Viral Hemorrhagic Fever (VHF)

 

Background

Viral hemorrhagic fevers (VHFs) are feared because they have the highest mortality rate in human hosts of all known viral agents (Burgett, 2020).

Potential as a bioweapon

VHF viruses can be engineered for delivery and infection of large groups of victims. At least one VHF, Rift Valley fever – has caused infection when released into the air in the laboratory (MDH 2019).

The former Soviet Union developed the Marburg virus for use as a weapon, and conducted research on Ebola, Lassa, Rift Valley fever, Yellow fever and New World arenaviruses. The U.S. has done research on these viruses, except Marburg and Ebola. North Korea is believed to have developed the yellow fever virus as a weapon (MDH 2019).

For example, ebola virus can be obtained from natural sources or produced synthetically and weaponized to kill. There have been eight instances reported before 2001 where terrorists have tried to acquire the ebola virus. One obtained ebola from a legitimate supplier, one sample was stolen, one was self-manufactured, two were obtained from natural sources and three had unknown sources (Carus, 2001).

March 25, 2013, The Atlantic magazine reported "University of Texas Medical Branch officials discovered the missing vial containing less than a teaspoon of Guanarito virus during a routine inspection last week"(Simpson 2013). UTMB, Galveston Galveston National Laboratory was supposed to have five vials of Guanarito virus, but one was missing. Guanarito virus like other VHFs is naturally limited to the geographic area where it is endemic in a rodent population.

The CDC identifies three categories of Viral Hemorrhagic Fever, VHFs as Bioterrorism agents

Category A  Viral Hemorrhagic Fever agents

  • can be easily disseminated or transmitted from person to person;
  • result in high mortality rates and have the potential for major public health impact
  • might cause public panic and social disruption
  • require special action for public health preparedness.
  • Filoviruses
    • Ebola
      • Symptoms: begin 2-21 days after contact, include: fever, headache, joint and muscle pain, diarrhea, vomiting, stomach pain, lack of appetite and abnormal bleeding (WHO, 2021)
      • Mortality rate of the 2020 outbreak in Democratic Republic of the Congo was 66% (WHO, 2020).
      • Transmission person-to-person,
        • Blood, body fluids and fomites. 
        • Animal to human transmission
      • Pathophysiology:
        • Target cells include monocytes, macrophages, and dendritic cells involved in systemic dissemination.
        • viral replication induces destruction of these cells leading to
      • Vaccines have been approved
      • Two monoclonal antibodies (Inmazeb and Ebanga) have been approved
    • Marburg disease
      • Symptoms: commonly begin 2-21 days after contact; include Abdominal cramps, nausea and vomiting may appear on the third day. Diarrhea may persist for a week. Between the fifth and seventh day, many patients may experience severe hemorrhagic manifestations in vomit or stool, along with nosebleeds.
      • Transmission person-to-person
        • Blood, body fluids and fomites. 
        • Animal to human transmission
      • Mortality rate is around 50%, ranging from 24 to 88%
      • No approved treatment that can cure the virus.
      • Supportive care, maintain hydration (UN, 2022).
  • Arenaviruses (Lassa, Machupo)
    • Lassa fever
      • Symptoms begin 6-21 days after contact, including fever, weakness, and malaise. After a few days: headache, sore throat, muscle pain, chest pain, nausea, vomiting, diarrhea, cough, and abdominal pain. In severe cases: facial swelling, fluid in the lung cavity, Oral, nasal, vaginal, gastrointestinal bleeding, and hypotension may develop. Proteinuria, shock, seizures, tremors, disorientation, coma, and death may occur within 14 days of onset. In third-trimester cases, maternal death and fetal loss occur in up to 80% of cases. Survivors experience deafness (25%) and other neurologic effects that may improve (WHO, 2017).
      • Transmission in endemic areas is usually from direct contact with infected rodent excreta, by touching fomites with cuts or open sores, ingesting rodent contaminated food, or inhalation of airborne desiccated rodent excreta. In non-endemic areas, transfer often occurs through exposure to the virus in a Lassa virus-infected individual's blood, tissue, secretions, or excretions.
      • Mortality occurs in only about 1% of infections, but about 15-20% of patients hospitalized for Lassa fever die.  During epidemics, up to 50% of hospitalized patients can die.
      • Treatment - No approved vaccine is available.  Ribavirin and convalescent plasma are used with limited success. Favipiravir, taribavirin, Arevirumab-3 are also being used off-label.

Category B  Viral Hemorrhagic Fever agents

  • are moderately easy to disseminate;
  • result in moderate morbidity rates and low mortality rates
  • require specific enhancements of CDC’s diagnostic capacity and enhanced disease surveillance.
  • Viral encephalitis (alphaviruses)
    • Easily weaponized and aerosolized
    • Symptoms: fever, headache and muscle pain. Severe headache, stiff neck, confusion, seizures, coma and possibly even death (IDPH. n.d.)
      • eastern equine encephalomyelitis
      • Venezuelan equine encephalomyelitis
        • VEE virus is transmitted by hematophagus insects, primarily mosquitos. Black flies and ticks are also capable of being mechanical vectors (USDA, 2013).
        • mortality rate <1%
      • western equine encephalomyelitis
        • mortality rate up to <3%

Category C Viral Hemorrhagic Fever agents include emerging pathogens that could be engineered for mass dissemination

  • availability
  • ease of production and dissemination and
  • potential for high morbidity and mortality rates and major health impact.

Nipah virus (Nipah henipavirus)

  • Symptoms
    • mild to severe
    • death occurs in 40-70% of infection

Hanta virus (hantavirus) 20 different species mortality rate less than 1% to 15% depending on species.

  • “Old World” hantaviruses, are found mostly in Europe and Asia and may cause hemorrhagic fever with renal syndrome (HFRS).
    • Initial symptoms begin suddenly:
      intense headaches, back and abdominal pain, fever, chills, nausea, and blurred vision.
    • Later symptoms: low blood pressure, acute shock, vascular leakage, and acute kidney failure, and severe fluid overload.
  • “New World” hantaviruses may cause hantavirus pulmonary syndrome (HPS).
    • patients that develop HPS from New World Hantaviruses recover completely
    • medical care in an intensive care unit
   

 

 

INSTANT FEEDBACK:

Viral hemorrhagic fever can be acquired by being bitten by mosquitoes and tick carrying the disease.
True
 False

Management (including experimental)

Antivirals

Ribavirin may be active against Arenaviruses and Bunyaviruses

Vaccines

Supportive care for most forms of VHF includes:

The only established vaccine available for any of the hemorrhagic fever viruses is Yellow Fever vaccine, which is mandatory for travelers to endemic areas of Africa and Southern America.

Click for Healthcare worker guidance from the CDC for assessing VHF.

References

Animal Health Emergency Management. USDA APHIS | Animal Health Emergency Management. (n.d.). Retrieved August 25, 2022, from https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/emergency-management

Bugert, J.J., Hucke, F., Zanetta, P. et al. Antivirals in medical biodefense. Virus Genes 56, 150–167 (2020). https://doi.org/10.1007/s11262-020-01737-5

CDC. Viral Hemorrhagic Fevers (VHFs). What are VHFs? (Reviewed 2021) From https://www.cdc.gov/vhf/index.html

CDC. (2014) Ebola Treatment, retrieved from: http://www.cdc.gov/vhf/ebola/treatment/index.html.

Carus, W. S.,(2001) National Defense Univ Washington Dc.. Bioterrorism and biocrimes: The illicit use of biological agents since 1900. DTIC. Retrieved August 23, 2022, from https://apps.dtic.mil/sti/citations/ADA402108

Ebanga. Center for Drug Evaluation and Research. (2020). FDA approves treatment for ebola virus. U.S. Food and Drug Administration. Retrieved August 25, 2022, from https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-ebola-virus

Ervebo (2019). First FDA-approved vaccine for the prevention of ebola virus disease, marking a critical milestone in public health preparedness and response. U.S. Food and Drug Administration. Retrieved August 25, 2022, from https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-prevention-ebola-virus-disease-marking-critical-milestone-public-health

Illinois Department of Public Health (IDPH )(n.d.) Alphaviruses. Retrieved 8/26/2022 from http://www.idph.state.il.us/Bioterrorism/factsheets/alphaviruses.htm

Inmazeb. FDA approves first treatment for ebola virus. U.S. Food and Drug Administration (2020). Retrieved August 25, 2022, from https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-ebola-virus

Ippolito, G., Feldmann, H., Lanini, S. et al. (2012). Viral hemorrhagic fevers: advancing the level of treatment. BMC Med 10, 31 (2012). Retrieved 8/25/2022 from https://doi.org/10.1186/1741-7015-10-31

Joseph AA, Fasipe OJ, Joseph OA, Olatunji OA. (2022). Contemporary and emerging pharmacotherapeutic agents for the treatment of Lassa viral haemorrhagic fever disease. J Antimicrob Chemother. 29;77(6):1525-1531. doi: 10.1093/jac/dkac064.

Madu, I. G., Files, M., Gharaibeh, D. N., Moore, A. L., Jung, K. H., Gowen, B. B., Dai, D., Jones, K. F., Tyavanagimatt, S. R., Burgeson, J. R., Korth, M. J., Bedard, K. M., Iadonato, S. P., & Amberg, S. M. (2018). A potent Lassa virus antiviral targets an arenavirus virulence determinant. PLoS pathogens, 14(12), e1007439. https://doi.org/10.1371/journal.ppat.1007439

Minnesota Department of Health (MDH)(2019). Viral Hemorrhagic Fevers (VHFs) Fact Sheet. Retrieved 8/23/2022 from https://www.health.state.mn.us/diseases/vhf/vhf.html#weapons

Simpson, C. (2013) The Case of the Missing Deadly Virus Is Only a Problem If You Own Rats. The Atlantic. https://www.theatlantic.com/national/archive/2013/03/missing-deadly-virus-texas/317019/

United Nations (2022) Marburg virus disease: origins and symptoms. Retrieved 8/25/2022

Woolsey C, Cross RW, Agans KN, et al.(2022). A highly attenuated Vesiculovax vaccine rapidly protects nonhuman primates against lethal Marburg virus challenge. Plos Neglected Tropical Diseases. 16(5):e0010433. DOI: 10.1371/journal.pntd.0010433. Retrieved 8/26/2022 from https://europepmc.org/article/pmc/pmc9182267

World Health Organization (WHO, 2021). Ebola virus disease. Retrieved 8/25/2022 from https://www.who.int/news-room/fact-sheets/detail/ebola-virus-disease

World Health Organization (WHO, 2020). Ebola Virus Disease Democratic Republic of the Congo. External Situation Report 98. Retrieved 2/25/2022 from https://apps.who.int/iris/bitstream/handle/10665/332654/SITREP_EVD_DRC_20200623-eng.pdf

World Health Organization (WHO, 2017) Lassa fever. Retrieved 8/25/2022 from https://www.who.int/news-room/fact-sheets/detail/lassa-fever

 

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