# Viral hemorrhagic fever

Viral hemorrhagic fevers (VHFs) are a diverse group of diseases. Viral means a health problem caused by infection from a virus. Hemorrhagic means to bleed and fever means an unusually high body temperature. Both humans and non human animals can be infected. In the case of VHFs, bleeding and fever are common symptoms, and why they give the infection its common name.
There are five known families of RNA viruses which cause VHFs: Arenaviridae, Filoviridae, Flaviviridae, Hantaviridae, and Rhabdoviridae. Some VHFs are usually mild, such as nephropathia epidemica (within the family Hantaviridae). But some are usually severe and have a high death rate, such as Ebola virus (within the family Filoviridae). All VHFs can potentially cause severe blood loss, high fever, and death.

## Signs and symptoms

The following are signs and symptoms of most or all VHFs.
* Circulatory shock
* Diarrhea (feces which resemble more liquid than solid)
* Headache
* Hypotension (low blood pressure)
* Fever (high body temperature)
* Flushing (redness) of the face and chest
* Hemorrhage (bleeding) and sometimes bleeding diathesis (a person loses more blood than usual from an injury – for example, getting only a little cut, and losing a lot of blood)
* Malaise (a general feeling that you are sick)
* Myalgia (muscle pain)
* Petechiae (small red or purple spots – about four millimeters in diameter, which is less than one fourth the width of a human finger)
* Swelling (you can see a body part is larger than usual) caused by edema (there is more fluid in the body part than usual)
The severity of symptoms varies with the type of virus. The "VHF syndrome" causes bleeding diathesis, capillary leak, and circulatory shock. It happens to most people who have Filoviridae infections (such as Ebola virus or Marburg virus), Crimean–Congo hemorrhagic fever (CCHF), or the South American hemorrhagic fevers (which are caused by Arenaviridae). VHF syndrome only happens to a small minority of people who have dengue fever or Rift Valley fever.

## Causes

Five families of RNA viruses have been recognized as being able to cause hemorrhagic fevers.
* The order Bunyavirales includes the families Arenaviridae, Fimoviridae, and all members of the former family Bunyaviridae, especially Peribunyaviridae.
   * The family Arenaviridae include the viruses responsible for Lassa fever (Lassa virus), Lujo virus, Argentine (Junin virus), Bolivian (Machupo virus), Brazilian (Sabiá virus), Chapare hemorrhagic fever (Chapare virus), Venezuelan (Guanarito virus) and Whitewater Arroyo virus hemorrhagic fevers.
   * The former family Bunyaviridae includes
      * the causative agents of Hantavirus hemorrhagic fever with renal syndrome (HV-HFRS) (Hantaviridae),
      * the Crimean-Congo hemorrhagic fever (CCHF) virus from the genus Orthonairovirus (Nairoviridae),
      * Garissa virus and Ilesha virus from the genus Orthobunyavirus (Peribunyaviridae), and
      * the Rift Valley fever (RVF) virus from the genus Phlebovirus (Phenuiviridae).
* The family Filoviridae (order Mononegavirales) includes Ebola virus and Marburg virus.
* The family Flaviviridae (order Amarillovirales) includes dengue, yellow fever, and two viruses in the tick-borne encephalitis group that cause VHF: Omsk hemorrhagic fever virus and Kyasanur Forest disease virus.
* The family Rhabdoviridae (order Mononegavirales). In September 2012 scientists writing in the journal PLOS Pathogens reported the isolation of a member of the Rhabdoviridae responsible for two fatal and two non-fatal cases of hemorrhagic fever in the Bas-Congo district of the Democratic Republic of Congo. The virus was named Bas-Congo virus. The non-fatal cases occurred in healthcare workers involved in the treatment of the other two, suggesting the possibility of person-to-person transmission. This virus is related to the Ephemerovirus and Tibrovirus genera.
* The family Togaviridae (order Martellivirales) includes Chikungunya virus which causes Chikungunya fever.
The pathogen that caused the cocoliztli epidemics in Mexico of 1545 and 1576 is still unknown, and the 1545 epidemic may have been bacterial rather than viral.

## Pathophysiology

Different hemorrhagic fever viruses act on the body differently, resulting in variable symptoms. In most VHFs, several mechanisms likely contribute to symptoms, including liver damage, disseminated intravascular coagulation (DIC), and bone marrow dysfunction. In DIC, small blood clots form in blood vessels throughout the body, removing platelets necessary for clotting from the bloodstream and reducing clotting ability. DIC is thought to cause bleeding in Rift Valley, Marburg, and Ebola fevers. For filoviral hemorrhagic fevers, there are four general mechanisms of pathogenesis. The first mechanism is the dissemination of the virus due to suppressed responses by macrophages and dendritic cell (antigen-presenting cells). The second mechanism is prevention of antigen specific immune response. The third mechanism is apoptosis of lymphocytes. The fourth mechanism is when infected macrophages interact with toxic cytokines, leading to diapedesis and coagulation deficiency. From the vascular perspective, the virus will infect vascular endothelial cells, leading to the reorganization of the VE-cadherin catenin complex (a protein important in cell adhesion). This reorganization creates intercellular gaps in endothelial cells. The gaps lead to increased endothelial permeability and allow blood to escape from the vascular circulatory system.
The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Dengue fever becomes more virulent during a second infection by means of antibody-dependent enhancement. After the first infection, macrophages display antibodies on their cell membranes specific to the dengue virus. By attaching to these antibodies, dengue viruses from a second infection are better able to infect the macrophages, thus reducing the immune system's ability to fight off infection.

## Diagnosis

Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general, there is a decrease in the total white cell count (particularly the lymphocytes), a decrease in the platelet count, an increase in the blood serum liver enzymes, and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged.

## Prevention

With the exception of yellow fever vaccine and Ebola vaccines, vaccines for VHFs are generally not available. For someone exposed to CCHF, ribavirin is available as post-exposure prophylaxis (PEP). Ribavirin may also help in exposure to Lassa fever.
Any person who is taking care of a patient with any VHF (except dengue fever) should take multiple precautions against exposure and infection. The precautions include hand hygiene, double gloves, gowns, shoe and leg coverings, and face shields or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested, HEPA filter-equipped respirator (such as an N95 mask), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1.8 meters (six feet) of a VHF patient. Groups of patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants.

## Management

Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin may be useful in Bunyaviridae and Arenaviridae infections (specifically Lassa fever, RVF, CCHF, and HFRS due to Old World Hantavirus infection) and can be used only under an experimental protocol as IND approved by the U.S. Food and Drug Administration (FDA). Interferon may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND).

## Potential Therapies

A potential novel treatment, the NMT inhibitor, has been shown to completely inhibit lassa (LAS) and Junín (JUN) viral infections in cells based assays.

## Epidemiology

* Cocoliztli in Mexico 1545 and 1576 (suspected)
* The Great Yellow Fever Epidemic of 1793 in Philadelphia, PA, US. Nearly 10% of the population of 50,000 died from the disease.
* Mékambo in Gabon is the site of several outbreaks of Ebola virus disease.
* Orientale Province, Democratic Republic of the Congo villages of Durba and Watsa were the epicenter of the 1998–2000 outbreak of Marburg virus disease.
* Uíge Province in Angola was the site of another outbreak of Marburg virus disease in 2005, the largest one to date of this disease.
* A VHF outbreak in the village of Mweka, Democratic Republic of the Congo (DRC) that started in August 2007, and that has killed 103 people (100 adults and three children), has been shown to be caused (at least partially) by Ebola virus.
* A viral hemorrhagic fever is a possible cause of the Plague of Athens during the Peloponnesian War.
* A viral hemorrhagic fever is an alternate theory of the cause of the Black Death and the Plague of Justinian
* The initial, and currently only, outbreak of Lujo virus in September–October 2008 left four of five patients dead.
* The 2014 West Africa Ebola outbreak, which was the biggest outbreak in history.

## Biowarfare potential

The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. The viruses are considered by military medical planners to have a potential for aerosol dissemination, weaponization, or likelihood for confusion with similar agents that might be weaponized.
Scientific Research Institute of Medicine of the Ministry of Defense in Sergiyev Posad was researching the military use potential of hemorrhagic fever viruses.