Review
Bolivian hemorrhagic fever: A narrative review

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Highlights

  • Bolivian hemorrhagic fever (BHF) is a sporadic high-mortality febrile illness.

  • Two etiological agents are currently recognized: Machupo virus and Chapare virus.

  • Infection in humans occurs by exposure to excreta and secretions of wild native rodents in Bolivia.

  • The most recent outbreak was in 2019, in which health-care professionals were infected.

  • As tourism and travelling increase in Bolivia, travelers could be infected, and be a diagnostic challenge in non-endemic countries.

Abstract

Bolivian hemorrhagic fever (BHF) is a sporadic high-mortality febrile illness. Two etiological agents are currently recognized: Machupo virus and Chapare virus. Infection in humans occurs by exposure to excreta and secretions of wild native rodents in Bolivia. BHF is considered a severe disease that has three clinical phases: prodromal, hemorrhagic, and convalescent. Unspecific symptoms occur during the first phase, severe hemorrhagic manifestations occur during the second phase, and finally patients who survive experience a slow convalescent phase. The incubation period is variable and depends on host factors, viral pathogenicity, and severity of the disease. The diagnosis is primarily clinical and epidemiological, and though diagnosis should be confirmed by laboratory tests, viral agents of BHF are considered very pathogenic and need to be handled in reference laboratories that are not available in endemic areas. The most recent outbreak was in 2019, in which health-care professionals were infected and is recognized as the first outbreak in La Paz department, Bolivia, a place where no prior cases had been reported. In addition, as tourism and travelling increase in Bolivia, along with ecological practices that could represent a risk for acquiring BHF, travelers could be infected, develop the disease, and be a diagnostic challenge in non endemic countries. No vaccines or antiviral therapies are available and approved for human use. Control measures are focused on peridomicile rodent population eradication which demonstrated efficacy in reducing cases during the first outbreaks.

Introduction

Bolivian hemorrhagic fever (BHF), black typhus, or Ordog fever is a sporadic high mortality hemorrhagic febrile illness. Two etiological agents are recognized: Machupo virus (MACV) and Chapare virus (CHAPV) [1,2]. The first etiological agent to be isolated was MACV, an arenavirus identified in 1963 from the spleen of a deceased patient with hemorrhagic fever from San Joaquín town (Beni department, Bolivia) [2]. MACV is named as a reference to an Iténez river tributary that flows through the geographic region where first cases of the disease took place [3]. The first strain of MACV to be isolated is known as Carvallo strain [4]. MACV belongs to clade B of South American hemorrhagic fever arenaviruses carried by the Callomys callosus rodent species as viral reservoir [5]. MACV is antigenically similar to Junín virus from Argentina and Tacaribe virus from Trinidad [2]. Between 2003 and 2004, a new arenavirus was discovered by RT-PCR (real time polymerase chain reaction) in a small outbreak of hemorrhagic febrile illness in a municipality near Cochabamba, Bolivia. This new virus was named CHAPV as a reference to the geographic region where it was discovered. Although surveillance is limited, CHAPV might be implicated in hemorrhagic febrile cases in Beni department too, so co-circulation of both viral agents in this region may be possible [1]. CHAPV is also classified as a member of New World Clade B arenaviruses, however, it is not known if C. callosus is also a CHAPV reservoir [1,6]. Currently, there is no evidence of recombination between different species of arenaviruses to support the origin of the CHAPV [6].

Viral hemorrhagic fevers generally have an enigmatic behaviour, they can generate epidemic outbreaks at any time, but they are highly restricted to certain well-defined geographic areas. The mortality rate is variable during outbreaks, approximately 30% of infected people die as a result of the disease or the complications that occur during the hemorrhagic phase [7]. In areas where several similar diseases coexist (e.g. leptospirosis, dengue, etc.), BHF has a higher case fatality rate, even 100% under certain circumstances [8].

There have been no recent BHF reviews, so we aim to provide a narrative review of the scientific literature on BHF and address its etiological, epidemiological, and clinical profile. This is of particular relevance due to the recent BHF outbreak in the department of La Paz, Bolivia [9], with cases of inter-human transmission and whose etiological agent, after molecular analysis, correspond to CHAPV [10].

Section snippets

Methods

We conducted a comprehensive literature research using PubMed in order to identify studies about BHF. We used the terms “Bolivian hemorrhagic fever,” “Bolivian hemorrhagic fever,” “Machupo virus,” and “Chapare virus”. Of all the scientific publications available from the research performed, we chose the studies that had specific relevant information of BHF and its etiologic agents.

Incidence

Incidence data of BHF cases is not known because of the limited epidemiologic surveillance system in Bolivia. Between 1963 and 1964, in San Joaquin municipality (Beni department, Bolivia), a total of 637 cases were diagnosed, the largest incidence of BHF recorded to date [11] and with a mortality rate of 25–35% [2,11].

Geographic distribution

Callomys callosus have been identified in three of the nine departments of Bolivia, including Beni, Cochabamba, and La Paz. MACV has been identified in Mamoré, Iténez and Yucuma

Machupo virus

MACV is a single-stranded-negative RNA virus which genome is divided in two fragments, a large and a short [18]. It belongs to Mammarenavirus genus, Arenaviridae family, and clade B of new world arenaviruses [19]. The virion contains two major structural proteins GP1 and GP2, a nucleoprotein, an RNA-dependent RNA polymerase, an RNA endonuclease, and minor amounts of other proteins [[20], [21], [22]]. Major structural proteins are similar to other Tacaribe complex viruses, however, some

Natural reservoir

Arenavirus reservoirs mostly belong to Muridae family, Sigmodontinae subfamily [24]. Human infection occurs by exposure to excreta and secretions from infected rodents [5]. Northern Bolivian C. callosus is known to be the natural reservoir of MACV. These rodent species are considered a domestic plague, as they live on the forest's edge near villages and human dwellings [1,25]. Calomys genus is made up for at least twelve well-known members, and some are closely associated with non-forest biomes

Pathophysiology

BHF pathophysiology is not fully understood. After exposure to infectious aerosols, viral particles are inhaled, travel upon upper airway until reach the respiratory bronchioles, where are phagocytosed by alveolar macrophages producing the first cellular infection [24]. During this process, no damage or pulmonary consolidation is detectable [4]. Viral particles infect vascular endothelial cells as they cross the endothelial surface of blood vessels and manage to reach different organ

Clinical manifestations

BHF is considered a severe disease with a high rate of mortality and an incubation period that can be as short as three days or as long as twenty-one days after exposure to viral agents with an average of seven to fourteen days [1,37]. Clinically, BHF is similar to other New World hemorrhagic fevers [7]. Argentine hemorrhagic fever, the best known New World hemorrhagic fever, is the most similar to BHF. Neurologic damage is most common in Argentine hemorrhagic fever and hemorrhagic

Diagnosis

BHF diagnosis is mainly clinical and epidemiological and if possible should be confirmed by laboratory. Clinical data including symptomatology, course of the disease, travel to endemic areas, history and exposure to rodents, or contact with patients with suggestive symptomatology [9,16].

There is no available data of sensitivity and specificity for BHF laboratory tests, however some authors say that they have generally high sensitivity from the third day after the onset of symptoms [1]. Acute

Treatment

Currently, there are no antiviral therapies approved by the FDA for the treatment of BHF. Antiviral therapies proposed have not yet been tested in clinical trials to support efficacy and safety for human treatment [1]. In recent years, some molecules with antiviral activity have been efficacious for hemorrhagic fever treatment in vitro, including BHF, however they have not been evaluated in vivo because of the lack of animal models that resemble the pathophysiology in humans [46].

Human

Prevention

“Candid 1” is a live-attenuated vaccine against Junin virus, Argentine hemorrhagic fever viral agent, and is only authorized and available for use in Argentina [5]. It is not permitted to be used Bolivia, however, “Candid 1” can cross-react against MACV, as Junin virus and MACV have antigenic similarity [50], so it potentially could be used as a prophylactic against BHF caused by MACV. This likely could be used only in people who are at very high risk, as sufficient clinical trials have not yet

Conclusions

BHF is a disease that needs to be considered as a differential diagnosis on the undifferentiated acute febrile illnesses in Bolivia. It is necessary to establish a surveillance system in order to know more about BHF epidemiology. Although studies helped to determine some endemic areas, a robust surveillance system would provide information to determine the incidence and prevalence of the disease and determine other endemic areas. The last epidemic caused by CHAPV demonstrated the limited local

Funding

This research did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgements

We thank Dr. Jordan Cahn for providing an English review of the manuscript.

References (58)

  • P.E. Kilgore et al.

    Prospects for the control of Bolivian hemorrhagic fever

    Emerg Infect Dis

    (1995)
  • Alerta epidemiológica: fiebre hemorrágica por arenavirus en Bolivia. 18 de julio de 2019

    (2019)
  • JP Escalera-Antezana et al.

    Clinical features of fatal cases of Chapare virus hemorrhagic fever originating from rural La Paz, Bolivia, 2019: a cluster analysis

    Travel Med Infect Dis.

    (2020 Jul-Aug)
  • P.V. Aguilar et al.

    Reemergence of Bolivian hemorrhagic fever, 2007–2008

    Emerg Infect Dis

    (2009)
  • R.B. Mackenzie

    Epidemiology of Machupo virus infection. I. Pattern of human infection, San Joaquín, Bolivia,

    Am J Trop Med Hyg

    (1962–1964)
  • K.M. Johnson

    Epidemiology of Machupo virus infection. III. Significance of virological observations in man and animals

    Am J Trop Med Hyg

    (1965)
  • R.G. Douglas et al.

    Bolivian hemorrhagic fever probably transmitted by personal contact

    Am J Epidemiol

    (1965)
  • I.S. Lukashevich et al.

    Ribonucleic acids of machupo and Lassa viruses

    Arch Virol

    (1984)
  • P.A. Webb

    Properties of machupo virus

    Am J Trop Med Hyg

    (1965)
  • J.D. Gangemi et al.

    Structural polypeptides of Machupo virus

    J Gen Virol

    (1978)
  • I.S. Lukashevich et al.

    Machupo virus polypeptides: identification by immunoprecipitation

    Arch Virol

    (1985)
  • P.J. Kranzusch et al.

    Assembly of a functional Machupo virus polymerase complex

    Proc Natl Acad Sci U S A

    (2010)
  • P.A. Webb et al.

    Some characteristics of Machupo virus, causative agent of Bolivian hemorrhagic fever

    Am J Trop Med Hyg

    (1967)
  • C.J. Peters

    Human infection with arenaviruses in the Americas

    Curr Top Microbiol Immunol

    (2002)
  • K.M. Johnson et al.

    Isolation of Machupo virus from wild rodent Calomys callosus

    Am J Trop Med Hyg

    (1966)
  • G. Justines et al.

    Immune tolerance in Calomys callosus infected with Machupo virus

    Nature

    (1969)
  • M.L. Kuns

    Epidemiology of Machupo virus infection. II. Ecological and control studies of hemorrhagic fever

    Am J Trop Med Hyg

    (1965)
  • S.K. Scott et al.

    Studies of the coagulation system and blood pressure during experimental Bolivian hemorrhagic fever in rhesus monkeys

    Am J Trop Med Hyg

    (1978)
  • T.A. Bowden et al.

    Unusual molecular architecture of the machupo virus attachment glycoprotein

    J Virol

    (2009)
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