Background
Viral hemorrhagic fevers (VHFs) are a group of lethal zoonotic diseases unified by common underlying pathophysiology. These febrile diseases result from infection by enveloped RNA viruses belonging to six taxonomic families: Arenaviridae, Hantaviridae, Nairoviridae, Phenuiviridae, Filoviridae, and Flaviviridae. [1, 2] Bunyavirales are single-stranded RNA viruses in the class Ellioviricetes. As a group, they are still commonly referred to as the Bunyaviridae family of viruses, or simply bunyaviruses.
These viruses share the feature of having a lipid envelope. Survival and perpetuation of the viruses is dependent on an animal host known as a natural reservoir; humans are not the natural reservoir. With the exception of a vaccine for yellow fever and ribavirin, which is used as a drug treatment for some arenaviral infections, no cures or drug treatments for viral hemorrhagic fever exist. Only supportive treatment is possible.
Not all viruses in these families cause viral hemorrhagic fever.
Viral hemorrhagic fevers share certain clinical manifestations, regardless of the virus that causes the disease. However, different viruses can cause a range of various clinical problems in addition to viral hemorrhagic fever. Common clinical manifestations of viral hemorrhagic fever are increased capillary permeability, leukopenia, and thrombocytopenia. Viral hemorrhagic fever is manifested by sudden onset, fever, headache, generalized myalgia, backache, petechiae, conjunctivitis, and severe prostration. Various hemorrhagic symptoms follow, ultimately resulting in focal inflammatory reaction and necrosis with leukocytosis.
Although the viruses are distributed all over the world, they have a higher occurrence in tropical areas, such as South America, Africa, and the Pacific Islands. They have a higher likelihood of importation because of increased travel and scientific research involving the use of imported tropical animals, which often serve as intermediate hosts. The viruses are transmitted by two main categories of natural reservoirs: arthropods and rodents. Arenaviruses and Hantavirus (a Bunyavirus) are primarily rodent-borne, whereas flaviviruses, as well as nairoviruses and phleboviruses (both bunyaviruses), are arthropod-borne.
Transmission occurs mainly by means of contact with the following: natural reservoirs (eg, mosquito bites, rodent bites); reservoir excretions, secretions, or blood; aerosolized particles contaminated by reservoir secretions, excretions, or blood; or intermediate hosts (eg, monkeys, livestock) or their excretions, secretions, or blood. Person-to-person transmission and nosocomial transmission also occur. Nosocomial outbreaks are not uncommon in developing countries, where safe infectious disease practices have not been implemented and supplies are in shortage.
See the Medscape articles CBRNE - Viral Hemorrhagic Fevers and Pediatric Viral Hemorrhagic Fevers for more information.
Also see Ebola: Care, Recommendations, and Protecting Practitioners, a Critical Images slideshow, to review treatment, recommendations, and safeguards for healthcare personnel.
Pathophysiology
Despite the diverse taxonomy of the six virus families involved in viral hemorrhagic fevers (VHFs), they share some common characteristics. They are all RNA viruses that have a lipid envelope, rendering them relatively susceptible to detergents and a low-pH environment, as well as household bleach. On the other hand, they are quite stable at neutral pH; this factor helps these viruses to stay stable in blood for a long period, which allows them to be isolated from a patient’s blood after weeks of storage at refrigerator temperature. In addition, these viruses are stable as fine-particle aerosols, which renders them highly infectious.
Viral-targeted cells in the body include monocytes, dendritic cells, macrophages, and vascular endothelial cells, which then disseminate through lymphatics to other organs. [3]
Recognition of viral infection by the innate immune system occurs through the cytoplasmic recognition of cellular receptors of viral nucleic acids. Following this recognition and activation of cellular receptors, type I interferon is activated, resulting in initiation of interferon signaling. [4]
The main common underlying pathophysiologic feature of viral hemorrhagic fevers is that the vascular bed is attacked, with resultant microvascular damage and changes in vascular permeability. However, specific pathophysiologic findings can vary depending on the virus family and the species involved.
In general, an initial febrile illness is followed by hemorrhaging into the skin and the mucous membranes, hemorrhagic rashes, and hemorrhaging from body orifices, especially gastrointestinal and genitourinary bleeding. Lassa fever, although fatal, is not characterized by significant bleeding. Other clinical findings include thrombocytopenia and leukocytopenia.
Ebola (Filoviridae) viral protein VP35 was found to inhibit interferon regulatory factor 3, which is necessary for the induction of an antiviral immune response and interferon. Ebola virus was also found to alter the immune signaling pathways through its ability to interfere with dendritic cells that link adaptive and innate immune responses, [5] in addition to the release of extensive cytokines, which cause endothelial damage, coagulopathy, and, finally, multiorgan failure. [3]
Similarities regarding the pattern of cytokine production between Ebola virus disease and Crimean-Congo hemorrhagic fever (CCHF) were noted. Positive correlation was noted between viral load and interleukin (IL)‒10 and monocyte chemoattractant protein (MCP)‒1, and negatively correlated with the IL-12/IL-10 ratio. [6]
In severe dengue fever (Flavivirus), marked capillary permeability and coagulopathy are noted as a result of the immune response. [7] HLA-B44 has been found to be protective against dengue hemorrhagic fever. [8] In contrast, diabetic patients were found to be more susceptible to developing severe dengue hemorrhagic fever and dengue shock syndrome. [9] Circulating immune complexes, serum cryoglobulins, and IL-8 were found to be higher by 9-fold and 2.2-fold in dengue hemorrhagic fever and dengue fever, respectively, compared with healthy individuals. Peak levels of circulating immune complexes, IL-8, and cryoglobulins were found to be associated with thrombocytopenia. [10] Serum IgM levels specific for dengue fever virus were found to be significantly higher in dengue fever when compared with dengue hemorrhagic fever cases, while IgG, IgA, and IgE levels were found to be higher in dengue hemorrhagic fever cases. Higher titer of IgG was found to be associated with lower platelet counts. [11]
In Rift Valley fever (Bunyavirus), IL-8, IL-10, and CXCL9 were detected at significantly higher levels when comparing fatal cases to uninfected individuals and infected survivors. [12]
In Hantavirus (Bunyaviridae) infection, endothelial dysfunction is noted, wherein high levels of endothelial glycocalyx degradation is found to correlate with early disease activity, which eventually results in tissue edema, hypotension, and shock. [13]
Etiology
Causes of viral hemorrhagic fevers (VHFs) are the specific RNA viruses mentioned above. Infection by different viruses results in hemorrhagic fever with different complications, symptoms, and severity, as previously discussed. See the list below [2] :
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Flaviviruses: Yellow fever, dengue, Kyasanur Forest disease, Alkhumra viruses, Omsk hemorrhagic fever
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Filoviruses: Ebola and Marburg virus
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Arenaviruses: Lassa and other Old World arenaviruses and New World arenaviruses
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Hantaviruses, nairoviruses, and phenuiviruses, formerly included in Bunyaviridae family: Rift Valley fever, Congo-Crimean hemorrhagic fever (CCHF), Huaiyangshan virus (alternatively known as severe fever with thrombocytopenia syndrome virus) and hantaviruses
Viruses are usually transmitted by mosquitoes, ticks, or rodents. Some species of bats may also prove to be virus carriers. [14]
In a study that included 200 ticks collected from south of Iran analyzed by reverse-transcription polymerase chain reaction for the presence of CCHF virus genome, viral genome was detected in 4.5% of studied ticks, which indicates that ticks in that area are widely infected and necessitates regular control and monitoring of livestock in order to reduce the dispersion of ticks. [15]
An epidemiologic survey of ticks, rodents, and infected individuals with CCHF in Northern region of Xiniang, China isolated a two new CCHF virus strains, which were different from the previously reported strain in China. [16]
Person-to-person transmission may occur through mucous membranes or through contact with body fluids from the infected patient. Transmission can even occur after the death of the infected person, as their skin is heavily infected. [17]
Contaminated syringes and needles played a role in the recent outbreak of Ebola hemorrhagic fever.
Persistence of Ebola virus in semen was reported in the Ebola virus outbreak of 2014-2015 in three men. The semen was positive for Ebola virus RNA on days 199, 140, and 284 after symptom onset. [18, 19, 20] Evidence of persisting Ebola virus in feces, sweat, saliva, and urine were also reported up to 26 days after initial symptoms. [21, 22]
The strong immunologic response to the viruses may be central to the pathophysiology of plasma leakage associated with these diseases. [23]
Epidemiology
Frequency
United States
Most of the natural reservoirs of these viruses live in tropical areas. Hence, the virus does not typically infect persons in the United States. Random cases of infection occur as a result of the importation of viruses by travelers or the importation of scientific research animal subjects.
Several cases of infection resulting in Hantavirus pulmonary syndrome (HPS), however, have been reported across the United States. [24]
During the 2014 Ebola outbreak, several US healthcare personnel have been infected while in Africa and have been transported to the United States for treatment. A traveller from Liberia also became ill and sought treatment during a visit to Texas, and he later died of the infection. One of his treating nurses then presented with a low-grade fever and tested positive for Ebola virus infection. Further, individuals in several US states who recently travelled to West Africa have developed fever and other symptoms, prompting evaluation for Ebola virus infection at US hospitals. [25]
International
The geographic distribution is dependent on the reservoir host and ecology of each disease. [26]
Table 1. Geographic Distribution of Viral Hemorrhagic Fevers (Open Table in a new window)
Virus Family and Genus |
Type of Hemorrhagic Fever |
Reservoir Host |
Geographic Distribution |
Arenaviridae Guanarito Junin Machupo Lassa Sabia |
Venezuelan Argentinian Bolivian Lassa (West Africa) Brazilian or Sao Paulo |
Rodents |
Venezuela Argentina Bolivia West Africa Brazil |
Bunyaviridae Nairovirus Phlebovirus Hantaan virus |
Crimean-Congo Rift Valley Korean HPS |
Ticks Mosquito and contact with infected blood in slaughter houses Contact with infected rodents and their excreta |
Crimea, Central Africa, South Africa, Iraq, Pakistan, Turkey, Iran, Afghanistan, Russia Africa, Egypt Korea, Eastern Europe, Russia, Scandinavia North, Central, and South America |
Flaviviridae Flavivirus Flavivirus Flavivirus Flavivirus |
Yellow Dengue Chikungunya Omsk |
Mosquito Mosquito Mosquito Tick |
Tropical Africa, South America Entire tropical zone India, Southeast Asia Siberia |
Filoviridae Marburg Ebola |
Marburg Ebola |
Infected monkeys were implicated but no known definite reservoir |
Africa West Africa |
In West Africa, the 2014-2015 Ebola epidemic was first reported in Guinea in March 2014. It was the largest Ebola virus epidemic documented, with a total of 28,220 reported cases and 11,291 deaths (WHO September 16, 2015). In July 2014, a local outbreak was declared in Sierra Leone, and the affected district was the first to be declared Ebola-free by local authorities on January 10, 2015. [27, 28, 29]
Guinea demonstrated consistent low transmissibility and, accordingly, the smallest number of reported cases. Liberia showed the highest level of transmission before October 2014 and remained low since that time. Sierra Leone showed detectable waves of the disease up to mid March 2015, resulting in the largest number of cases reported. [30]
Four confirmed CCHF outbreaks within the past 2 years have been reported in Uganda after more than 50 years of no reported cases of human CCHF. [31]
A Chikungunya outbreak in southeastern Senegal in 2010 included 45 confirmed cases. In addition, 83% of monkeys that were randomly sampled were found to be seropositive, and Chikungunya virus was detected in 42 pools of mosquitos, mainly Aedes furcifer. [32]
A study conducted on 3,322 confirmed dengue cases in Kaohsiung city in Taiwan found that the outbreak of dengue fever was initiated by imported cases from other endemic countries. It took a median of 5 days after the appearance of symptoms for patients to report to a medical facility. [33] A positive correlation was found between confirmed cases and weather parameters (temperature, relative humidity, and rainfall) at a time lag of 1 month and 2 months. This may help in developing an early warning surveillance system.
Poverty was associated with high rates of transmission in a study done in Montserrado County, Liberia. [34]
In an attempt to understand the heterogenicity in dengue disease transmission, a study analyzing 18 years of monthly dengue surveillance was conducted in a total of 273 provinces in eight countries in Southeast Asia. A strong pattern of synchronous transmission across the entire region was detected. This synchrony in dengue incidence was noted to coincide with elevated temperatures in 1997-1998 and the strongest El Niño episode of the century. A low incidence was noted during the period of 2001-2002. Localized travelling waves of epidemic cycles were detected in Laos, Thailand, and the Philippines. [35]
Table 2. Viral Hemorrhagic Fever Outbreaks from January 2018 to April 2019 According to WHO Emergencies Preparedness, Response Disease Outbreak News. [36] (Open Table in a new window)
Year |
Disease |
Country |
2019 2019 2019 2019 2019 2019 2019 2019 2018 2018 2018 2018 2018 2018 2018 2018 2018 2018 |
Ebola virus disease Rift Valley fever Yellow fever Lassa fever Dengue fever HPS Yellow fever HPS Yellow fever Yellow fever Yellow fever Rift Valley fever Dengue Ebola virus disease Lassa fever Yellow fever Rift Valley fever Lassa Fever |
Democratic Republic of the Congo Mayotte (France) Brazil Nigeria Jamaica Argentine Republic Nigeria Republic of Panama Kingdom of the Netherlands Democratic Republic of the Congo French Guyana (France) Kenya Reunion, France Democratic Republic of the Congo Nigeria Brazil Gambia Liberia |
Race
No race is known to be more vulnerable than another to RNA viral infection. Geography is a determining factor.
Sex
Neither sex is known to be more or less vulnerable to RNA viral infection.
Age
Age plays a role in increasing the vulnerability to infection in only 2 circumstances. First, young and elderly persons are more susceptible because of their weaker immune systems. Second, adults are more susceptible if they work in settings in which the exposure risk is increased (eg, clinics or hospitals, agrarian settings).
A shift in dengue fever towards older adults has been noted in the past decade. [37]
Prognosis
Survival may be possible with appropriate support care, depending on the virus.
Table 3. Viral Hemorrhagic Fever Mortality Rates (Open Table in a new window)
Virus Family and Type of VHF |
Mortality Rate, % |
Arenaviridae Argentinian and Bolivian Lassa (West African) Venezuelan and Sao Paulo |
10-30 30-40 33 |
Bunyaviridae Korean and Seoul Rift Valley Congo-Crimean HPS |
5-15 1 10-50 15-50 |
Flaviviridae Yellow Dengue |
< 1 5 |
Filoviridae Marburg Ebola |
23-25 25-100 |
The estimated case fatality rate for the recent Ebola outbreak was 76.4%. The proportion of total deaths in Guinea, Sierra Leone, and Liberia was 21.6%, 35.8%, and 42.5%, respectively. The highest risk of dying was among healthcare workers in areas with intense transmission and countries with insufficient bed capacities. Other factors that enhanced the spread and magnitude of this outbreak were the insufficient enforcement of public health regulations and deplorable healthcare delivery infrastructure in war-ravaged regions. [38] In the recent Ebola virus disease outbreak in Sierra Leone, it was found that chest pain, symptoms of confusion, coma and viral load greater than 106 copies/mL were significantly associated with a poor prognosis. Viral load was the most important factor that affected the survival of patients from the disease. [39]
A total of 278 human cases were confirmed with Rift Valley fever in the recent outbreak in South Africa in 2010-2011, with 25 deaths.
Children can develop dengue hemorrhagic shock syndrome (DHSS), a complication with a mortality rate of 4-12%.
Patient Education
Educate travelers and geographically vulnerable groups, especially health care workers, agrarian workers, and rural populations, about the following risks:
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Transmission via rodent or arthropod bites
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Potential contamination of food and/or water reservoirs with excretions or secretions
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Contact with animals that may be intermediate hosts
Educate health care workers and others about the detrimental effects of nosocomial transmission and about how such spread can be prevented by implementing infectious disease safety and contact precautions, such as the following:
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Equipment sterilization
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Isolation of individuals who are infected
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Barrier nursing
Educate health care workers and others about decontamination procedures, such as the use of hypochlorite or phenolic disinfectants.
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New World Arenavirus - Machupo. Oral mucosal hyperemia and hemorrhage in a patient with Bolivian hemorrhagic fever.
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Bunyavirus infection. Ecchymoses encompassing left upper extremity one week after onset of CCHF. Ecchymoses often are accompanied by hemorrhage in other locations: epistaxis, puncture sites, hematemesis, melena, and hematuria. Image provided by Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.
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Filovirus disease - Ebola fever. Patient with Ebola hemorrhagic fever during 1976 outbreak in Zaire demonstrating palatal petechiae and hemorrhage. Photo courtesy of Joel Breman.
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Patient with morbilliform exanthem of dengue fever. Note islands of sparing characteristics for dengue. Photo courtesy Duane Gubler, PhD.
Tables
Virus Family and Genus |
Type of Hemorrhagic Fever |
Reservoir Host |
Geographic Distribution |
Arenaviridae Guanarito Junin Machupo Lassa Sabia |
Venezuelan Argentinian Bolivian Lassa (West Africa) Brazilian or Sao Paulo |
Rodents |
Venezuela Argentina Bolivia West Africa Brazil |
Bunyaviridae Nairovirus Phlebovirus Hantaan virus |
Crimean-Congo Rift Valley Korean HPS |
Ticks Mosquito and contact with infected blood in slaughter houses Contact with infected rodents and their excreta |
Crimea, Central Africa, South Africa, Iraq, Pakistan, Turkey, Iran, Afghanistan, Russia Africa, Egypt Korea, Eastern Europe, Russia, Scandinavia North, Central, and South America |
Flaviviridae Flavivirus Flavivirus Flavivirus Flavivirus |
Yellow Dengue Chikungunya Omsk |
Mosquito Mosquito Mosquito Tick |
Tropical Africa, South America Entire tropical zone India, Southeast Asia Siberia |
Filoviridae Marburg Ebola |
Marburg Ebola |
Infected monkeys were implicated but no known definite reservoir |
Africa West Africa |
Year |
Disease |
Country |
2019 2019 2019 2019 2019 2019 2019 2019 2018 2018 2018 2018 2018 2018 2018 2018 2018 2018 |
Ebola virus disease Rift Valley fever Yellow fever Lassa fever Dengue fever HPS Yellow fever HPS Yellow fever Yellow fever Yellow fever Rift Valley fever Dengue Ebola virus disease Lassa fever Yellow fever Rift Valley fever Lassa Fever |
Democratic Republic of the Congo Mayotte (France) Brazil Nigeria Jamaica Argentine Republic Nigeria Republic of Panama Kingdom of the Netherlands Democratic Republic of the Congo French Guyana (France) Kenya Reunion, France Democratic Republic of the Congo Nigeria Brazil Gambia Liberia |
Virus Family and Type of VHF |
Mortality Rate, % |
Arenaviridae Argentinian and Bolivian Lassa (West African) Venezuelan and Sao Paulo |
10-30 30-40 33 |
Bunyaviridae Korean and Seoul Rift Valley Congo-Crimean HPS |
5-15 1 10-50 15-50 |
Flaviviridae Yellow Dengue |
< 1 5 |
Filoviridae Marburg Ebola |
23-25 25-100 |
