o aumento de casos de microcefalia no país. Enfocamos referências a medo e risco e propusemos algumas reflexões sobre a relação entre a comunicação e a saúde...

Typical case of an emerging virus, Zika had circulated in a limited extent when it arrived in Brazil, where wouldbecome part of a public health emergency and a theme with very strong presence in the media in 2015. In thisarticle, based on a work prepared in the context of the Health in the Media Observatory, we draw a timelinethat seeks to outline the main points of attention on the Zika virus in Brazilian media in 2015, including mediacoverage and official announcements. This timeline was confronted with the analysis of covers from nine Braziliannewspapers, published in November and December 2015, when the Brazilian Ministry of Health admited apossible correlation between the Zika virus and the increase in microcephaly cases. We focus on references to fearand risk and propose some reflections on the relationship between communication and health...

Caso típico de un virus emergente, el Zika había circulado de forma limitada cuando llegó a Brasil, donde seconvertiría en parte de una emergencia de salud pública y un tema con presencia muy fuerte en los mediosde comunicación en 2015. En este artículo, basado en trabajo realizado en el marco del Observatorio de laSalud en los Medios de Comunicación, dibujamos una línea de tiempo que busca delinear los principalespuntos de atención sobre el virus Zika en medios brasileños en 2015, incluyendo la cobertura de los mediosde comunicación y los anuncios oficiales. Esta linea de tiempo fue confrontada con el análisis de lasportadas de nueve periódicos impresos en noviembre y diciembre de 2015, período en el cual el Ministeriode Salud de Brasil reconoció la posible correlación del virus con el aumento de los casos de microcefalia enel país. Enfocamos referencias a miedo y riesgoy y planteamos algunas reflexiones sobre la relación entrecomunicación y salud...