Hantavirus in humans: a review of clinical aspects and management.

Hantavirus infections are part of the broad group of viral haemorrhagic fevers. They are also recognised as a distinct model of an emergent zoonotic infection with a global distribution. Many factors influence their epidemiology and transmission, such as climate, environment, social development, ecology of rodent hosts, and human behaviour in endemic regions. Transmission to humans occurs by exposure to infected rodents in endemic areas; however, Andes hantavirus is unique in that it can be transmitted from person to person. As hantaviruses target endothelial cells, they can affect diverse organ systems; increased vascular permeability is central to pathogenesis. The main clinical syndromes associated with hantaviruses are haemorrhagic fever with renal syndrome (HFRS), which is endemic in Europe and Asia, and hantavirus cardiopulmonary syndrome (HCPS), which is endemic in the Americas. HCPS and HFRS are separate clinical entities, but they share several features and have many overlapping symptoms, signs, and pathogenic alterations. For HCPS in particular, clinical outcomes are highly associated with early clinical suspicion, access to rapid diagnostic testing or algorithms for presumptive diagnosis, and prompt transfer to a facility with critical care units. No specific effective antiviral treatment is available.

[Controversies on corticosteroid therapy in hantavirus cardiopulmonary syndrome]. / Controversias sobre el uso de corticoides en el síndrome cardiopulmonar por hantavirus.

Hantavirus cardiopulmonary syndrome is an emerging zoonosis in Argentina, which has low incidence but high death rates. No specific pharmacological therapy is available and symptomatic therapy is the only current alternative. This article presents the pathogenesis of hantavirus cardiopulmonary syndrome through a review of clinical experiences in neighbor South American countries, mainly Chile, and the experience acquired at the Infectious Diseases Hospital Francisco Javier Muñiz, Buenos Aires, Argentina. The role of early corticosteroid therapy is discussed taking into account that there is insufficient evidence favoring its use in the hantavirus cardiopulmonary syndrome.

El síndrome cardiopulmonar por hantavirus es una zoonosis emergente en la Argentina, que presenta baja incidencia, pero elevada mortalidad. No existe tratamiento farmacológico especifico y la única alternativa actual es la terapia de apoyo. En este artículo se expone la patogenia del síndrome cardiopulmonar por hantavirus a través de la revisión de las experiencias clínicas de otros países de Sudamérica, en particular Chile, y la adquirida en el Hospital de Infecciosas Francisco Javier Muñiz de Buenos Aires, Argentina. Se discute sobre la administración temprana de corticoides en este síndrome, teniendo en cuenta que la evidencia a favor de su uso es insuficiente.

Controversias sobre el uso de corticoides en el síndrome cardiopulmonar por hantavirus / Controversies on corticosteroid therapy in hantavirus cardiopulmonary syndrome

Resumen El síndrome cardiopulmonar por hantavirus es una zoonosis emergente en la Argentina, que presenta baja incidencia, pero elevada mortalidad. No existe tratamiento farmacológico especifico y la única alternativa actual es la terapia de apoyo. En este artículo se expone la patogenia del síndrome cardiopulmonar por hantavirus a través de la revisión de las experiencias clínicas de otros países de Sudamérica, en particular Chile, y la adquirida en el Hospital de Infecciosas Francisco Javier Muñiz de Buenos Aires, Argentina. Se discute sobre la administración temprana de corticoides en este síndrome, teniendo en cuenta que la evidencia a favor de su uso es insuficiente.

Abstract Hantavirus cardiopulmonary syndrome is an emerging zoonosis in Argentina, which has low incidence but high death rates. No specific pharmacological therapy is available and symptomatic therapy is the only current alterna tive. This article presents the pathogenesis of hantavirus cardiopulmonary syndrome through a review of clinical experiences in neighbor South American countries, mainly Chile, and the experience acquired at the Infectious Diseases Hospital Francisco Javier Muñiz, Buenos Aires, Argentina. The role of early corticosteroid therapy is discussed taking into account that there is insufficient evidence favoring its use in the hantavirus cardiopulmonary syndrome.

Hantavirus Infection Is Inhibited by Griffithsin in Cell Culture.

Andes virus (ANDV) and Sin Nombre virus (SNV), highly pathogenic hantaviruses, cause hantavirus pulmonary syndrome in the Americas. Currently no therapeutics are approved for use against these infections. Griffithsin (GRFT) is a high-mannose oligosaccharide-binding lectin currently being evaluated in phase I clinical trials as a topical microbicide for the prevention of human immunodeficiency virus (HIV-1) infection (ClinicalTrials.gov Identifiers: NCT04032717, NCT02875119) and has shown broad-spectrum in vivo activity against other viruses, including severe acute respiratory syndrome coronavirus, hepatitis C virus, Japanese encephalitis virus, and Nipah virus. In this study, we evaluated the in vitro antiviral activity of GRFT and its synthetic trimeric tandemer 3mGRFT against ANDV and SNV. Our results demonstrate that GRFT is a potent inhibitor of ANDV infection. GRFT inhibited entry of pseudo-particles typed with ANDV envelope glycoprotein into host cells, suggesting that it inhibits viral envelope protein function during entry. 3mGRFT is more potent than GRFT against ANDV and SNV infection. Our results warrant the testing of GRFT and 3mGRFT against ANDV infection in animal models.

Debería usarse ribavirina frente al tratamiento de soporte para pacientes con infección confirmada por Hantavirus Andes Sur en fase de incubación o prodrómica? / Should Ribavirin be used as a supportive treatment for patients with confirmed Southern Hantavirus infection in the incubation or prodromal phase?

JUSTIFICACIÓN: Brote de Hantavirus por Virus Andes que afecta desde el mes de Noviembre de 2018 a la comarca Andina (con epicentro en la localidad de Epuyén, Chubut) com 28 pacientes infectados en el mes 2 de brote y 35% de mortalidad global (elevada mortalidad global). Evidencia de contagio interhumano relacionado con el brote Existencia de contactos sospechosos posteriormente confirmados para infección por Hantavirus (ADN viral por PCR) en fase asintomática (contactos de riesgo) o prodrômica. Disponibilidad de Ribavirina oral, con eficacia probada en animales y eventos adversos (seguridad) leves, detectables, monitoreables y reversibles. Falta de alternativas terapéuticas en esta etapa para evitar la progresión a Síndrome pulmonar por Hantavirus con la consecuente mortalidad asociada con dicho evento. TECNOLOGÍA: La Ribavirina es un antiviral -Análogo de la guanina con actividad antiviral contra una amplia variedad de virus DNA y RNA entre los que se encuentran los bunyavirus familia a la que pertenece el Hanta virus. OBJETIVOS: Analizar si es útil la Ribavirina oral para la prevención del síndrome pulmonar por hantavirus y disminución de la mortalidad en pacientes con infección confirmada por Hantavirus, tanto en fase asintomática (viremia por PCR) o en fase prodrómica (PCR + o igM con síntomas) sin síndrome pulmonar por hantavirus, Definir la dosis adecuada para esta indicación. Analizar si la Ribavirina es segura en este contexto. INDICACIONES: Se ha planteado en el contexto de un brote de Hantavirus por Virus Andes que afecta desde el mes de Noviembre de 2018 a la comarca Andina (con epicentro en la localidad de Epuyén, Chubut) el tratamiento de pacientes confirmados para infección por Hantavirus (ADN viral por PCR) en fase asintomática (contactos de riesgo) o prodrómica el tratamiento con Ribavirina oral, dada la eficacia probada em animales, la seguridad de la Ribavirina (o la posibilidad de detectar tempranamente eventos adversos) y la falta de alternativas terapéuticas en esta etapa para evitar la progresión a Síndrome pulmonar por Hantavirus con la consecuente mortalidad asociada con dicho evento (al momento 35%). CARACTERÍSTICAS DE LA TECNOLOGÍA: La Ribavirina es un antiviral -Análogo de la guanina con actividad antiviral contra una amplia variedad de virus DNA y RNA entre los que se encuentran los bunyavirus familia a la que pertenece el Hanta virus. Inhibe la sínteses de RNA e induce mutagénesis letal en virus RNA. PREGUNTAS: ¿Es útil la Ribavirina oral para la prevención del síndrome pulmonar por hantavirus y disminución de la mortalidad? En pacientes con infección confirmada por Hantavirus, ya sea en fase asintomática (viremia por PCR) o en fase prodrómica (PCR + o igM con síntomas) sin síndrome pulmonar por hantavirus, Cuál es la dosis adecuada para esta indicación? Es la Ribavirina segura en este contexto? METODOLOGÍA: Búsqueda y análisis de la evidencia científica: Se realizó una búsqueda sistemática de bibliografía científica independientemente entre tres operadores, priorizando la inclusión de revisiones sistemáticas y metanálisis, evaluaciones de tecnologias sanitarias e informes de seguridad, Guías de Práctica Clínica basadas en la evidencia que fueran independientes, sin restricciones de idiomas y sin filtros (detallada en el cuerpo). Se realizó búsqueda secundaria de la bibliografía, contacto con expertos em búsqueda de estudios no publicados y eventos no publicados, así como estudios en fase de desarrollo. RESUMEN DE LOS RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: En estudios realizados en humanos con HCPS, los resultados fueron contrarios a aquellos que utilizaron animales, donde la efectividad para prevenir el desarrollo del HCPS fue abrumadora. Por lo tanto, los efectos de esta droga en humanos con HCPS sigue sin estar claro por las siguientes razones: (1) el pequeño número de estudios existentes y la dificultad en reclutar participantes así como una incapacidad para valorar el efectos de la terapia antiviral debido a la gravedad de la enfermedad con la que los pacientes fueron incluidos en los estudios. RECOMENDACIONES: Se recomienda en forma condicional el uso de Ribavirina oral en el contexto del brote de Hantavirus que afecta la región Andina en individuos con infección confirmada por Hantavirus en fase asintomática o prodrómica (ELISA igM + o PCR+) por un período no mayor a los 7 días. Se recomienda el uso de consentimento informado, descartar la presencia de embarazo y aconsejar la anticoncepción eficaz por un período no inferior a los 6 meses. Descartar anemia severa y monitorear luego del día 7 de tratamiento la presencia de anemia y alteraciones en el hepatograma.(AU)

Síndrome cardiopulmonar por Hantavirus luego del brote de Epuyén, Argentina: la necesidad de investigar nuevas formas de intervención terapéutica / Cardiopulmonary syndrome due to Hantavirus after the outbreak in Epuyén, Argentina: the need to investigate new forms of therapeutic intervention / Síndrome cardiopulmonar por Hantavírus depois do surto de Epuyén, Argentina: a necessidade de investigar novas formas de intervenção terapêutica

Los Hantavirus son virus con ARN de cadena simple pertenecientes a la familia Bunyaviridae. A diferencia de otros virus de la familia, no tienen artrópodos como vectores; sus hospederos en la naturaleza son roedores y algunos mamíferos pequeños. La transmisión al hombre ocurre por la inhalación de excretas de los animales infectados, rara vez por mordeduras y se ha documentado la posibilidad de transmisión persona a persona. Existen dos formas clínicas de la enfermedad: fiebre hemorrágica con síndrome renal (FHSR) distribuida en Europa y Asia, y síndrome cardiopulmonar por Hantavirus (SCPH), en las Américas. El SCPH se presenta clinicamente en cuatro fases: incubación, prodrómica, cardiopulmonar y convalescencia. En el laboratorio es frecuente el hallazgo de trombocitopenia, junto con otros cambios hematológicos y bioquímicos. El diagnóstico se realiza por la detección de anticuerpos o PCR. Recientemente en Epuyén, Provincia de Chubut, Argentina, ocurrió un brote que afectó a 34 personas con 12 muertes asociado a la transmisión interpersonal. Se revisa la situación actual con respecto al tratamiento y las posibilidades futuras de intervención. Aunque se trate de una enfermedad con una baja prevalencia, la alta tasa de letalidad y el alto impacto emocional y económico que sufren las localidades afectadas hacen necesario seguir investigando la búsqueda de nuevas alternativas de tratamiento.

Hantaviruses are single-stranded RNA viruses that belong to the Bunyaviridae family. Unlike other viruses in the family, they do not have arthropods as vectors; their hosts in the wild are rodents and some small mammals. Human transmission takes place through inhalation of excreta from infected animals, rarely from bites, and the possibility of person-to-person transmission has been documented. There are two clinical forms of the disease: hemorrhagic fever with renal syndrome (HFRS) distributed in Europe and Asia, and cardiopulmonary Hantavirus syndrome (HCPS) distributed in the Americas. The HCPS presents clinically in four phases: incubation, prodromal, cardiopulmonary and convalescence. In the laboratory, a thrombocytopenia is common, together with other hematological and biochemical changes. Diagnosis is made through the detection of antibodies or PCR. Recently, in Epuyén, Province of Chubut, Argentina, an outbreak occurred, affecting 34 people with 12 deaths associated with interpersonal transmission. The current situation is reviewed with respect to the treatment and the future possibilities of intervention. Although it is a disease with a low prevalence, the high rate of lethality and the high emotional and economic impact suffered by the affected areas make it necessary to continue investigating in search of new treatment alternatives.

Os Hantavírus são vírus RNA de cadeia simples pertencentes à família Bunyaviridae. Diferente de outros vírus da família, não têm artrópodes como vetores; seus anfitrões na natureza são roedores e alguns mamíferos pequenos. A transmissão para o homem acontece através da inalação de excrementos dos animais infectados, raras vezes por mordeduras e foi documentada a possibilidade de transmissão de pessoa para pessoa. Existem duas formas clínicas da doença: febre hemorrágica com síndrome renal (FHSR) distribuída na Europa e Ásia, e síndrome cardiopulmonar por Hantavírus (SCPH), nas Américas. O SCPH apresenta-se clinicamente em quatro fases: incubação, prodrômica, cardiopulmonar e convalescença. No laboratório é frequente o achado de trombocitopenia, junto a outras mudanças hematológicas e bioquímicas. O diagnóstico é realizado pela detecção de anticorpos ou PCR. Recentemente em Epuyén, Província de Chubut, Argentina, houve um surto que afetou 34 pessoas com 12 mortes associado à transmissão interpessoal. Revê-se a situação atual relativa ao tratamento e às possibilidades futuras de intervenção. Embora se trate de uma doença com uma baixa prevalência, a alta taxa de letalidade e o alto impacto emocional e econômico que sofrem as localidades afetadas tornam necessário continuar investigando em busca de novas alternativas de tratamento.

A neuropathic pain syndrome associated with hantavirus infection.

Hantaviruses are a group of single-stranded RNA viruses of the Bunyaviridae family. "New World" hantaviruses cause hantavirus cardiopulmonary syndrome (HCPS) in North America. HCPS carries with it significant mortality and those patients who survive the disease are often left with substantial morbidity. Neurologic complications of hantavirus infections are rare, with only sparse cases of central nervous system involvement having been documented in the literature. To our knowledge, there are no reports of hantavirus infection contributing to peripheral nervous system dysfunction. Here we report a case of possible small fiber neuropathy associated with hantavirus infection, in a patient who survived HCPS. Persistent and treatment-resistant neuropathic pain may be a prominent feature in hantavirus-associated peripheral neuropathy.

Hantavirus pulmonary syndrome, Southern Chile, 1995-2012.

Hantavirus is endemic to the Region de Los Lagos in southern Chile; its incidence is 8.5 times higher in the communes of the Andean area than in the rest of the region. We analyzed the epidemiologic aspects of the 103 cases diagnosed by serology and the clinical aspects of 80 hospitalized patients during 1995-2012. Cases in this region clearly predominated during winter, whereas in the rest of the country, they occur mostly during summer. Mild, moderate, and severe disease was observed, and the case-fatality rate was 32%. Shock caused death in 75% of those cases; high respiratory frequency and elevated creatinine plasma level were independent factors associated with death. Early clinical suspicion, especially in rural areas, should prompt urgent transfer to a hospital with an intensive care unit and might help decrease the high case-fatality rate.

Human hantavirus infections: epidemiology, clinical features, pathogenesis and immunology.

In humans, hantaviruses can cause haemorrhagic fever with renal syndrome (HFRS) or hantavirus cardiopulmonary syndrome (HCPS). Currently it is estimated that 150,000 to 200,000 cases of hantavirus disease occur each year, the majority being reported in Asia. However, human hantavirus infections are increasingly reported in the Americas and Europe. Although many of the underlying pathogenic mechanisms still remain unclear, recent evidence rather argues against a purely immune-mediated pathophysiology of human disease. Despite the high morbidity and case-fatality rates of HFRS and HCPS, respectively, no vaccine or drug is currently proven to be preventive or therapeutic. This review summarises clinical features and current epidemiological findings, as well as concepts regarding the immunology, pathogenesis and intervention strategies of human hantaviral diseases.

A lethal disease model for hantavirus pulmonary syndrome in immunosuppressed Syrian hamsters infected with Sin Nombre virus.

Sin Nombre virus (SNV) is a rodent-borne hantavirus that causes hantavirus pulmonary syndrome (HPS) predominantly in North America. SNV infection of immunocompetent hamsters results in an asymptomatic infection; the only lethal disease model for a pathogenic hantavirus is Andes virus (ANDV) infection of Syrian hamsters. Efforts to create a lethal SNV disease model in hamsters by repeatedly passaging virus through the hamster have demonstrated increased dissemination of the virus but no signs of disease. In this study, we demonstrate that immunosuppression of hamsters through the administration of a combination of dexamethasone and cyclophosphamide, followed by infection with SNV, results in a vascular leak syndrome that accurately mimics both HPS disease in humans and ANDV infection of hamsters. Immunosuppressed hamsters infected with SNV have a mean number of days to death of 13 and display clinical signs associated with HPS, including pulmonary edema. Viral antigen was widely detectable throughout the pulmonary endothelium. Histologic analysis of lung sections showed marked inflammation and edema within the alveolar septa of SNV-infected hamsters, results which are similar to what is exhibited by hamsters infected with ANDV. Importantly, SNV-specific neutralizing polyclonal antibody administered 5 days after SNV infection conferred significant protection against disease. This experiment not only demonstrated that the disease was caused by SNV, it also demonstrated the utility of this animal model for testing candidate medical countermeasures. This is the first report of lethal disease caused by SNV in an adult small-animal model.

Ribavirin protects Syrian hamsters against lethal hantavirus pulmonary syndrome--after intranasal exposure to Andes virus.

Andes virus, ANDV, harbored by wild rodents, causes the highly lethal hantavirus pulmonary syndrome (HPS) upon transmission to humans resulting in death in 30% to 50% of the cases. As there is no treatment for this disease, we systematically tested the efficacy of ribavirin in vitro and in an animal model. In vitro assays confirmed antiviral activity and determined that the most effective doses were 40 µg/mL and above. We tested three different concentrations of ribavirin for their capability to prevent HPS in the ANDV hamster model following an intranasal challenge. While the highest level of ribavirin (200 mg/kg) was toxic to the hamster, both the middle (100 mg/kg) and the lowest concentration (50 mg/kg) prevented HPS in hamsters without toxicity. Specifically, 8 of 8 hamsters survived intranasal challenge for both of those groups whereas 7 of 8 PBS control-treated animals developed lethal HPS. Further, we report that administration of ribavirin at 50 mg/kg/day starting on days 6, 8, 10, or 12 post-infection resulted in significant protection against HPS in all groups. Administration of ribavirin at 14 days post-infection also provided a significant level of protection against lethal HPS. These data provide in vivo evidence supporting the potential use of ribavirin as a post-exposure treatment to prevent HPS after exposure by the respiratory route.

Role of vascular and lymphatic endothelial cells in hantavirus pulmonary syndrome suggests targeted therapeutic approaches.

BACKGROUND: Hantaviruses in the Americas cause a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). Hantaviruses nonlytically infect microvascular and lymphatic endothelial cells and cause dramatic changes in barrier functions without disrupting the endothelium. Hantaviruses cause changes in the function of infected endothelial cells that normally regulate fluid barrier functions. The endothelium of arteries, veins, and lymphatic vessels are unique and central to the function of vast pulmonary capillary beds that regulate pulmonary fluid accumulation. RESULTS: We have found that HPS-causing hantaviruses alter vascular barrier functions of microvascular and lymphatic endothelial cells by altering receptor and signaling pathway responses that serve to permit fluid tissue influx and clear tissue edema. Infection of the endothelium provides several mechanisms for hantaviruses to cause acute pulmonary edema, as well as potential therapeutic targets for reducing the severity of HPS disease. CONCLUSIONS: Here we discuss interactions of HPS-causing hantaviruses with the endothelium, roles for unique lymphatic endothelial responses in HPS, and therapeutic targeting of the endothelium as a means of reducing the severity of HPS disease.

Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome.

Hantavirus pulmonary syndrome (HPS) is caused by infection with several Sigmodontinae- and Neotominae-borne hantaviruses and has a case fatality rate of 30 to 50%. Humans often become infected by inhalation of materials contaminated with virus-laden rodent urine or saliva, although human-to-human transmission has also been documented for Andes virus (ANDV). The ability to transmit via aerosolization, coupled with the high mortality rates and lack of therapeutic options, makes the development of medical countermeasures against HPS imperative. In the present study, we evaluated the efficacy of the broad-spectrum antiviral agent favipiravir (T-705) against Sin Nombre virus (SNV) and ANDV, the predominant causes of HPS in North and South America, respectively. In vitro, T-705 potently inhibited SNV and ANDV, as evidenced by decreased detection of viral RNA and reduced infectious titers. For both viruses, the 90% effective concentration was estimated at ≤5 µg/ml (≤31.8 µM). In the lethal ANDV hamster model, daily administration of oral T-705 at 50 or 100 mg/kg of body weight diminished the detection of viral RNA and antigen in tissue specimens and significantly improved survival rates. Oral T-705 therapy remained protective against HPS when treatment was initiated prior to the onset of viremia. No disease model for SNV exists; however, using a hamster-adapted SNV, we found that daily administration of oral T-705 significantly reduced the detection of SNV RNA and antigen in tissue specimens, suggesting that the compound would also be effective against HPS in North America. Combined, these results suggest that T-705 treatment is beneficial for postexposure prophylaxis against HPS-causing viruses and should be considered for probable exposures.

High-dose intravenous methylprednisolone for hantavirus cardiopulmonary syndrome in Chile: a double-blind, randomized controlled clinical trial.

BACKGROUND: Andes virus (ANDV)-related hantavirus cardiopulmonary syndrome (HCPS) has a 35% case fatality rate in Chile and no specific treatment. In an immunomodulatory approach, we evaluated the efficacy of intravenous methylprednisolone for HCPS treatment, through a parallel-group, placebo-controlled clinical trial. METHODS: Patients aged >2 years, with confirmed or suspected HCPS in cardiopulmonary stage, admitted to any of 13 study sites in Chile, were randomized by study center in blocks of 4 with a 1:1 allocation and assigned through sequentially numbered envelopes to receive placebo or methylprednisolone 16 mg/kg/day (≤1000 mg) for 3 days. All personnel remained blinded except the local pharmacist. Infection was confirmed by immunoglobulin M antibodies or ANDV RNA in blood. The composite primary endpoint was death, partial pressure of arterial oxygen/fraction of inspired oxygen ratio ≤55, cardiac index ≤2.2, or ventricular tachycardia or fibrillation within 28 days. Safety endpoints included the number of serious adverse events (SAEs) and quantification of viral RNA in blood. Analysis was by intention to treat. RESULTS: Infection was confirmed in 60 of 66 (91%) enrollees. Fifteen of 30 placebo-treated patients and 11 of 30 methylprednisolone-treated patients progressed to the primary endpoint (P = .43). We observed no significant difference in mortality between treatment groups (P = .41). There was a trend toward more severe disease in placebo recipients at entry. More subjects in the placebo group experienced SAEs (P = .02). There were no SAEs clearly related to methylprednisolone administration, and methylprednisolone did not increase viral load. CONCLUSIONS: Although methylprednisolone appears to be safe, it did not provide significant clinical benefit to patients. Our results do not support the use of methylprednisolone for HCPS. CLINICAL TRIALS REGISTRATION: NCT00128180.

Hantavirus pulmonary syndrome.

Hantavirus pulmonary syndrome (HPS) is a severe disease characterized by a rapid onset of pulmonary edema followed by respiratory failure and cardiogenic shock. The HPS associated viruses are members of the genus Hantavirus, family Bunyaviridae. Hantaviruses have a worldwide distribution and are broadly split into the New World hantaviruses, which includes those causing HPS, and the Old World hantaviruses [including the prototype Hantaan virus (HTNV)], which are associated with a different disease, hemorrhagic fever with renal syndrome (HFRS). Sin Nombre virus (SNV) and Andes virus (ANDV) are the most common causes of HPS in North and South America, respectively. Case fatality of HPS is approximately 40%. Pathogenic New World hantaviruses infect the lung microvascular endothelium without causing any virus induced cytopathic effect. However, virus infection results in microvascular leakage, which is the hallmark of HPS. This article briefly reviews the knowledge on HPS-associated hantaviruses accumulated since their discovery, less than 20 years ago.

VEGFR2 and Src kinase inhibitors suppress Andes virus-induced endothelial cell permeability.

Hantaviruses predominantly infect human endothelial cells and, in the absence of cell lysis, cause two diseases resulting from increased vascular permeability. Andes virus (ANDV) causes a highly lethal acute pulmonary edema termed hantavirus pulmonary syndrome (HPS). ANDV infection enhances the permeability of endothelial cells in response to vascular endothelial growth factor (VEGF) by increasing signaling responses directed by the VEGFR2-Src-VE-cadherin pathway, which directs adherens junction (AJ) disassembly. Here we demonstrate that inhibiting pathway-specific VEGFR2 and Src family kinases (SFKs) blocks ANDV-induced endothelial cell permeability. Small interfering RNA (siRNA) knockdown of Src within ANDV-infected endothelial cells resulted in an ∼70% decrease in endothelial cell permeability compared to that for siRNA controls. This finding suggested that existing FDA-approved small-molecule kinase inhibitors might similarly block ANDV-induced permeability. The VEGFR2 kinase inhibitor pazopanib as well as SFK inhibitors dasatinib, PP1, bosutinib, and Src inhibitor 1 dramatically inhibited ANDV-induced endothelial cell permeability. Consistent with their kinase-inhibitory concentrations, dasatinib, PP1, and pazopanib inhibited ANDV-induced permeability at 1, 10, and 100 nanomolar 50% inhibitory concentrations (IC(50)s), respectively. We further demonstrated that dasatinib and pazopanib blocked VE-cadherin dissociation from the AJs of ANDV-infected endothelial cells by >90%. These findings indicate that VEGFR2 and Src kinases are potential targets for therapeutically reducing ANDV-induced endothelial cell permeability and, as a result, capillary permeability during HPS. Since the functions of VEGFR2 and SFK inhibitors are already well defined and FDA approved for clinical use, these findings rationalize their therapeutic evaluation for efficacy in reducing HPS disease. Endothelial cell barrier functions are disrupted by a number of viruses that cause hemorrhagic, edematous, or neurologic disease, and as a result, our findings suggest that VEGFR2 and SFK inhibitors should be considered for regulating endothelial cell barrier functions altered by additional viral pathogens.

Hantavirus pulmonary syndrome in five pediatric patients - four states, 2009.

Hantavirus pulmonary syndrome (HPS) is a reportable infectious disease with a high case-fatality rate, transmitted to humans by exposure to rodents. Each year, 20--40 cases of HPS occur in the United States; cases in persons aged <17 years make up fewer than 7% of those cases, and cases in children aged <10 years are exceptionally rare. CDC received reports of five pediatric cases of HPS occurring during May 16--November 25, 2009, among children aged 6--14 years from Arizona, California, Colorado, and Washington. Three of the children were aged <10 years, and all five had exposure to rodents. This report summarizes the five cases, including the clinical findings and likely means of transmission of a hantavirus. Thrombocytopenia, elevated white blood cell (WBC) count, and pulmonary infiltrates were observed in all five children; elevated hematocrit was observed in three. One child died, and three of the four children who recovered required mechanical ventilation during hospitalization. Clinicians should consider HPS in the differential diagnosis for children with unexplained acute respiratory distress, especially if recent rodent exposure is noted. Public health agencies should promote preventive measures, including rodent control in housing and play areas, and children should be advised to avoid contact with rodents and areas of infestation.

Bilateral acute acquired toxoplasmic retinochoroiditis after steroid therapy for hantavirus pulmonary syndrome: case report.

Description of a case of acute acquired ocular toxoplasmosis following hantavirus pulmonary syndrome. A 41-year-old man presenting hantavirus pulmonary syndrome, confirmed in the laboratory by detection of IgM antibodies to the virus, was submitted to high doses of intravenous corticosteroids for two months. After clinical improvement of hantavirus pulmonary syndrome the patient presented visual loss in both eyes that was secondary to a toxoplasmosis retinitis. The retinitis resolved with anti-toxoplasma therapy. Acquired toxoplasmic retinochoroiditis can occur following steroid therapy for hantavirus pulmonary syndrome.

Bilateral acute acquired toxoplasmic retinochoroiditis after steroid therapy for hantavirus pulmonary syndrome: case report

Description of a case of acute acquired ocular toxoplasmosis following hantavirus pulmonary syndrome. A 41-year-old man presenting hantavirus pulmonary syndrome, confirmed in the laboratory by detection of IgM antibodies to the virus, was submitted to high doses of intravenous corticosteroids for two months. After clinical improvement of hantavirus pulmonary syndrome the patient presented visual loss in both eyes that was secondary to a toxoplasmosis retinitis. The retinitis resolved with anti-toxoplasma therapy. Acquired toxoplasmic retinochoroiditis can occur following steroid therapy for hantavirus pulmonary syndrome.

Descrição de um caso de toxoplasmose ocular adquirida pós-síndrome pulmonar por hantavírus. Paciente com 41 anos do sexo masculino apresentando síndrome pulmonar por hantavírus, confirmado no laboratório pela detecção de anticorpos IGM para o vírus, foi submetido a altas doses de corticosteróides intravenosos durante dois meses. Após melhora clínica da síndrome pulmonar por hantavírus, apresentou perda visual em ambos os olhos secundária a retinite por toxoplasmose confirmada com sorologia (IGG e IGM positivo) A retinite resolveu após terapia sistêmica específica. A retinite por toxoplasmose pode ocorrer após terapia sistêmica com esteróide para síndrome pulmonar por hantavírus.