Treatment of Argentine hemorrhagic fever
Introduction
Argentine hemorrhagic fever (AHF) is a severe viral hemorrhagic fever endemic to the fertile farming plain of central Argentina, the “humid pampas” (Fig. 1) (Maiztegui, 1975). Junin virus (family Arenaviridae), the etiologic agent of AHF, is a rodent-borne virus. Calomys musculinus has been identified as its principal reservoir. Human exposure to Junin virus is believed to occur through inhalation of aerosolized body fluids or excretions of infected rodents, typically during agricultural work.
The emergence of AHF in the 1950s is hypothesized to have resulted from human alterations of the habitat in relation to agricultural practices. Such changes in the environment are reported to have favored the population growth of C. musculinus. Since the recognition of the illness, annual outbreaks have been registered without interruption, with number of cases between 300 and 1000, approximately. With the availability of an effective live attenuated Junin virus vaccine, a consistent reduction in the incidence of AHF was achieved in the 1990s (Enria and Barrera Oro, 2002, Enria et al., 2004). The objective of this article is to review knowledge acquired on the treatment of this illness and to discuss future expectations.
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Clinical disease in AHF
The incubation period is usually from 6 to 14 days. Most infections with Junin virus (80%) result in clinical disease. Three phases are recognized in the illness: prodromal, neurological–hemorrhagic, and convalescence (Enria et al., 2004).
Prodromal phase: This phase lasts for the first week from onset of symptoms. The onset is insidious, with chills, malaise, anorexia, headache, myalgia centered particularly over the lower back, and moderate hyperthermia (38–39 °C). Other common symptoms include
Pathogenesis and immunology
As noted, most cases of AHF are believed to result from inhalation of virus-containing material from infected rodents. Viral replication is thought to occur at the initial site of infection, generally the lungs, with subsequent dissemination to other parenchymal tissues. A wide variety of organs may be affected, including vascular endothelium, myocardium, kidneys and the central nervous system (Buchmeier et al., 2006). Gross pathologic changes are generalized but non-specific (Maiztegui, 1975).
Animal models useful for preclinical studies
Laboratory-bred mice, rats, guinea pigs, and non-human primates infected experimentally with Junin virus have given useful data for the understanding of the pathogenic process of AHF (Boxaca et al., 1961, Green et al., 1987, Kenyon et al., 1988, McKee et al., 1985, McKee et al., 1987). Guinea pigs reproduce most of the human lesions, with increasing viraemia from day 7 post-infection until death around day 13. Infected guinea pigs developed leucopenia and thrombocytopenia, reproduced the
Immune plasma
Historical aspects: At the end of the 1950s, several viral human infections were treated either with immune sera or with gamma globulins obtained from them. They were used based on the beneficial effect obtained either preventing the development of the illness, decreasing the severity of the disease or preventing the development of complications, according to the time at which they were administered (Gross et al., 1959, Rinaldo, 2005). In AHF, almost since the discovery of Junin virus, plasma
New antiviral drugs
Junin virus as well as all South American pathogenic arenaviruses are included by the National Institute of Allergy and Infectious Diseases (NIAID) among Category A agents that could be weaponized by bioterrorists. For this reason, hemorrhagic fevers of arenaviral origin are considered priority for the biodefense programs. Some projects for the development of new antiviral drugs for potential inclusion in a strategic stockpile were initiated and resulted in products that might deserve an
Immune globulins from human immune plasma
The Instituto de Hemoderivados de Córdoba, belonging to the Universidad Nacional de Córdoba, Argentina, produced in the 1980s immune immunoglobulin for intramuscular use that was derived from immune plasma obtained at INEVH. This was never used in a clinical trial, considering that for a therapeutic effect the immunoglobulin should be given intravenously. On the other hand, intramuscular injections are contraindicated in the viral hemorrhagic fevers. A project to produce immune immunoglobulin
Feasibility of a clinical trial of new drugs
Although for AHF we already have an effective treatment that can reduce the mortality and an effective vaccine that can reduce the morbidity, there would be still the need for better therapeutic options. It is expected that even with adequate vaccine coverage, AHF cases could occur (between 0 and 15 cases per year, distributed in three main sites). As recognition of the illness by physicians is now worse than before, it is also expected that we would more frequently see severe forms. The
Discussion
Immune plasma is the specific therapy that has been successfully used in AHF. This success is strongly linked to the fact that epidemics involving 300–1000 cases were registered every year in a restricted endemic area, mostly rural. With the availability of the effective live attenuated Junin virus vaccine Candid #1, a marked reduction in the incidence of AHF was achieved (Fig. 1, Fig. 2). On the other hand, a new geographic extension of the endemic area was registered in the last decades
Conclusion
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Current specific treatment for AHF consists of the early transfusion of immune plasma in standardized doses of neutralizing antibodies.
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Alternative forms of treatment are required, given the difficulties in maintaining a sufficient stock of immune plasma and possible adverse events. On the other hand, new treatments for severe cases that evolve to a hemorrhagic and/or neurological form of the illness are also needed.
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There are suitable animal models and there would be some possibilities for the
Acknowledgements
To Mara Eraso and Diego Bonnano for their secretarial assistance.
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