Bolivian hemorrhagic fever

Other names| Black typhus, ordog fever[1]
Specialty| Infectious disease
Symptoms| Fever, malaise, bleeding[2]
Usual onset| 3–21 Days[3]
Causes| Machupo Virus[4]
Risk factors| Exposure to the Large Vesper Mouse[5]
Treatment| Supportive care[4]
Frequency| Rare, no cases since 2008[6]
Deaths| 20%–41% fatality rate[7]

Bolivian hemorrhagic fever (BHF), also known as black typhus or Ordog Fever, is a hemorrhagic fever and zoonotic infectious disease endemic to Bolivia after infection by Machupo virus (MACV).[1] The virus is spread primarily by the large vesper mouse (Calomys callosus).[5]

BHF was first recognized in 1959 during the first reported outbreak near the city of San Joaquin in the Beni district of northeast Bolivia.[2] Symptoms include fever, malaise, bleeding, and in some cases, death.[2] The mortality rate is estimated at about 20% but during early outbreaks has been as high as 41%.[7]

The most recent cases of Bolivian hemorrhagic fever occurred in February 2008. Over 200 suspected cases of BHF were reported.[6]

## Contents

* 1 Cause
* 1.1 Discovery
* 1.2 Virology
* 2 Transmission
* 2.1 Reservoirs and Vectors
* 3 Symptoms
* 3.1 Prodromal Phase
* 3.2 Hemorrhagic Phase
* 3.3 Convalescence Phase
* 4 Treatment
* 4.1 Experimental Treatments
* 4.1.1 Immunoglobulin
* 4.1.2 Antivirals
* 5 Prevention
* 5.1 Vaccine
* 5.2 Pest Reduction
* 6 History
* 6.1 Outbreaks
* 6.1.1 1959 - 1964
* 6.1.2 1965
* 6.1.3 1966 - 1968
* 6.1.4 1969 and 1970
* 6.1.5 1971
* 6.1.6 1976- 1993
* 6.1.7 1994
* 6.1.8 2007-2008 Outbreak
* 6.1.9 Outbreak Confusion with Chapare Virus
* 6.2 Weaponization
* 7 References
* 7.1 Bibliography
* 8 External links

## Cause

### Discovery

Machupo virus

Virus classification
(unranked):  | Virus
Realm:  | Riboviria
Kingdom:  | Orthornavirae
Phylum:  | Negarnaviricota
Class:  | Ellioviricetes
Order:  | Bunyavirales
Family:  | Arenaviridae
Genus:  | Mammarenavirus
Species:  |

Mammarenavirus machupoense

Synonyms[4]

* Machupo mammarenavirus

Machupo virus is the etiological agent of Bolivian hemorrhagic fever. The virus was first isolated in 1963 using the spleen of a diseased patient from the 1963 -1964 BHF outbreak. The virus was then subsequently named after a river near the location of the outbreak.[8]

### Virology

Machupo virus is a part of the arenaviridae family which includes viruses like Lassa virus and Chapare Virus which was once thought to be an additional strain of Machupo.[5][9] Machupo is specifically a New World arenaviridae virus (those from the western hemisphere). In humans, arenaviruses are known to cause viral hemorrhagic fevers.[7] Arenaviridae viruses are enveloped, single-stranded, bi-segmented, negative-sense RNA viruses.[2] Under the microscope, Machupo virions are spherical and pleomorphic. They often appear 'sandy' due to their internal ribosomes.[1]

Due to its pathogenicity, Machupo virus requires Biosafety Level Four conditions, the highest level.[2]

## Transmission

### Reservoirs and Vectors

The large vesper mouse, the natural transmission vector for Bolivian hemorrhagic fever

The known primary reservoir and vector for Bolivian hemorrhagic fever is the large vesper mouse (Calomys callosus) a rodent indigenous to northern Bolivia.[5][10] Infected animals are asymptomatic and shed the virus in excreta and secreta. Transmission is believed to be from contact with aerosolized particles of infected excreta or secreta to the mucosal membrane. This can be through eating contaminated food, breathing in infected particles, or the direct contact of infected particles with the mucosal membrane.[2]

While rare, nosocomial transmission is known to occur with BHF.[5] In 1971, three healthcare workers were infected through interhuman transmission after the admission of an infected patient.[3]

## Symptoms

Bolivian hemorrhagic fever has an incubation period between 3 and 21 days with an average incubation period of 7 to 14 days.[11] Once symptoms appear, similar to many hemorrhagic fevers, the progression of BHF is biphasic followed by a convalescence period for survivors.[2]

### Prodromal Phase

The prodromal phase begins with the onset of symptoms and lasts between 1 and 5 days. The phase starts with nonspecific, flu-like symptoms including but not limited to; fever, malaise, headache, dehydration, dizziness, arthralgia, myalgia, and cough. Symptoms continue to increase in severity over the course of the prodromal phase. Late-stage prodromal phase symptoms can include; vomiting, diarrhea, abdominal pain, skin hypersensitivity, petechiae, and gingival-bleeding.[2][11]

### Hemorrhagic Phase

One-third of patients progress into the hemorrhagic phase.[11] This phase lasts between 2 and 10 days.[2] The hemorrhagic phase is characterized by systemic hemorrhagic manifestations. This can present as; petechiae, gingival-bleeding, hemorrhage of mucosal membranes, subconjunctival hemorrhage, bradycardia, hypotension, pulmonary edema, tremors, spasms, delirium, and at its extreme, coma and death.[2][11] Fatality typically occurs between 7 and 12 days post onset of symptoms.[11] The mortality rate for BHF is estimated at 20%.[7]

### Convalescence Phase

Of those who progress to the convalescence phase, it takes weeks to months to recover. During this phase, patients may experience weakness, hair loss, Beau's lines, rapid pulse, and dizziness.[2][11]

## Treatment

There are currently no virus-specific FDA approved therapies for Bolivian hemorrhagic fever. Supportive care is the current recommended treatment for BHF.[8]

### Experimental Treatments

Since 1963, there have been multiple experimental treatments for BHF tested on both humans and non-human primates that have been infected with Machupo.

#### Immunoglobulin

Immunoglobulin treatment consists of administering human immunoglobulin from a recent survivor of BHF. This serum contains antibodies to MACV. This treatment plan proves difficult as there are few survivors of BHF and of those, few are strong enough to donate the necessary plasma.[11]

In 1975, researchers inoculated infected rhesus monkeys with human immunoglobulin. All but four of the 12 monkeys survived the initial infection. However, those with higher dosages of the immunoglobulin went on to develop a severe neurological condition that resulted in the death of three subsequent monkeys.[12]

In 2007, immunoglobulin was administered to three patients presenting with BHF. Despite the immunoglobulin and other supportive therapies, two of the three patients died days later.[6]

In 2008, immunoglobulin was administered to two patients presenting with BHF. One of the two patients did not survive.[6]

#### Antivirals

Ribavirin, an antiviral medication, has been widely tested against Lassa Virus, an Old World arenaviridae virus that is related to MACV. Some studies demonstrate its effectiveness against arenaviridae viruses while others highlight its inefficacy and toxicity to humans.[5][8] However, in terms of MACV specifically, it is believed that more research needs to be done to.[13]

## Prevention

### Vaccine

Currently, there is no FDA approved human vaccine for Bolivian hemorrhagic fever.[5]

### Pest Reduction

Reduction of the vector species, the large vesper mouse, has been found effective at reducing the number of reported BHF cases. Prior to the identification of transmission vector, and therefore any reduction programs, Bolivia faced its largest BHF epidemic from 1963-64. The magnitude of this epidemic is thought to have been caused by the rapid proliferation of the large vesper mouse due to the use of DDT that significantly harmed the local feline population, inhibiting them from effectively hunting the rodent populations.[11]

However, since, the identification of the transmission vector, rodent reduction programs have been put in place by local health agencies. These include the systemic trapping and poisoning of the mice as well as the expansion of the local feline population.[2][14] These efforts are believed to be responsible for the lack of BHF cases identified between 1976 and 1993.[2]

## History

Map of Bolivia showing spread of Bolivian hemorrhagic fever

### Outbreaks

#### 1959 - 1964

This was both the first and most severe outbreak of Bolivian hemorrhagic fever. The outbreak had two major geographic origins. From 1959 to 1962, the spread was contained within the Iténez province, just west of the City of San Joaquín in Mamoré. In 1963, however, the focus of the outbreak shifted to San Joaquín as the number of cases peaked.[14] While the number of estimated cases vary, around 984 to 1028 cases were reported with between 245 and 256 fatalities during the five year outbreak.[2][14] The suspected cause of this outbreak was the proliferation of the large vesper mouse following a decrease in the feline population.[11]

#### 1965

In 1965, there were an additional 24 cases originating in San Joaquín that closely followed rodent concentration patterns.[14]

#### 1966 - 1968

During this period of time there was little Machupo activity. There were two suspected and 13 proven cases of BHF with zero fatalities. The cases were all from San Joaquín and its smaller surrounding villages. It is of note that this was the largest outbreak without fatalities.[14]

#### 1969 and 1970

In early 1969, there were ten cases of BHF reported with six fatalities in the town of La Cayoba outside the city of Magdalena. Residents of La Cayoba fled to Magdalena in the order to avoid the outbreak. However, in March 1969, BHF was reported in Magdalena. Through the end of 1969, 20 cases were reported in Magdalena followed by an additional 12 in 1970.[14]

#### 1971

The 1971 outbreak of BHF occurred in Cochabamba, Bolivia, a city in central Bolivia. While far from the habitat of the lineage of large vesper mice known to carry Machupo virus, patient zero had recently traveled to that area. Once back in Cochabamba, the virus was spread to two family members and three medical personnel of the hospital in which she was admitted. Of the six total people infected, there was five fatalities including patient zero. This outbreak was of serious significance due to the primary transmission of direct human to human contact and the prevalence of the disease outside of northeast Bolivia.[3]

#### 1976- 1993

During this time period there were no reported cases of Bolivian hemorrhagic fever. This is believed to have been caused by rodent reduction programs or potentially underreporting.[2]

#### 1994

The 1994 outbreak began in July with a familial outbreak in Magdalena. Seven family members of an extended family became ill over the course of a month. Patient zero was the only survivor. Additionally, a lab technician handling the blood of an infected family member became infected but survived after a test tube broke. In August, there was an additional unrelated case in Magdalena that resulted in one fatality. Finally in September, an agricultural worker in Poponas was infected but survived.[15]

#### 2007-2008 Outbreak

In early 2007, there were at least 20 suspected cases of Bolivian hemorrhagic fever reported in Beni, including three from Magdalena in which two of the patients did not survive. Additionally, one other suspected case ended in a fatality.[6]

In February 2008, over 200 suspected cases of BHF were reported with 12 fatalities. These cases included incidents in Huacaraje, Iténez and San Ramon, Mamoré.[6]

#### Outbreak Confusion with Chapare Virus

Chapare Virus (CHAPV) was first described during an outbreak near Cochabamba during December 2003 and January 2004.[9] Originally thought to be an etiological agent of BHF along with Machupo virus, it is now considered to be significantly genetically distinct and the etiological agent of Chapare hemorrhagic fever (CHHF).[7][9][16] However, this has lead to confusion of what is and is not a BHF outbreak. Some sources may show BHF cases beyond 2000 that are now understood to be CHHF rather than BHF including the 2003-2004, 2019, and 2020 outbreaks.[2][7]

### Weaponization

Due to its high lethality, Bolivian hemorrhagic fever was one of three hemorrhagic fevers and one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program in 1969. During this program, Albert Nickel, a 53-year old animal caretaker at Fort Detrick, died in 1964 from BHF after being bitten by an infected mouse. Nickel Place, on Fort Detrick, is named in his honor. BHF was also being researched by the Soviet Union, under the Biopreparat bureau.[17]

## References

1. ↑ 1.0 1.1 1.2 Public Health Agency of Canada: Machupo Virus Pathogen Safety Data Sheet, http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/machupo-eng.php, Date Modified: 2011-02-18.
2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 Patterson, Michael; Grant, Ashley; Paessler, Slobodan (April 2014). "Epidemiology and pathogenesis of Bolivian hemorrhagic fever". Current Opinion in Virology 5: 82–90. doi:10.1016/j.coviro.2014.02.007. ISSN 1879-6265. PMID 24636947.
3. ↑ 3.0 3.1 3.2 Peters, C. J.; Kuehne, R. W.; Mercado, R. R.; Le Bow, R. H.; Spertzel, R. O.; Webb, P. A. (June 1974). "Hemorrhagic Fever in Cochabamba, Bolivia, 1971" (in en). American Journal of Epidemiology 99 (6): 425–433. doi:10.1093/oxfordjournals.aje.a121631. ISSN 1476-6256. PMID 4601699. https://academic.oup.com/aje/article/135524/HEMORRHAGIC.
4. ↑ 4.0 4.1 4.2 "History of the taxon: Species: Mammarenavirus machupoense (2024 Release, MSL #40)". International Committee on Taxonomy of Viruses. https://ictv.global/taxonomy/taxondetails?taxnode_id=202402587&taxon_name=Mammarenavirus machupoense.
5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Hewson, Roger (2024-10-18). "Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies". Pathogens (Basel, Switzerland) 13 (10): 909. doi:10.3390/pathogens13100909. ISSN 2076-0817. PMID 39452780.
6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Aguilar, Patricia V.; Camargo, Wilfredo; Vargas, Jorge; Guevara, Carolina; Roca, Yelin; Felices, Vidal; Laguna-Torres, V. Alberto; Tesh, Robert et al. (September 2009). "Reemergence of Bolivian hemorrhagic fever, 2007-2008". Emerging Infectious Diseases 15 (9): 1526–1528. doi:10.3201/eid1509.090017. ISSN 1080-6059. PMID 19788833.
7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Center for Food Security & Public Health and Institute for International Cooperation in Animal Biologics, Iowa State University: Viral Hemorrhagic Fevers Caused by Arenaviruses, http://www.cfsph.iastate.edu/Factsheets/pdfs/viral_hemorrhagic_fever_arenavirus.pdf last updated: February 2023.
8. ↑ 8.0 8.1 8.2 Radoshitzky, Sheli R.; Kuhn, Jens H.; de Kok-Mercado, Fabian; Jahrling, Peter B.; Bavari, Sina (July 2012). "Drug discovery technologies and strategies for Machupo virus and other New World arenaviruses". Expert Opinion on Drug Discovery 7 (7): 613–632. doi:10.1517/17460441.2012.687719. ISSN 1746-045X. PMID 22607481.
9. ↑ 9.0 9.1 9.2 Delgado, Simon; Erickson, Bobbie R.; Agudo, Roberto; Blair, Patrick J.; Vallejo, Efrain; Albariño, César G.; Vargas, Jorge; Comer, James A. et al. (2008-04-18). "Chapare virus, a newly discovered arenavirus isolated from a fatal hemorrhagic fever case in Bolivia". PLOS Pathogens 4 (4). doi:10.1371/journal.ppat.1000047. ISSN 1553-7374. PMID 18421377.
10. ↑ "Calomys callosus • Large Vesper Mouse". https://www.mammaldiversity.org/taxon/1002686/.
11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Silva-Ramos, Carlos Ramiro; Faccini-Martínez, Álvaro A.; Calixto, Omar-Javier; Hidalgo, Marylin (2021-03-01). "Bolivian hemorrhagic fever: A narrative review". Travel Medicine and Infectious Disease 40. doi:10.1016/j.tmaid.2021.102001. ISSN 1477-8939. PMID 33640478. https://www.sciencedirect.com/science/article/pii/S1477893921000429.
12. ↑ Eddy, G. A.; Wagner, F. S.; Scott, S. K.; Mahlandt, B. J. (1975). "Protection of monkeys against Machupo virus by the passive administration of Bolivian haemorrhagic fever immunoglobulin (human origin)". Bulletin of the World Health Organization 52 (4–6): 723–727. ISSN 0042-9686. PMID 182406.
13. ↑ Kilgore, P. E.; Ksiazek, T. G.; Rollin, P. E.; Mills, J. N.; Villagra, M. R.; Montenegro, M. J.; Costales, M. A.; Paredes, L. C. et al. (1997-04-01). "Treatment of Bolivian Hemorrhagic Fever with Intravenous Ribavirin" (in en). Clinical Infectious Diseases 24 (4): 718–722. doi:10.1093/clind/24.4.718. ISSN 1058-4838. https://academic.oup.com/cid/article-lookup/doi/10.1093/clind/24.4.718.
14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Mercado, R. (1975). "Rodent control programmes in areas affected by Bolivian haemorrhagic fever". Bulletin of the World Health Organization 52 (4–6): 691–696. ISSN 0042-9686. PMID 182405.
15. ↑ "International Notes Bolivian Hemorrhagic Fever -- El Beni Department, Bolivia, 1994". https://www.cdc.gov/mmwr/preview/mmwrhtml/00035133.htm.
16. ↑ CDC (2025-08-22). "About Chapare Hemorrhagic Fever" (in en-us). https://www.cdc.gov/chapare/about/index.html.
17. ↑ Alibek, Ken and Steven Handelman (1999), Biohazard: The Chilling True Story of the Largest Covert Biological Weapons Program in the World - Told from Inside by the Man Who Ran It, Random House, ISBN 0-385-33496-6.

### Bibliography

* "Prospects for the control of Bolivian hemorrhagic fever". Emerging Infect. Dis. 1 (3): 97–100. 1995. doi:10.3201/eid0103.950308. PMID 8903174.

* Medical Microbiology 2nd Edition Mims et al. Mosby Publishing 1998 p 371

## External links

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* ICD-9-CM: 078.7
* MeSH: D006478
* DiseasesDB: 31899

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