Longitudinal Assessment of Cytokine Expression and Plasminogen Activation in Hantavirus Cardiopulmonary Syndrome Reveals Immune Regulatory Dysfunction in End-Stage Disease.

Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors' and decedents' cases. However, total uPA in decedents' cases was significantly higher compared to survivors'. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-γ. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.

Dendritic Cells (DCs) as "Fire Accelerants" of Hantaviral Pathogenesis.

Hantaviruses are widespread zoonotic pathogens found around the globe. Depending on their geographical location, hantaviruses can cause two human syndromes, haemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). HPS and HFRS have many commonalities amongst which excessive activation of immune cells is a prominent feature. Hantaviruses replicate in endothelial cells (ECs), the major battlefield of hantavirus-induced pathogenesis, without causing cytopathic effects. This indicates that a misdirected response of human immune cells to hantaviruses is causing damage. As dendritic cells (DCs) orchestrate antiviral immune responses, they are in the focus of research analysing hantavirus-induced immunopathogenesis. In this review, we discuss the interplay between hantaviruses and DCs and the immunological consequences thereof.

Capillary leak-syndrome triggered by Maripa virus in French Guiana: case report and implication for pathogenesis.

BACKGROUND: We report hereby a severe case of Hantavirus Pulmonary Syndrome" (HPS) induced by Maripa virus in French Guiana and describe the mechanism of severity of the human disease. CASE PRESENTATION: A 47-year- old patient started presenting a prodromic period with fever, dyspnea, cough and head ache. This clinical presentation was followed by a rapid respiratory, hemodynamic and renal failure leading to admission in the ICU. Biological exams revealed an increased haematocrit level with a paradoxical low protein level. Echocardiographic and hemodynamic monitoring showed a normal left ventricular function with low filling pressures, an elevated extravascular lung water index and pulmonary vascular permeability index. These findings were compatible with a capillary leak-syndrome (CLS). CONCLUSIONS: The severity of HPS caused by the virus Maripa in French Guiana can be explained by the tropism of hantavirus for the microvascular endothelial cell leading to a CLS.

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.

Serum levels of interleukin-6 are linked to the severity of the disease caused by Andes Virus.

Andes virus (ANDV) is the etiological agent of hantavirus cardiopulmonary syndrome in Chile. In this study, we evaluated the profile of the pro-inflammatory cytokines IL-1ß, IL-12p70, IL-21, TNF-α, IFN-γ, IL-10 and IL-6 in serum samples of ANDV-infected patients at the time of hospitalization. The mean levels of circulating cytokines were determined by a Bead-Based Multiplex assay coupled with Luminex detection technology, in order to compare 43 serum samples of healthy controls and 43 samples of ANDV-infected patients that had been categorized according to the severity of disease. When compared to the controls, no significant differences in IL-1ß concentration were observed in ANDV-infected patients (p = 0.9672), whereas levels of IL-12p70 and IL-21 were significantly lower in infected cases (p = <0.0001). Significantly elevated levels of TNF-α, IFN-γ, IL-10, and IL-6 were detected in ANDV-infected individuals (p = <0.0001, 0.0036, <0.0001, <0.0001, respectively). Notably, IL-6 levels were significantly higher (40-fold) in the 22 patients with severe symptoms compared to the 21 individuals with mild symptoms (p = <0.0001). Using multivariate regression models, we show that IL-6 levels has a crude OR of 14.4 (CI: 3.3-63.1). In conclusion, the serum level of IL-6 is a significant predictor of the severity of the clinical outcome of ANDV-induced disease.

Hantavirus cardiopulmonary syndrome successfully treated with high-volume hemofiltration. / Tratamento bem-sucedido da síndrome cardiopulmonar por hantavírus com uso de hemofiltração de alto volume.

Hantavirus cardiopulmonary syndrome has a high mortality rate, and early connection to extracorporeal membrane oxygenation has been suggested to improve outcomes. We report the case of a patient with demonstrated Hantavirus cardiopulmonary syndrome and refractory shock who fulfilled the criteria for extracorporeal membrane oxygenation and responded successfully to high volume continuous hemofiltration. The implementation of high volume continuous hemofiltration along with protective ventilation reversed the shock within a few hours and may have prompted recovery. In patients with Hantavirus cardiopulmonary syndrome, a short course of high volume continuous hemofiltration may help differentiate patients who can be treated with conventional intensive care unit management from those who will require more complex therapies, such as extracorporeal membrane oxygenation.

Tratamento bem-sucedido da síndrome cardiopulmonar por hantavírus com uso de hemofiltração de alto volume / Hantavirus cardiopulmonary syndrome successfully treated with high-volume hemofiltration

RESUMO A síndrome cardiopulmonar por hantavírus tem elevada taxa de mortalidade. Sugere-se que uma conexão precoce com oxigenação por membrana extracorpórea melhore os resultados. Relatamos o caso de uma paciente que apresentou síndrome cardiopulmonar por hantavírus e choque refratário, que preenchia os critérios para oxigenação por membrana extracorpórea e que teve resposta satisfatória com uso de hemofiltração contínua de alto volume. A implantação de hemofiltração contínua de alto volume, juntamente da ventilação protetora, reverteu o choque dentro de poucas horas e pode ter levado à recuperação. Em pacientes com síndrome cardiopulmonar por hantavírus, um curso rápido de hemofiltração contínua de alto volume pode ajudar a diferenciar pacientes que podem ser tratados com cuidados convencionais da unidade de terapia intensiva dos que necessitarão de terapias mais complexas, como oxigenação por membrana extracorpórea.

ABSTRACT Hantavirus cardiopulmonary syndrome has a high mortality rate, and early connection to extracorporeal membrane oxygenation has been suggested to improve outcomes. We report the case of a patient with demonstrated Hantavirus cardiopulmonary syndrome and refractory shock who fulfilled the criteria for extracorporeal membrane oxygenation and responded successfully to high volume continuous hemofiltration. The implementation of high volume continuous hemofiltration along with protective ventilation reversed the shock within a few hours and may have prompted recovery. In patients with Hantavirus cardiopulmonary syndrome, a short course of high volume continuous hemofiltration may help differentiate patients who can be treated with conventional intensive care unit management from those who will require more complex therapies, such as extracorporeal membrane oxygenation.

Extracorporeal life support during pregnancy.

OBJECTIVES: To review the literature on extracorporeal life support (ECLS) during pregnancy to determine its efficacy and safety for the mother and fetus. METHODS: A comprehensive literature search was obtained from MEDLINE via PubMed.gov and from ScienceDirect.com using the following search queries: ECLS and pregnancy, extracorporeal membrane oxygenation (ECMO) and pregnancy, ECMO and H1N1 influenza, acute respiratory distress syndrome (ARDS) and pregnancy, pregnancy and H1N1 influenza, and Extracorporeal Life Support Organization registry. RESULTS: Our literature search produced 332 articles for review. A total of 45 patients treated with ECLS or ECMO during pregnancy were reported in 26 publications. Postpartum patients were not included. Indications for ECLS were severe H1N1 influenza with ARDS (n = 33), other ARDS (n = 8), cardiogenic shock (n = 3), and cardiac arrest (n = 1). The mean gestational age was 26.5 weeks (range, 12-38 weeks), and the median duration of ECLS was 12.2 days (range, 1-57 days). The survival rate was 77.8% (35 of 45) for mothers and 65.1% (28 of 43) for fetuses. In addition, we report a 25-year-old pregnant patient with hantavirus cardiopulmonary syndrome unresponsive to pressors and inotropes. The patient was placed on venoarterial ECMO for 72 hours, recovered without complications, and delivered a healthy infant. The mother and son remain asymptomatic 6 years later. CONCLUSIONS: ECLS during pregnancy is effective and relatively safe for the mother and fetus. The first successful use of ECLS in a pregnant patient with life-threatening hantavirus cardiopulmonary syndrome is being reported together with this review.

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques.

The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

Hantaviruses and cardiopulmonary syndrome in South America.

Hantavirus (Bunyaviridae) cardiopulmonary syndrome (HCPS) is an emerging health problem in South America due to urban growth and to the expansion of agriculture and cattle-raising areas into ecosystems containing most of the species of Sigmodontinae rodents that act as hantavirus reservoirs. About 4000 HCPS cases have been reported in South America up to 2013, associated with the following hantaviruses: Andes, Anajatuba, Araraquara (ARQV), Paranoá, Bermejo, Castelo dos Sonhos, Juquitiba, Araucária, Laguna Negra, Lechiguanas, Maripa, Oran, Rio Mamore and Tunari. The transmission of hantavirus to man occurs by contact with or through aerosols of excreta and secretions of infected rodents. Person-to-person transmission of hantavirus has also been reported in Argentina and Chile. HCPS courses with a capillary leaking syndrome produced by the hantavirus infecting lung endothelial cells and mostly with a severe inflammatory process associated with a cytokine storm. HCPS starts as a dengue-like acute febrile illness but after about 3 days progresses to respiratory failure and cardiogenic shock, leading to a high fatality rate that reaches 50% for patients infected with ARQV.

Old World hantaviruses: aspects of pathogenesis and clinical course of acute renal failure.

Hantavirus-associated diseases represent emerging infections that are ranked in the highest priority group of communicable diseases for surveillance and epidemiological research. In the last years, several novel hantavirus species were described and the number of host reservoir species harboring hantaviruses is also increasing. Reports of cases with severe or atypical clinical courses become also more frequent. These facts raise more and more questions concerning host reservoir specificity, pathogenicity and molecular mechanism of pathogenesis. Hantavirus disease is characterized by vascular leakage due to increased capillary permeability. The infection manifests often in the lung (hantaviral cardiopulmonary syndrome; HCPS) or in the kidney (hemorrhagic fever with renal syndrome, HFRS). The underlying mechanisms of both syndromes are probably similar despite the difference in organ tropism. Characterization of hantaviral replication cycle and of patient-specific determinants will help to identify factors responsible for the clinical symptoms and course.

Hemorrhagic Fever with Renal Syndrome in the New, and Hantavirus Pulmonary Syndrome in the Old World: paradi(se)gm lost or regained?

Since the first clinical description in 1994 of the so-called "Hantavirus Pulmonary Syndrome" (HPS) as a "newly recognized disease", hantavirus infections have always been characterized as presenting in two distinct syndromes, the so-called "Hemorrhagic Fever with Renal Syndrome" (HFRS) in the Old World, with the kidney as main target organ, in contrast to HPS in the New World, with the lung as main target organ. However, European literature mentions already since 1934 a mostly milder local HFRS form, aptly named "nephropathia epidemica" (NE), and caused by the prototype European hantavirus species Puumala virus (PUUV). Several NE reports dating from the 1980s and early 1990s described already non-cardiogenic HPS-like lung involvement, prior to any kidney involvement, and increasing evidence is now mounting that a considerable clinical overlap exists between HPS and HFRS. Moreover, growing immunologic insights point to common pathologic mechanisms, leading to capillary hyperpermeability, the cardinal feature of all hantavirus infections, both of the New and Old World. It is now perhaps time to reconsider the paradigm of two "different" syndromes caused by viruses of the same Hantavirus genus in the same Bunyaviridae family, and to agree on a common, more logical disease denomination, such as simply and briefly "Hantavirus fever".

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.

The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome.

The loss of the endothelium barrier and vascular leakage play a central role in the pathogenesis of hemorrhagic fever viruses. This can be caused either directly by the viral infection and damage of the vascular endothelium, or indirectly by a dysregulated immune response resulting in an excessive activation of the endothelium. This article briefly reviews our knowledge of the importance of the disruption of the vascular endothelial barrier in two severe disease syndromes, dengue hemorrhagic fever and hantavirus pulmonary syndrome. Both viruses cause changes in vascular permeability without damaging the endothelium. Here we focus on our understanding of the virus interaction with the endothelium, the role of the endothelium in the induced pathogenesis, and the possible mechanisms by which each virus causes vascular leakage. Understanding the dynamics between viral infection and the dysregulation of the endothelial cell barrier will help us to define potential therapeutic targets for reducing disease severity.

Hantavirus pulmonary syndrome: prognostic factors for death in reported cases in Brazil.

Hantavirus pulmonary syndrome (HPS) was described for the first time in Brazil in 1993 and has occurred endemically throughout the country. This study analysed clinical and laboratory aspects as well as death-related factors for HPS cases in Brazil from 1993 to 2006. The investigation comprised a descriptive and exploratory study of the history of cases as well as an analytical retrospective cohort survey to identify prognostic factors for death due to HPS. A total of 855 Brazilian HPS cases were assessed. The majority of cases occurred during spring (33.5%) and winter (27.6%), mainly among young male adults working in rural areas. The global case fatality rate was 39.3%. The mean interval between the onset of symptoms and hospitalisation was 4 days and that between hospitalisation and death was 1 day. In the multiple regression analysis, adult respiratory distress syndrome and mechanical respiratory support were associated with risk of death; when these two variables were excluded from the model, dyspnoea and haemoconcentration were associated with a higher risk of death.

[Hantapulmonary syndrome].

Features of hantavirus pulmonary syndrome are considered in the review - zoonosis natural focal polyetiological viral infection, that is characterized by lung injury. Etiology of the disease, main characteristics of the agents, epidemiology, contagiousness, pathogenesis, clinical presentation of this pathology are examined. Laboratory diagnostics, therapy and prophylaxis ofhantavirus pulmonary syndrome are described.

Hantavirus pulmonary syndrome, United States, 1993-2009.

Hantavirus pulmonary syndrome (HPS) is a severe respiratory illness identified in 1993. Since its identification, the Centers for Disease Control and Prevention has obtained standardized information about and maintained a registry of all laboratory-confirmed HPS cases in the United States. During 1993-2009, a total of 510 HPS cases were identified. Case counts have varied from 11 to 48 per year (case-fatality rate 35%). However, there were no trends suggesting increasing or decreasing case counts or fatality rates. Although cases were reported in 30 states, most cases occurred in the western half of the country; annual case counts varied most in the southwestern United States. Increased hematocrits, leukocyte counts, and creatinine levels were more common in HPS case-patients who died. HPS is a severe disease with a high case-fatality rate, and cases continue to occur. The greatest potential for high annual HPS incidence exists in the southwestern United States.

Hantavirus pulmonary syndrome: encephalitis caused by virus Andes.

Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS) are rodent-borne emerging diseases caused by members of the genus Hantavirus, family Bunyaviridae. Some species of hantavirus may cause encephalitis, but this is the first report in Andes virus associated to HPS.

Hantavirus protein interactions regulate cellular functions and signaling responses.

Rodent-borne pathogenic hantaviruses cause two severe and often lethal zoonotic diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Currently, no US FDA-approved therapeutics or vaccines are available for HFRS/HCPS. Infections with hantaviruses are not lytic, and it is currently not known exactly why infections in humans cause disease. A better understanding of how hantaviruses interfere with normal cell functions and activation of innate and adaptive immune responses might provide clues to future development of specific treatment and/or vaccines against hantavirus infection. In this article, the current knowledge regarding immune responses observed in patients, hantavirus interference with cellular proteins and signaling pathways, and possible approaches in the development of therapeutics are discussed.

Síndrome cardiopulmonar por hantavirus: a propósito de un caso: [revisión] / Hantavirus pulmonary syndrome: a case report: [review]

El Hantavirus es un patógeno de aparición relativamente nueva. El año 1996 fue publicado el primer en Chile y un año antes se habla establecido el primer diagnostico de síndrome cardiopulmonar (SCPH) en nuestro país. En Chile el tipo de Hantavirus es el Andes cuyo reservorio es el ratón de cola larga (Oligoryzomys longicaudatus). Se puede presentar como infección inaparente, como una enfermedad leve por Hantavirus o como su expresión más grave que es el SCPH. En general se manifiesta como un cuadro rápidamente progresivo, que tiene 3 etapas, la prodrómica, la cardiopulmonar y la de convalecencia. Comienza como si fuera un cuadro gripal, con fiebre y mialgias o como un cuadro gastrointestinal, seguido por aparición súbita de insuficiencia respiratoria con o sin aparición de inestabilidad hemodinámica que puede progresar en algunos casos hasta edema agudo de pulmón, shock y muerte. En Chile se han confirmado casos de SCPH desde la ciudad de Valparaíso hasta Aysén, siendo esta última la de mayor incidencia en el país. A la fecha, durante el 2010 se han confirmado 30 casos. La letalidad alcanza a un 33 por ciento El objetivo de este trabajo es comunicar un caso de SCPH de rápida regresión y revisar la literatura respecto al tema.