"Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina.

BACKGROUND: From November 2018 through February 2019, person-to-person transmission of Andes virus (ANDV) hantavirus pulmonary syndrome occurred in Chubut Province, Argentina, and resulted in 34 confirmed infections and 11 deaths. Understanding the genomic, epidemiologic, and clinical characteristics of person-to-person transmission of ANDV is crucial to designing effective interventions. METHODS: Clinical and epidemiologic information was obtained by means of patient report and from public health centers. Serologic testing, contact-tracing, and next-generation sequencing were used to identify ANDV infection as the cause of this outbreak of hantavirus pulmonary syndrome and to reconstruct person-to-person transmission events. RESULTS: After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events. After 18 cases were confirmed, public health officials enforced isolation of persons with confirmed cases and self-quarantine of possible contacts; these measures most likely curtailed further spread. The median reproductive number (the number of secondary cases caused by an infected person during the infectious period) was 2.12 before the control measures were enforced and decreased to 0.96 after the measures were implemented. Full genome sequencing of the ANDV strain involved in this outbreak was performed with specimens from 27 patients and showed that the strain that was present (Epuyén/18-19) was similar to the causative strain (Epilink/96) in the first known person-to-person transmission of hantavirus pulmonary syndrome caused by ANDV, which occurred in El Bolsón, Argentina, in 1996. Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection. Disease severity, genomic diversity, age, and time spent in the hospital had no clear association with secondary transmission. CONCLUSIONS: Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission. (Funded by the Ministerio de Salud y Desarrollo Social de la Nación Argentina and others.).

[Sociodemographic risk factors of hantavirus cardiopulmonary syndrome]. / Factores de riesgo socio-demográficos del síndrome cardiopulmonar por hantavirus.

BACKGROUND: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. AIM: To evaluate sociodemographic factors as risk factors in severity of HCPS. PATIENTS AND METHODS: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. RESULTS: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. CONCLUSION: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Clinical and anatomopathological aspects of patients with hantavirus cardiopulmonary syndrome in Uberaba, Minas Gerais, Brazil.

The hantavirus cardiopulmonary syndrome is considered an emerging disease in the Americas. Since 1993, thousands of cases have been reported from different countries, but mainly from Brazil. This study aims to describe some epidemiological, clinical and anatomopathological aspects of patients with hantavirus who presented poor outcome and were autopsied in a teaching hospital in Brazil, from 2000 to 2014. Of the 10 patients included, nine were male (mean age 43.5 years) and seven reported previous contact with rodents. Fever was present in eight of ten patients, dyspnea in nine of ten and myalgia in seven of ten patients; hemoconcentration, leukocytosis, thrombocytopenia and renal involvement were evidenced in all the 10 cases. At autopsy, the main alterations were seen in the lungs: pleural effusion (8/10 cases), increased weight 2.5 to 3 times, congestion/edema (10/10), interstitial mononuclear inflammation (10/10), alveolar hemorrhage (7/10), pulmonary collapse (7/10), hyaline membranes (7/10) and alveolar neutrophilic infiltrate (2/10). Pericardial effusion (2/10), mild myocardium inflammation (4/10), right ventricle dilation (1/10), polyploidy nuclei (3/10) and pericardial diffuse petechial (1/10) were also observed. The other organs exhibited discrete and non-specific alterations. Currently, this syndrome continues to be associated with high mortality directly linked to a late diagnosis and/or a misdiagnosis in the medical centers where these patients were seen for the first time. The anatomopathological findings at autopsy revealed the final phase of the process with pulmonary alterations, allowing a direct correlation with the severity of respiratory distress observed in these patients at admission.

Factores de riesgo socio-demográficos del síndrome cardiopulmonar por hantavirus / Sociodemographic risk factors of hantavirus cardiopulmonary syndrome

Resumen Introducción: El síndrome cardiopulmonar por hantavirus (SCPH) es causado en Chile y en el sur de Argentina por el Andes hantavirus (ANDV), el que es endémico en esta zona. La enfermedad causada por ANDV produce un aumento de permeabilidad vascular y filtración de plasma con una alta tasa de letalidad (35%), debido principalmente a insuficiencia respiratoria por edema pulmonar y al desarrollo en los casos graves de compromiso miocárdico, hipoperfusión y shock. Aunque se sabe que los factores socio-demográficos del hospedero pueden influir en el curso y el resultado de la enfermedad, estos no se han caracterizado previamente en la población chilena. Objetivo: Evaluar la relación entre los factores socio-demográficos y la gravedad del SCPH. Pacientes y Métodos: Período de análisis 2004-20013, pacientes atendidos en ocho centros colaboradores, diagnóstico etiológico serológico o por biología molecular, se comparan SCPH leve y grave. Se analizaron 139 pacientes chilenos, 64 (46%) con enfermedad grave, entre los cuales 12 murieron (19%). Resultados: La etnia europea tuvo un riesgo 5,1 veces mayor de desarrollar un SCPH grave que la etnia amerindia, gravedad mayor que también se asoció a una residencia urbana. Conclusiones: Se observó una asociación estadísticamente significativa entre etnia, lugar de residencia y evolución de SCPH. Se discuten hipótesis que expliquen estos hallazgos.

Background: Hantavirus cardiopulmonary syndrome (HCPS) is caused by new world hantaviruses, among which Andes hantavirus (ANDV) is endemic to Chile and Southern Argentina. The disease caused by ANDV produces plasma leakage leading to enhanced vascular permeability and has a high case fatality rate (35%), mainly due to respiratory failure, pulmonary edema and myocardial dysfunction, hypoperfusion and shock. Host sociodemographic and genetic factors might influence the course and outcome of the disease. Yet, they have not been thoroughly characterized. Aim: To evaluate sociodemographic factors as risk factors in severity of HCPS. Patients and Methods: Study period: 2004-20013, attending in eight collaborative centers, etiological diagnosis was performed by serology or molecular biology, mild and severe HCPS were compared.139 Chilean patients were analyzed, 64 (46%) with severe disease among which 12 (19 %) died. Results: European ethnicity had 5,1 times higher risk than Amerindian ethnic group to develop a severe HCPS, greater seriousness that was also associated with an urban residence. Conclusion: It was observed that ethnicity and type of residence were significant risk factors for HCPS severity. Hypotheses explaining these findings are discussed.

Epidemiological description, case-fatality rate, and trends of Hantavirus Pulmonary Syndrome: 9 years of surveillance in Argentina.

Hantavirus pulmonary syndrome (HPS) is an endemic disease in Argentina, one of the most affected countries in the Americas. Andes virus (ANDV) is the main Orthohantavirus species causing HPS in Argentina. In this study, the geographical distribution, clinical presentation, and epidemiological features of HPS from all endemic regions of Argentina were analyzed. We focused on the clinical and epidemiological data from 533 HPS cases confirmed during the period 2009 to 2017 by the National Reference Laboratory for Hantavirus. A case-fatality rate of 21.4% was registered, and most of the cases presented a severe clinical picture requiring intensive care treatment (84%). Since HPS first detection in 1995 the case-fatality rate showed a general trend towards a decrease. After more than 22 years of experience in HPS diagnosis and surveillance, we discuss some possible factors implicated in this tendency. This clinical and epidemiological analysis gives a global perspective, being useful to detect trends and patterns, to update preventive actions at a national level, and evaluate their impact on public health.

Maripa Virus RNA Load and Antibody Response in Hantavirus Pulmonary Syndrome, French Guiana.

We report viral RNA loads and antibody responses in 6 severe human cases of Maripa virus infection (2 favorable outcomes) and monitored both measures during the 6-week course of disease in 1 nonfatal case. Further research is needed to determine prevalence of this virus and its effect on other hantaviruses.

Hantavirus induced cardiopulmonary syndrome: A public health concern.

Hantavirus cardiopulmonary syndrome is characterized by pulmonary capillary leakage and alveolar flooding, resulting in 50% mortality due to fulminant hypoxic respiratory failure. In addition, depression of cardiac function ensues, which complicates the picture with cardiogenic shock. Early diagnosis and appropriate use of extracorporeal membrane oxygenation (ECMO) are amongst the lifesaving interventions in this fatal illness. However, a recent case report demonstrates that implementation of high volume continuous hemofilteration along with protective ventilation reverses the cardiogenic shock within few hours in hantavirus infected patients. This review article is focused on the recent advances in clinical features, diagnosis, management, epidemiology, and pathogenesis of hantavirus induced cardiopulmonary syndrome. It provides information for clinicians to help in correct diagnosis during the early stages of viral infection that could improve the prognosis of this viral illness.

Hantavirus Pulmonary Syndrome Caused by Maripa Virus in French Guiana, 2008-2016.

We report 5 human cases of hantavirus pulmonary syndrome found during surveillance in French Guiana in 2008-2016; of the 5 patients, 4 died. This pathogen should continue to be monitored in humans and rodents in effort to reduce the occurrence of these lethal infections in humans stemming from ecosystem disturbances.

Climate change and sugarcane expansion increase Hantavirus infection risk.

Hantavirus Cardiopulmonary Syndrome (HCPS) is a disease caused by Hantavirus, which is highly virulent for humans. High temperatures and conversion of native vegetation to agriculture, particularly sugarcane cultivation can alter abundance of rodent generalist species that serve as the principal reservoir host for HCPS, but our understanding of the compound effects of land use and climate on HCPS incidence remains limited, particularly in tropical regions. Here we rely on a Bayesian model to fill this research gap and to predict the effects of sugarcane expansion and expected changes in temperature on Hantavirus infection risk in the state of São Paulo, Brazil. The sugarcane expansion scenario was based on historical data between 2000 and 2010 combined with an agro-environment zoning guideline for the sugar and ethanol industry. Future evolution of temperature anomalies was derived using 32 general circulation models from scenarios RCP4.5 and RCP8.5 (Representative greenhouse gases Concentration Pathways adopted by IPCC). Currently, the state of São Paulo has an average Hantavirus risk of 1.3%, with 6% of the 645 municipalities of the state being classified as high risk (HCPS risk ≥ 5%). Our results indicate that sugarcane expansion alone will increase average HCPS risk to 1.5%, placing 20% more people at HCPS risk. Temperature anomalies alone increase HCPS risk even more (1.6% for RCP4.5 and 1.7%, for RCP8.5), and place 31% and 34% more people at risk. Combined sugarcane and temperature increases led to the same predictions as scenarios that only included temperature. Our results demonstrate that climate change effects are likely to be more severe than those from sugarcane expansion. Forecasting disease is critical for the timely and efficient planning of operational control programs that can address the expected effects of sugarcane expansion and climate change on HCPS infection risk. The predicted spatial location of HCPS infection risks obtained here can be used to prioritize management actions and develop educational campaigns.

A Fatal Hantavirus Pulmonary Syndrome Misdiagnosed as Dengue: An Investigation into the First Reported Case in Rio de Janeiro State, Brazil.

We report the results of an investigation into a fatal case of hantavirus pulmonary syndrome (HPS) in Rio de Janeiro State, Brazil, where the disease had not been reported previous to 2015. Following the notification of an HPS case, serum samples were collected from the household members and work contacts of the HPS patient and tested for antibody to hantaviruses. Seroprevalence of 22% (10/45) was indicated for hantavirus out of 45 human samples tested. Blood and tissue samples were collected from 72 rodents during fieldwork to evaluate the prevalence of hantavirus infection, by using enzyme-linked immunosorbent assay IgG, and to characterize the rodent hantavirus reservoir(s), by reverse transcription polymerase chain reaction and sequencing. Antibody prevalence was 6.9%. The circulation of a single genotype, the Juquitiba hantavirus, carried by two rodent species, black-footed pigmy rice rat (Oligoryzomys nigripes) and cursor grass mouse (Akodon cursor), was shown by analysis of the nucleotide sequences of the S segment. Juquitiba hantavirus circulates in rodents of various species, but mainly in the black-footed pigmy rice rat. HPS is a newly recognized clinical entity in Rio de Janeiro State and should be considered in patients with febrile illness and acute respiratory distress.

Effect of Vandetanib on Andes virus survival in the hamster model of Hantavirus pulmonary syndrome.

Hantavirus pulmonary syndrome (HPS) is a severe disease caused by hantavirus infection of pulmonary microvascular endothelial cells leading to microvascular leakage, pulmonary edema, pleural effusion and high case fatality. Previously, we demonstrated that Andes virus (ANDV) infection caused up-regulation of vascular endothelial growth factor (VEGF) and concomitant downregulation of the cellular adhesion molecule VE-cadherin leading to increased permeability. Analyses of human HPS-patient sera have further demonstrated increased circulating levels of VEGF. Here we investigate the impact of a small molecule antagonist of the VEGF receptor 2 (VEGFR-2) activation in vitro, and overall impact on survival in the Syrian hamster model of HPS.

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.

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.

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".

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.

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: 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.