Viral hemorrhagic fever
Encyclopedia
The viral
hemorrhagic fever
s (VHFs) are a diverse group of animal and human illnesses that are caused by four distinct families of RNA virus
es: the families Arenaviridae, Filoviridae
, Bunyaviridae
, and Flaviviridae
. All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in extreme cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica
, while others, such as the African Ebola virus
, can cause severe, life-threatening disease.
The most recently recognized virus capable of causing hemorrhagic fever is Lujo virus
, a new arenavirus described in 2009 and found in Zambia
and South Africa
.
and bleeding diathesis
. Manifestations of VHF often also include flushing of the face and chest, petechiae, frank bleeding, edema
, hypotension
, and shock. Malaise, myalgia
s, headache, vomiting, and diarrhea occur frequently. 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 lymphocyte
s, a decrease in the platelet
count, an increase in the serum
liver
enzyme
s and 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.
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 investigational new drug
(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). Experimental vaccines for other VHFs are not readily available.
Prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections (again, available only as IND).
VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and faceshield 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 N-95 mask), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within six feet of a VHF patient. Multiple 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 or phenolic disinfectants.
.” In contrast, disseminated intravascular coagulation
(DIC) is thought to underlie the hemorrhagic features of Rift Valley, Marburg and Ebola fevers. In most VHFs, however, the etiology of the coagulopathy is most likely multifactorial (e.g., hepatic damage, consumptive coagulopathy, primary marrow dysfunction, etc).
The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Moreover, why some infected persons develop full-blown VHF while others do not also remains an unresolved issue. Virulence of the infecting agent clearly plays an important role. The “VHF syndrome” (capillary leak, bleeding diathesis and hemodynamic compromise leading to shock) occurs in a majority of patients manifesting disease from filoviruses, CCHF, and the South American hemorrhagic fever viruses, while it occurs in a small minority of patients with dengue, RVF and Lassa fever.
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
hemorrhagic fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
s (VHFs) are a diverse group of animal and human illnesses that are caused by four distinct families of RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
es: the families Arenaviridae, Filoviridae
Filoviridae
The family Filoviridae is the taxonomic home of several related viruses that form filamentous virions. Two members of the family that are commonly known are Ebola virus and Marburg virus. Both viruses, and some of their lesser known relatives, cause severe disease in humans and nonhuman primates in...
, Bunyaviridae
Bunyaviridae
Bunyaviridae is a family of negative-stranded RNA viruses. Though generally found in arthropods or rodents, certain viruses in this family occasionally infect humans. Some of them also infect plants....
, and Flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...
. All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in extreme cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica
Nephropathia epidemica
Nephropathia epidemica is a type of viral haemorrhagic fever with renal syndrome caused by the Puumala virus. The incubation period is three weeks. Nephropathia epidemica has a sudden onset with fever, abdominal pain, headache, back pain and gastrointestinal symptoms. More severe symptoms include...
, while others, such as the African Ebola virus
Ebola virus
Ebola virus causes severe disease in humans and in nonhuman primates in the form of viral hemorrhagic fever. EBOV is a Select Agent, World Health Organization Risk Group 4 Pathogen , National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen,...
, can cause severe, life-threatening disease.
Etiologic agents
- The family Arenaviridae include the viruses responsible for Lassa feverLassa feverLassa fever is an acute viral hemorrhagic fever caused by the Lassa virus and first described in 1969 in the town of Lassa, in Borno State, Nigeria, in the Yedseram river valley at the south end of Lake Chad. Clinical cases of the disease had been known for over a decade but had not been connected...
and ArgentineArgentine hemorrhagic feverArgentine hemorrhagic fever or O'Higgins disease, also known in Argentina as mal de los rastrojos, stubble disease, is a hemorrhagic fever and zoonotic infectious disease occurring in Argentina. It is caused by the Junín virus...
, BolivianBolivian hemorrhagic feverBolivian hemorrhagic fever , also known as black typhus or Ordog Fever, is a hemorrhagic fever and zoonotic infectious disease originating in Bolivia after infection by Machupo virus....
, BrazilianBrazilian hemorrhagic feverBrazilian hemorrhagic fever is an infectious disease caused by the Sabiá virus, an Arenavirus. The Sabiá virus is an enveloped RNA virus and is highly infectious and lethal....
and Venezuelan hemorrhagic feverVenezuelan hemorrhagic feverVenezuelan hemorrhagic fever is a zoonotic human illness, first identified in 1989.-Presentation:It causes fever and malaise followed by hemorrhagic manifestations and convulsions. It is fatal in 30% of cases. The disease is endemic to Portuguesa state and Barinas state in Venezuela . This virus...
s. - The family Bunyaviridae include the members of the HantavirusHantavirusHantaviruses are negative sense RNA viruses in the Bunyaviridae family. Humans may be infected with hantaviruses through rodent bites, urine, saliva or contact with rodent waste products...
genus that cause hemorrhagic fever with renal syndrome (HFRS), the Crimean-Congo hemorrhagic feverCrimean-Congo hemorrhagic feverCrimean–Congo hemorrhagic fever is a widespread tick-borne viral disease, a zoonosis of domestic animals and wild animals, that may affect humans. The pathogenic virus, especially common in East and West Africa, is a member of the Bunyaviridae family of RNA viruses. Clinical disease is rare in...
(CCHF) virus from the NairovirusNairovirusNairovirus is a genus in the family Bunyaviridae that include viruses with circular, negative-sense single stranded RNA. It got its name from the Nairobi sheep disease that affects the gastrointestinal tracts of sheep and goats...
genus, and the Rift Valley feverRift Valley feverRift Valley Fever is a viral zoonosis causing fever. It is spread by the bite of infected mosquitoes, typically the Aedes or Culex genera. The disease is caused by the RVF virus, a member of the genus Phlebovirus...
(RVF) virus from the Phlebovirus genus. - The family Filoviridae include Ebola virusEbola virusEbola virus causes severe disease in humans and in nonhuman primates in the form of viral hemorrhagic fever. EBOV is a Select Agent, World Health Organization Risk Group 4 Pathogen , National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen,...
and Marburg virusMarburg virusMarburg virus disease is the name for the human disease caused by any of the two marburgviruses Marburg virus and Ravn virus...
. - Finally, the family Flaviviridae include dengue, yellow feverYellow feverYellow fever is an acute viral hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the Flaviviridae family....
, and two viruses in the tick-borne encephalitis group that cause VHF: Omsk hemorrhagic feverOmsk hemorrhagic feverOmsk Hemorrhagic Fever is a viral hemorrhagic fever caused by a Flavivirus.It is found in Siberia. It is named for an outbreak in Omsk.-Virology:...
virus and Kyasanur Forest diseaseKyasanur forest diseaseKyasanur forest disease is a tick-borne viral hemorrhagic fever endemic to South Asia. The disease is caused by a virus belonging to the family flaviviridae, which also includes yellow fever and dengue fever.-History:...
virus.
The most recently recognized virus capable of causing hemorrhagic fever is Lujo virus
Lujo virus
Lujo is a bisegmented RNA virus and a member of the Arenaviridae. Its name was suggested by the Special Pathogens Unit of the National Institute for Communicable Diseases of the National Health Laboratory Service by using the first two letters of the names of the cities involved in the 2008...
, a new arenavirus described in 2009 and found in Zambia
Zambia
Zambia , officially the Republic of Zambia, is a landlocked country in Southern Africa. The neighbouring countries are the Democratic Republic of the Congo to the north, Tanzania to the north-east, Malawi to the east, Mozambique, Zimbabwe, Botswana and Namibia to the south, and Angola to the west....
and South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...
.
Clinical and treatment aspects
Signs and symptoms of VHFs include (by definition) feverFever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and bleeding diathesis
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...
. Manifestations of VHF often also include flushing of the face and chest, petechiae, frank bleeding, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and shock. Malaise, myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
s, headache, vomiting, and diarrhea occur frequently. Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment
Biocontainment
The concept of biocontainment, also called laboratory biosafety, pertains to microbiology laboratories in which the physical containment of highly pathogenic organisms or agents is required, usually by isolation in environmentally and biologically secure cabinets or rooms, to prevent accidental...
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 lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s, a decrease in the platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
count, an increase in the serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s and 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.
Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...
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 investigational new drug
Investigational New Drug
The United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...
(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). Experimental vaccines for other VHFs are not readily available.
Prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections (again, available only as IND).
VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and faceshield 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 N-95 mask), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within six feet of a VHF patient. Multiple 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 or phenolic disinfectants.
Pathophysiology
The diversity of clinical features seen among the VHF infections probably originates from varying mechanisms of pathogenesis. An immunopathogenic mechanism, for example, has been identified for dengue hemorrhagic fever, which usually occurs among patients previously infected with a heterologous dengue serotype. An influential theory explaining this phenomenon is called “antibody-dependent enhancementAntibody dependent enhancement
Antibody dependent enhancement occurs when non-neutralising antiviral antibodies enhance viral entry into host cells, leading to increased infectivity in the host cells. Some cells do not have the usual receptors on their surfaces that viruses use to gain entry. The antibodies bind to antibody Fc...
.” In contrast, disseminated intravascular coagulation
Disseminated intravascular coagulation
Disseminated intravascular coagulation , also known as disseminated intravascular coagulopathy or consumptive coagulopathy, is a pathological activation of coagulation mechanisms that happens in response to a variety of diseases. DIC leads to the formation of small blood clots inside the blood...
(DIC) is thought to underlie the hemorrhagic features of Rift Valley, Marburg and Ebola fevers. In most VHFs, however, the etiology of the coagulopathy is most likely multifactorial (e.g., hepatic damage, consumptive coagulopathy, primary marrow dysfunction, etc).
The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Moreover, why some infected persons develop full-blown VHF while others do not also remains an unresolved issue. Virulence of the infecting agent clearly plays an important role. The “VHF syndrome” (capillary leak, bleeding diathesis and hemodynamic compromise leading to shock) occurs in a majority of patients manifesting disease from filoviruses, CCHF, and the South American hemorrhagic fever viruses, while it occurs in a small minority of patients with dengue, RVF and Lassa fever.
Biowarfare/bioterrorism potential
The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. Although evidence for a history of “weaponization” (development into a biological weapon) does not exist for many of these viruses, all 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. Woods, Op. cit., pg 145.Notable VHF outbreaks
- Cocoliztli in New Mexico 1545.
- MékamboMékamboMékambo is a small village in on the banks of the Zadié river. It is located in the Ogooué-Ivindo province of Gabon. It has received international press for recent outbreaks of Ebola hemorrhagic fever in 1994 and 1997.- References :...
in GabonGabonGabon , officially the Gabonese Republic is a state in west central Africa sharing borders with Equatorial Guinea to the northwest, Cameroon to the north, and with the Republic of the Congo curving around the east and south. The Gulf of Guinea, an arm of the Atlantic Ocean is to the west...
is the site of several outbreaks of Ebola virusEbola virusEbola virus causes severe disease in humans and in nonhuman primates in the form of viral hemorrhagic fever. EBOV is a Select Agent, World Health Organization Risk Group 4 Pathogen , National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen,...
disease. - Orientale, CongoOrientale, CongoOrientale is one of the ten provinces of the Democratic Republic of the Congo. The province lies in the northeast of the country. It borders Équateur province to the west, Kasai-Oriental province to the southwest, Maniema province to the south, and Nord-Kivu province to the southeast...
villages of Durba and WatsaWatsaWatsa is a community in Province Orientale of the Democratic Republic of the Congo, administrative center of the Watsa Territory.Watsa was the location of the VI battalion of the Force Publique in the 1940s and 1950s....
were the epicenter of the 1998–2000 outbreak of Marburg virusMarburg virusMarburg virus disease is the name for the human disease caused by any of the two marburgviruses Marburg virus and Ravn virus...
disease. - Uíge Province in AngolaAngolaAngola, officially the Republic of Angola , is a country in south-central Africa bordered by Namibia on the south, the Democratic Republic of the Congo on the north, and Zambia on the east; its west coast is on the Atlantic Ocean with Luanda as its capital city...
is the site of world's worst hemorrhagic fever epidemicEpidemicIn epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
, which occurred in 2005. - An VHF outbreak in the village of Mweka, Democratic Republic of the CongoMweka, Democratic Republic of the CongoMweka is a town in southern-central Democratic Republic of the Congo, situated on the Kasai railway line between Kananga and the Kasai River port of Ilebo ....
(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 virusEbola virusEbola virus causes severe disease in humans and in nonhuman primates in the form of viral hemorrhagic fever. EBOV is a Select Agent, World Health Organization Risk Group 4 Pathogen , National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen,...
. - Some experts believe that the Black DeathBlack DeathThe Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have...
of the Middle AgesMiddle AgesThe Middle Ages is a periodization of European history from the 5th century to the 15th century. The Middle Ages follows the fall of the Western Roman Empire in 476 and precedes the Early Modern Era. It is the middle period of a three-period division of Western history: Classic, Medieval and Modern...
may have been caused by a VHF and not by the bubonic plagueBubonic plaguePlague is a deadly infectious disease that is caused by the enterobacteria Yersinia pestis, named after the French-Swiss bacteriologist Alexandre Yersin. Primarily carried by rodents and spread to humans via fleas, the disease is notorious throughout history, due to the unrivaled scale of death...
. - A viral haemorrhagic fever is a possible cause of the Plague of AthensPlague of AthensThe Plague of Athens was a devastating epidemic which hit the city-state of Athens in ancient Greece during the second year of the Peloponnesian War , when an Athenian victory still seemed within reach. It is believed to have entered Athens through Piraeus, the city's port and sole source of food...
during the Peloponnesian WarPeloponnesian WarThe Peloponnesian War, 431 to 404 BC, was an ancient Greek war fought by Athens and its empire against the Peloponnesian League led by Sparta. Historians have traditionally divided the war into three phases...
.
See also
- Biological agentBiological agentA biological agent — also called bio-agent or biological threat agent — is a bacterium, virus, prion, or fungus which may cause infection, allergy, toxicity or otherwise create a hazard to human health. They can be used as a biological weapon in bioterrorism or biological warfare...
- BiopreparatBiopreparatBiopreparat was the Soviet Union's major biological warfare agency from the 1970s on. It was a vast network of secret laboratories, each focused on a different deadly agent...
- BioterrorismBioterrorismBioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, or toxins, and may be in a naturally occurring or a human-modified form. For the use of this method in warfare, see biological warfare.-Definition:According to the...
- FeverFeverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
- List of viruses
- Dr. Matthew LukwiyaMatthew LukwiyaDr. Matthew Lukwiya was a Ugandan physician and the supervisor of St. Mary's Hospital Lacor, outside of Gulu. He was at the forefront of the 2000 ebola outbreak and the first doctor to die of the disease.-Biography:...
(1957–2000) - C.J. PetersC.J. PetersClarence James Peters, Jr, M.D. , known as C. J. Peters, is a physician, field virologist and former U.S. Army colonel. He is noted for his efforts in trying to stem epidemics of exotic infectious diseases such as the Ebola virus, Hanta virus and Rift Valley fever...
Sources
- Health Protection Agency
- This article includes information that originally came from US Government publications and websites and is in the public domain.