South American Hemorrhagic Fevers: A summary for clinicians.

OBJECTIVES: This article is one of a series on acute, severe diseases of humans caused by emerging viruses for which there are no or limited licensed medical countermeasures. We approached this summary on South American Hemorrhagic Fevers (SAHF) from a clinical perspective that focuses on pathogenesis, clinical features, and diagnostics with an emphasis on therapies and vaccines that have demonstrated potential for use in an emergency situation through their evaluation in nonhuman primates (NHPs) and/or in humans. METHODS: A standardized literature review was conducted on the clinical, pathological, vaccine, and treatment factors for SAHF as a group and for each individual virus/disease. RESULTS: We identified 2 treatments and 1 vaccine platform that have demonstrated potential benefit for treating or preventing infection in humans and 4 other potential treatments currently under investigation. CONCLUSION: We provide succinct summaries of these countermeasures to give the busy clinician a head start in reviewing the literature if faced with a patient with South American Hemorrhagic Fever. We also provide links to other authoritative sources of information.

Differential Immune Responses to New World and Old World Mammalian Arenaviruses.

Some New World (NW) and Old World (OW) mammalian arenaviruses are emerging, zoonotic viruses that can cause lethal hemorrhagic fever (HF) infections in humans. While these are closely related RNA viruses, the infected hosts appear to mount different types of immune responses against them. Lassa virus (LASV) infection, for example, results in suppressed immune function in progressive disease stage, whereas patients infected with Junín virus (JUNV) develop overt pro-inflammatory cytokine production. These viruses have also evolved different molecular strategies to evade host immune recognition and activation. This paper summarizes current progress in understanding the differential immune responses to pathogenic arenaviruses and how the information can be exploited toward the development of vaccines against them.

[Bolivian hemorrhagic fever].

Analysis of data of the available literature on epidemiology of Bolivian hemorrhagic fever, manifestations of human disease, biological properties of the causative agent and development carried out abroad of means and methods of diagnostics, prophylaxis and therapy of this infection that presents a potential threat for the population and economy of the Russian Federation in case of introduction of the causative agent is presented.

Mentha x piperita L. y su potencial en el control del vector del dengue (Aedes aegypti L.). Revisión / Mentha x piperita L. and its potential in controlling the dengue vector (Aedes aegypti L.). Review

El dengue es una de las enfermedades tropicales más fatales, afectando a 50-100 millones de personas al año. Endémico en más de cien países y transmitido a los humanos por la picadura subcutánea del mosquito Aedes aegypti L., puede desencadenar los síntomas de una gripe normal, episodios de fiebre hemorrágica y shock. Las medidas de erradicación del vector adoptadas por las autoridades sanitarias mundiales, como la eliminación del hábitat y uso de repelentes y/o insecticidas) no logran frenar la propagación del dengue, ya extendido por las áreas no endémicas, como Portugal. Se sabe que el mosquito es vulnerable a algunos productos vegetales y varios estudios los han considerado como alternativas potenciales a los productos químicos sintéticos, a la que el mosquito se ha vuelto resistente. Algunas de esas plantas pertenecen a la flora nativa, espontánea y subespontánea, estando accesibles a un gran número de personas. Es el caso de la Mentha x piperita., elegida como ejemplo por las propiedades insecticidas y repelentes de su aceite esencial (AU)

Dengue is one of the most fatal tropical diseases which affect 50-100 billion people/ year. It is endemic in more than 100 countries and transmitted to humans by the subcutaneous bite of the Aedes aegypti L., it can trigger different symptoms like normal flu, hemorrhagic fever and shock. The eradication of the vector adopted by global health authorities, like the elimination of its habitat, the use of repellents and/or insecticides, fail to curb the spread of the disease, which are expanding into non-endemic areas (Portugal). Vector is vulnerable to some herbal products and scientific studies have considered them as a potential alternative to the synthetic ones in use, to which the mosquito may become resistant. Some of these herbs belong to native, spontaneous and subspontaneous flora, resulting accessible to the population. Mentha x piperita L., was chosen as example due to insecticide and repellent properties of it essential oil (AU)

Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever.

A number of arenaviruses are pathogenic for humans, but they differ significantly in virulence. Lassa virus, found in West Africa, causes severe hemorrhagic fever (HF), while the other principal Old World arenavirus, lymphocytic choriomeningitis virus, causes mild illness in persons with normal immune function, and poses a threat only to immunocompromised individuals. The New World agents, including Junin, Machupo and Sabia virus, are highly pathogenic for humans. Arenaviral HF is characterized by high viremia and general immune suppression, the mechanism of which is unknown. Studies using viral reverse genetics, cell-based assays, animal models and human genome-wide association analysis have revealed potential mechanisms by which arenaviruses cause severe disease in humans. Each of the four viral gene products (GPC, L polymerase, NP, and Z matrix protein) and several host-cell factors (e.g., α-dystroglycan) are responsible for mediating viral entry, genome replication, and the inhibition of apoptosis, translation and interferon-beta (IFNß) production. This review summarizes current knowledge of the role of each viral protein and host factor in the pathogenesis of arenaviral HF. Insights from recent studies are being exploited for the development of novel therapies.

Treatment of Argentine hemorrhagic fever.

Argentine hemorrhagic fever (AHF) is a rodent-borne illness caused by the arenavirus Junin that is endemic to the humid pampas of Argentina. AHF has had significant morbidity since its emergence in the 1950s, with a case-fatality rate of the illness without treatment between 15% and 30%. The use of a live attenuated vaccine has markedly reduced the incidence of AHF. Present specific therapy involves the transfusion of immune plasma in defined doses of neutralizing antibodies during the prodromal phase of illness. However, alternative forms of treatment are called for due to current difficulties in early detection of AHF, related to its decrease in incidence, troubles in maintaining adequate stocks of immune plasma, and the absence of effective therapies for severely ill patients that progress to a neurologic-hemorrhagic phase. Ribavirin might be a substitute for immune plasma, provided that the supply is guaranteed. Immune immunoglobulin or monoclonal antibodies should also be considered. New therapeutic options such as those being developed for systemic inflammatory syndromes should also be valuated in severe forms of AHF.

[Hemorrhagic (Marburg, Ebola, Lassa, and Bolivian) fevers: epidemiology, clinical pictures, and treatment].

The evaluation of the biological and epidemiological properties of Ebola, Marburg, Lassa, and Machupo viruses suggests that they are of social importance for health care authorities. The studies have created prerequisites to the development of reliable biosafety means against these pathogens. Particular emphasis is laid on the methods for infection diagnosis and on the studies to design specific protective agents--immunoglobulins and inactivated vaccines.

Protective efficacy of a live attenuated vaccine against Argentine hemorrhagic fever. AHF Study Group.

Argentine hemorrhagic fever (AHF), caused by the arenavirus Junin, is a major public health problem among agricultural workers in Argentina. A prospective, randomized, double-blind, placebo-controlled, efficacy trial of Candid 1, a live attenuated Junin virus vaccine, was conducted over two consecutive epidemic seasons among 6500 male agricultural workers in the AHF-endemic region. Twenty-three men developed laboratory-confirmed AHF during the study; 22 received placebo and 1 received vaccine (vaccine efficacy 95%; 95% confidence interval [CI], 82%-99%). Three additional subjects in each group developed laboratory-confirmed Junin virus infection associated with mild illnesses that did not fulfill the clinical case definition for AHF, yielding a protective efficacy for prevention of any illness associated with Junin virus infection of 84% (95% CI, 60%-94%). No serious adverse events were attributed to vaccination. Candid 1, the first vaccine for the prevention of illness caused by an arenavirus, is safe and highly efficacious.

Manifestaciones cutáneas y mucosas de la fiebre hemorrágica argentina / Cutaneous and mucosal manifestations of argentine hemorrhagic fever

La presente monografía tiene como finalidad describir las manifestaciones clínicas cutáneas y mucosas de la Fiebre Hemorrágica Argentina, así como también hacer una breve reseña general de la enfermedad y describir en forma cronológica las etapas para la comprensión de la patología, la historia de la enfermedad hasta nuestros días, concluyendo con el descubrimiento de una vacuna para prevenirla. No existe hasta la fecha ninguna publicación en la literatura dermatológica de esta enfermedad. Se consideró de interés difundir en el medio dermatológico una patología viral general, con compromiso cutáneo-mucoso de importancia

Manifestaciones cutáneas y mucosas de la fiebre hemorrágica argentina / Cutaneous and mucosal manifestations of argentine hemorrhagic fever

La presente monografía tiene como finalidad describir las manifestaciones clínicas cutáneas y mucosas de la Fiebre Hemorrágica Argentina, así como también hacer una breve reseña general de la enfermedad y describir en forma cronológica las etapas para la comprensión de la patología, la historia de la enfermedad hasta nuestros días, concluyendo con el descubrimiento de una vacuna para prevenirla. No existe hasta la fecha ninguna publicación en la literatura dermatológica de esta enfermedad. Se consideró de interés difundir en el medio dermatológico una patología viral general, con compromiso cutáneo-mucoso de importancia (AU)

[Prevalence of hepatitis C antibodies in plasma donors for the treatment of Argentine hemorrhagic fever]. / Prevalencia de anticuerpos para el virus de la hepatitis C en donantes de plasma para el tratamiento de la fiebre hemorrágica Argentina.

For Argentine Hemorrhagic Fever, a disease caused by Junin virus (JV), there is an effective treatment, consisting of the transfusion of immune plasma (IP). This plasma is obtained from individuals who have had the disease. Since Hepatitis C virus (HCV) is transmitted parenterally, this study was aimed to estimate the prevalence of anti-HCV in a population of IP donors. In this study, 376 donors (47 females and 329 males) were studied: 95 individuals (24 females and 71 males) who had had FHA but had not received treatment and 88 laboratory workers (57 females and 31 males) who were included as controls. Serum samples were tested by EIA (Abbott, Germany) for HCV, and later confirmed by LIATEK (Organon, Ireland). Antibodies to HCV were detected in 29/376 donors (7.7%), in only 1/95 (1.0%) untreated convalescents of AHF and in 1/ 88 (1.1%) of laboratory workers. Retrospective analysis of the seroconversion for HCV in these individuals demonstrated that in 16/24 donors (66.6%) the infection by HCV was probably associated with the IP transfusion. The data presented herein show how the infection with HCV was disseminated among donors of IP, stressing the risk associated to transfusional practices, and emphasizing the need of vaccination to prevent AHF and also the risk inherent to its treatment.

Prevalencia de anticuerpos para el virus de la hepatitis C en donantes de plasma para el tratamiento de la fiebre hemorragica Argentina / Prevalence of hepatitis C antibodies in donor plasma for the treatment of Argentine hemorrahagic fever

La fiebre Hemorrágica Argentina (FHA) es una enfermedad causada por el virus Junin (VJ) cuyo único tratamiento efectivo es la transfusión de plasma inmune (PI) obtenido de convalecientes de la enfermedad. Dado que el virus de la Hepatitis C (HCV) se transmite principalmente por vía parenteral, en este trabajo se intentó estimar la prevalencia de anticuerpos anti-HCV en una problación de donantes de unbanco de PI. Se estudiaron retrospectivamente 253 convalencientes de FHA y 123 en forma prospectiva, quines concurrieron al Instituto Nacional de Enfermedades Virales Humanas (INEVH) a donar PI entre 1991 y 1995. Como población control se estudiaron 95 individuos que tuvieron FHA pero no fueron transfundidos con PI y un grupo de 88 individuos pertenecientes al personal del INEVH. Mediante pruebas de ELISA de 2 generación, confirmadas por LIA-TEK se detectaron anticuerpos anti-HCV en 29/376 donantes (7,7 por ciento). Sólo uno de los 95 individuos del grupo control fue anti-HCV positivo (1,0 por ciento) y uno de los 88 individuos del personal fue anti-HCV positivo (1,1 por ciento). El análisis retrospectivo de la seroconversión para HCV demonstró que en 16/24 donantes (66,6 por ciento) la infección por HCV estuvo propablemente asociada a la transfusión de PI. Los datos presentados enfatizan los riesgos asociados a prácticas transfusionales y las posibilidades de su prevención. En el caso de la FHA, la demonstración de la inocuidad, inmunogenicidad y eficacia protectora de la vacuna Candid 1 contra la FHA, señala la necesidad de la vacunación para evitar esta enfermedad y los riesgos de su tratamiento.

Prevalencia de anticuerpos para el virus de la hepatitis C en donantes de plasma para el tratamiento de la fiebre hemorragica Argentina / Prevalence of hepatitis C antibodies in donor plasma for the treatment of Argentine hemorrahagic fever

La fiebre Hemorrágica Argentina (FHA) es una enfermedad causada por el virus Junin (VJ) cuyo único tratamiento efectivo es la transfusión de plasma inmune (PI) obtenido de convalecientes de la enfermedad. Dado que el virus de la Hepatitis C (HCV) se transmite principalmente por vía parenteral, en este trabajo se intentó estimar la prevalencia de anticuerpos anti-HCV en una problación de donantes de unbanco de PI. Se estudiaron retrospectivamente 253 convalencientes de FHA y 123 en forma prospectiva, quines concurrieron al Instituto Nacional de Enfermedades Virales Humanas (INEVH) a donar PI entre 1991 y 1995. Como población control se estudiaron 95 individuos que tuvieron FHA pero no fueron transfundidos con PI y un grupo de 88 individuos pertenecientes al personal del INEVH. Mediante pruebas de ELISA de 2 generación, confirmadas por LIA-TEK se detectaron anticuerpos anti-HCV en 29/376 donantes (7,7 por ciento). Sólo uno de los 95 individuos del grupo control fue anti-HCV positivo (1,0 por ciento) y uno de los 88 individuos del personal fue anti-HCV positivo (1,1 por ciento). El análisis retrospectivo de la seroconversión para HCV demonstró que en 16/24 donantes (66,6 por ciento) la infección por HCV estuvo propablemente asociada a la transfusión de PI. Los datos presentados enfatizan los riesgos asociados a prácticas transfusionales y las posibilidades de su prevención. En el caso de la FHA, la demonstración de la inocuidad, inmunogenicidad y eficacia protectora de la vacuna Candid 1 contra la FHA, señala la necesidad de la vacunación para evitar esta enfermedad y los riesgos de su tratamiento. (AU)

Latin American hemorrhagic fever.

Several viral and bacterial agents are responsible for hemorrhagic fever in Latin America, but there are three agents that are only present in this region: (1) the Junin virus, (2) the Machupo virus, and (3) the Guanaritovirus, members of the Tacaribe complex of the family Arenaviridae and responsible for the Argentinian, Bolivian, and Venezuelan hemorrhagic fever. The clinical manifestations of hemorrhagic fever are similar for the three viruses, mainly myalgia, arthralgia, headache, relative bradycardia, conjunctivitis, nausea, vomiting, diarrhea, and hemorrhagic disorders. In this article, the three viruses, their causes, and manifestations are discussed.

Antiviral treatment of Argentine hemorrhagic fever.

Argentine hemorrhagic fever is a systemic viral disease caused by Junin virus, with a mortality of 15-30% in untreated individuals. Current specific therapy is highly effective in reducing mortality, and consists of the early administration of immune plasma in defined doses of specific neutralizing antibodies per kg of body weight. However, several reasons suggest the need to investigate alternative therapies. Ribavirin, a broad spectrum antiviral agent, is effective in the treatment of other viral hemorrhagic fevers, and the studies done with Junin virus infections to date indicate that this drug may also have a beneficial effect in Argentine hemorrhagic fever.

Activity of a platelet protein kinase that phosphorylates fibrinogen and histone in Argentine hemorragic fever

La actividad de una proteinoquinasa plaquetaria que fosforila la cadena alfa del fibrinógeno y la histona como substrato exógeno, se evaluo en 28 pacientes con fiebre hemorrágica argentina, agrupados de acuerdo a la forma clínica en: 13 leves, 6 comunes y 9 graves. Las muestras de sangre se obtuvieron antes del tratmiento con plasma inmune, 4 dias después y en la convalescencia. La fosforilación de la histona exógena y del fibrinógeno se estudió con 25 Ci/mmol ( gamma-32p)-ATP. Simultaneamente se efectuó el recuesto de plaquetas y se midió la actividad del interferon alfa (IFN). La fosforilación de la histona se halló por debajo de los valores normales en todos los pacientes durante la fase aguda de la enfermedad. Esta reducción fue coincidente con los titulos más altos de IFN. La fosforilación del fibrinógeno estuvo igualmente disminuida. La fosforilación de la histona y del fibrinógeno estaban aun disminuidos 4 dias después del tratamiento, cuando el IFN era practicamente no dosable. El bajo nivel de fosforilación no puede atribuirse solamente a una disminución del número de plaquetas y podría ser otra evidencia de la existencia de una alteración plaquetaria en los pacientes con fiebre hemorragica argentina

Activity of a platelet protein kinase that phosphorylates fibrinogen and histone in Argentine hemorragic fever

La actividad de una proteinoquinasa plaquetaria que fosforila la cadena alfa del fibrinógeno y la histona como substrato exógeno, se evaluo en 28 pacientes con fiebre hemorrágica argentina, agrupados de acuerdo a la forma clínica en: 13 leves, 6 comunes y 9 graves. Las muestras de sangre se obtuvieron antes del tratmiento con plasma inmune, 4 dias después y en la convalescencia. La fosforilación de la histona exógena y del fibrinógeno se estudió con 25 Ci/mmol ( gamma-32p)-ATP. Simultaneamente se efectuó el recuesto de plaquetas y se midió la actividad del interferon alfa (IFN). La fosforilación de la histona se halló por debajo de los valores normales en todos los pacientes durante la fase aguda de la enfermedad. Esta reducción fue coincidente con los titulos más altos de IFN. La fosforilación del fibrinógeno estuvo igualmente disminuida. La fosforilación de la histona y del fibrinógeno estaban aun disminuidos 4 dias después del tratamiento, cuando el IFN era practicamente no dosable. El bajo nivel de fosforilación no puede atribuirse solamente a una disminución del número de plaquetas y podría ser otra evidencia de la existencia de una alteración plaquetaria en los pacientes con fiebre hemorragica argentina (AU)

Activity of a platelet protein kinase that phosphorylates fibrinogen and histone in Argentine hemorrhagic fever.

The activity of a platelet protein kinase that phosphorylates the alpha-chain of fibrinogen and the exogenous substrate histone was evaluated in 28 patients with Argentine hemorrhagic fever, grouped into: 13 mild, 6 moderate and 9 severe clinical forms. Blood samples were obtained before treatment with immune plasma, 4 days later and at recovery. Exogenous histone and fibrinogen phosphorylation were assayed with 25 Ci/mmol (gamma-32P)-ATP. Platelet counts and interferon (IFN) activity were performed simultaneously. Histone phosphorylation was found below normal in all patients during the acute phase of illness. This reduction was coincident with the lowest platelet count and the highest IFN titers. Fibrinogen phosphorylation was similarly reduced. Histone and fibrinogen phosphorylation were still low after 4 days of treatment, when IFN levels were almost undetectable. The low level of phosphorylation was not simply due to the reduced number of platelets and may be another evidence of a platelet abnormality in patients with Argentine hemorrhagic fever.