Viral hemorrhagic fever

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Overview
The viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses that are caused by five distinct families of RNA viruses: the Arenaviridae, Filoviridae, Bunyaviridae, Togaviridae, 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, whilst others, such as the African Ebola virus, can cause severe, life-threatening disease.

Also known as:


 * Crimean-Congo hemorrhagic fever (CCHF)
 * Ebola hemorrhagic fever
 * Hantavirus Pulmonary Syndrome
 * Hemorrhagic fever with renal syndrome (HFRS)
 * Lassa Fever
 * Marburg hemorrhagic fever

Epidemiology and Demographics
Taken together, the viruses that cause VHFs are distributed over much of the globe. However, because each virus is associated with one or more particular host species, the virus and the disease it causes are usually seen only where the host species live(s). Some hosts, such as the rodent species carrying several of the New World arena viruses, live in geographically restricted areas. Therefore, the risk of getting VHFs caused by these viruses is restricted to those areas. Other hosts range over continents, such as the rodents that carry viruses which cause various forms of hantavirus pulmonary syndrome (HPS) in North and South America, or the different set of rodents that carry viruses which cause hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia. A few hosts are distributed nearly worldwide, such as the common rat. It can carry Seoul virus, a cause of HFRS; therefore, humans can get HFRS anywhere where the common rat is found.

While people usually become infected only in areas where the host lives, occasionally people become infected by a host that has been exported from its native habitat. For example, the first outbreaks of Marburg hemorrhagic fever, in Marburg and Frankfurt, Germany, and in Yugoslavia, occurred when laboratory workers handled imported monkeys infected with Marburg virus. Occasionally, a person becomes infected in an area where the virus occurs naturally and then travels elsewhere. If the virus is a type that can be transmitted further by person-to-person contact, the traveler could infect other people. For instance, in 1996, a medical professional treating patients with Ebola hemorrhagic fever (Ebola HF) in Gabon unknowingly became infected. When he later traveled to South Africa and was treated for Ebola HF in a hospital, the virus was transmitted to a nurse. She became ill and died. Because more and more people travel each year, outbreaks of these diseases are becoming an increasing threat in places where they rarely, if ever, have been seen before.

Etiologic agents
The Arenaviridae include the viruses responsible for Lassa fever and Argentine, Bolivian, and Venezuelan hemorrhagic fevers. The Bunyaviridae include the members of the Hantavirus genus that cause hemorrhagic fever with renal syndrome (HFRS), the Crimean-Congo hemorrhagic fever (CCHF) virus from the Nairovirus genus, and the Rift Valley fever (RVF) virus from the Phlebovirus genus. The Filoviridae include Ebola and Marburg viruses. Finally, the Flaviviridae include dengue, yellow fever, and two viruses in the tick-borne encephalitis group that cause VHF: Omsk hemorrhagic fever virus and Kyasanur Forest disease virus.

Risk Factors
VHF should be suspected in febrile persons who, within 3 weeks before onset of fever, have either

1) traveled in the specific local area of a country where VHF has recently occurred;

2) had direct unprotected contact with blood, other body fluids, secretions, or excretions of a person or animal with VHF; or

3) had a possible exposure when working in a laboratory that handles hemorrhagic fever viruses. The likelihood of acquiring VHF is considered low in persons who do not meet any of these criteria. Even following travel to areas where VHF has occurred, persons with fever are more likely to have infectious diseases other than VHF (e.g., common respiratory viruses, endemic infections such as malaria or typhoid fever). Clinicians should promptly evaluate and treat patients for these more common infections while awaiting confirmation of a VHF diagnosis.

In Africa, transmission of VHF in healthcare settings has been associated with reuse of contaminated needles and syringes and with provision of patient care without appropriate barrier precautions to prevent exposure to virus-containing blood and other body fluids (including vomitus, urine, and stool). The transmission risks associated with various body fluids have not been well defined because most caregivers who have acquired infection had contacts with multiple fluids.

The risk for person-to-person transmission of hemorrhagic fever viruses is greatest during the latter stages of illness when virus loads are highest; latter stages of illness are characterized by vomiting, diarrhea, shock, and, in less than half of infected patients, hemorrhage. No VHF infection has been reported in persons whose contact with an infected person occurred only during the incubation period (i.e., before onset of fever). The incubation period for VHF ranges from 2 days to 3 weeks, depending on the viral agent. There are reports of Ebola virus transmission occurring within a few days after onset of fever; however, the presence of other symptoms in the source patients and the level of exposure to body fluids among secondary cases are unknown in these instances (CDC, unpublished data, 1995). In studies involving three monkeys experimentally infected with Ebola virus (Reston strain), fever and other systemic signs of illness preceded detection of infectious virus in the animals’ pharynx by 2-4 days, in the conjunctiva and on anal swabs by 5-6 days, and in the nares by 5-10 days.

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 enhancement.” 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.

VHFs are caused by viruses of four distinct families: arenaviruses, filoviruses, bunyaviruses, and flaviviruses. Each of these families share a number of features:


 * They are all RNA viruses, and all are covered, or enveloped, in a fatty (lipid) coating.
 * Their survival is dependent on an animal or insect host, called the natural reservoir.
 * The viruses are geographically restricted to the areas where their host species live.
 * Humans are not the natural reservoir for any of these viruses. Humans are infected when they come into contact with infected hosts. However, with some viruses, after the accidental transmission from the host, humans can transmit the virus to one another.
 * Human cases or outbreaks of hemorrhagic fevers caused by these viruses occur sporadically and irregularly. The occurrence of outbreaks cannot be easily predicted.
 * With a few noteworthy exceptions, there is no cure or established drug treatment for VHFs.
 * In rare cases, other viral and bacterial infections can cause a hemorrhagic fever; scrub typhus is a good example.

Viruses associated with most VHFs are zoonotic. This means that these viruses naturally reside in an animal reservoir host or arthropod vector. They are totally dependent on their hosts for replication and overall survival. For the most part, rodents and arthropods are the main reservoirs for viruses causing VHFs. The multimammate rat, cotton rat, deer mouse, house mouse, and other field rodents are examples of reservoir hosts. Arthropod ticks and mosquitoes serve as vectors for some of the illnesses. However, the hosts of some viruses remain unknown -- Ebola and Marburg viruses are well-known examples.

How are hemorrhagic fever viruses transmitted?

Viruses causing hemorrhagic fever are initially transmitted to humans when the activities of infected reservoir hosts or vectors and humans overlap. The viruses carried in rodent reservoirs are transmitted when humans have contact with urine, fecal matter, saliva, or other body excretions from infected rodents. The viruses associated with arthropod vectors are spread most often when the vector mosquito or tick bites a human, or when a human crushes a tick. However, some of these vectors may spread virus to animals, livestock, for example. Humans then become infected when they care for or slaughter the animals.

Some viruses that cause hemorrhagic fever can spread from one person to another, once an initial person has become infected. Ebola, Marburg, Lassa and Crimean-Congo hemorrhagic fever viruses are examples. This type of secondary transmission of the virus can occur directly, through close contact with infected people or their body fluids. It can also occur indirectly, through contact with objects contaminated with infected body fluids. For example, contaminated syringes and needles have played an important role in spreading infection in outbreaks of Ebola hemorrhagic fever and Lassa fever.

History and Symptoms
Specific signs and symptoms vary by the type of VHF, but initial signs and symptoms often include marked fever, fatigue, dizziness, muscle aches, loss of strength, and exhaustion. Patients with severe cases of VHF often show signs of bleeding under the skin, in internal organs, or from body orifices like the mouth, eyes, or ears. However, although they may bleed from many sites around the body, patients rarely die because of blood loss. Severely ill patient cases may also show shock, nervous system malfunction, coma, delirium, and seizures. Some types of VHF are associated with renal (kidney) failure.

Clinical and treatment aspects
Signs and symptoms of VHFs include (by definition) fever and bleeding diathesis. Manifestations of VHF often also include flushing of the face and chest, petechiae, frank bleeding, edema, hypotension, and shock. Malaise, myalgias, headache, vomiting, and diarrhea occur frequently. Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities.

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 a US FDA approved investigational new drug (IND). Convalescent plasma may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND). The only licensed vaccine for a VHF is the 17D yellow fever vaccine. Experimental vaccines for other VHFs are not readily available.

Prophylactic (preventive) ribavirin may be effective for some Bunyaviridae and Arenaviridae 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.

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.

Treatment
Patients receive supportive therapy, but generally speaking, there is no other treatment or established cure for VHFs. Ribavirin, an anti-viral drug, has been effective in treating some individuals with Lassa fever or HFRS. Treatment with convalescent-phase plasma has been used with success in some patients with Argentine hemorrhagic fever.

Primary Prevention
With the exception of yellow fever and Argentine hemorrhagic fever, for which vaccines have been developed, no vaccines exist that can protect against these diseases. Therefore, prevention efforts must concentrate on avoiding contact with host species. If prevention methods fail and a case of VHF does occur, efforts should focus on preventing further transmission from person to person, if the virus can be transmitted in this way.Because many of the hosts that carry hemorrhagic fever viruses are rodents, disease prevention efforts include

Controlling rodent populations:


 * Discouraging rodents from entering or living in homes or workplaces.
 * Encouraging safe cleanup of rodent nests and droppings.
 * For hemorrhagic fever viruses spread by arthropod vectors, prevention efforts often focus on community-wide insect and arthropod control. In addition, people are encouraged to use insect repellant, proper clothing, bednets, window screens, and other insect barriers to avoid being bitten.

For those hemorrhagic fever viruses that can be transmitted from one person to another, avoiding close physical contact with infected people and their body fluids is the most important way of controlling the spread of disease. Barrier nursing or infection control techniques include isolating infected individuals and wearing protective clothing. Other infection control recommendations include proper use, disinfection, and disposal of instruments and equipment used in treating or caring for patients with VHF, such as needles and thermometers.

The following recommendations should be followed when caring for persons with suspected VHF:


 * Patients who are hospitalized or treated in an outpatient healthcare setting should be placed in a private room and Standard, Contact, and Droplet Precautions should be initiated. Patients with respiratory symptoms also should wear a face mask to contain respiratory droplets prior to placement in their hospital or examination room and during transport.
 * Caretakers should use barrier precautions to prevent skin or mucous membrane exposure of the eyes, nose, and mouth with patient blood, other body fluids, secretions (including respiratory droplets), or excretions. All persons entering the patient's room should wear gloves and gowns to prevent contact with items or environmental surfaces that may be soiled. In addition, face shields or surgical masks and eye protection (e.g., goggles or eyeglasses with side shields) should be worn by persons coming within approximately 3 feet of the patient.
 * Additional barriers may be needed depending on the likelihood and magnitude of contact with body fluids. For example, if copious amounts of blood, other body fluids, vomit, or feces are present in the environment, plastic apron, leg, and shoe coverings also may be needed.
 * Nonessential staff and visitors should be restricted from entering the room of patients with suspected VHF. Maintain a log of persons entering the patient’s room.
 * Before exiting the room of a patient with suspected VHF, safely remove and dispose of all protective gear, and clean and disinfect shoes that are soiled with body fluids as described in the section on environmental infection control below.
 * To prevent percutaneous injuries, needles and other sharps should be used and disposed of in accordance with recommendations for Standard Precautions.
 * If the patient requires a surgical or obstetric procedure, consult your state health department and CDC regarding appropriate precautions for these invasive procedures.
 * Although transmission by the airborne route has not been established, hospitals may choose to use Airborne Precautions for patients with suspected VHF who have severe pulmonary involvement or who undergo procedures that stimulate coughing and promote the generation of aerosols (e.g. aerosolized or nebulized medication administration, diagnostic sputum induction, bronchoscopy, airway suctioning, endotracheal intubation, positive pressure ventilation via face mask [e.g., biphasic intermittent positive airway pressure ventilation, continuous positive airway pressure ventilation], and high-frequency oscillatory ventilation) to prevent possible exposure to airborne particles that may contain virus.

Specimen Handling:


 * Alert laboratory staff to the nature of the specimens prior to sending them to the clinical laboratory. Specimens should remain in the custody of designated laboratory personnel until testing is completed. Due to the potential risks associated with handling infectious materials, laboratory testing should be limited to the minimum necessary for essential diagnostic evaluation and patient care.
 * While obtaining clinical laboratory specimens from the patient, use infection control precautions for patient care outlined in this document. Place specimens in sealed plastic bags, then transport them in a clearly labeled, durable, leak-proof container directly to the specimen handling area of the laboratory. Care should be taken not to contaminate the external surfaces of containers.
 * Process clinical specimens in a class II biological safety cabinet following biosafety level 3 practices. If possible, pretreat serum used in laboratory tests with the combination of heat-inactivation at 56° C and polyethylene glycol p-tert-octylphenyl ether (Triton(®) X-100)*; treatment with 10 uL of 10% Triton(®) X-100 per 1 mL of serum for 1 hour reduces the titer of hemorrhagic fever viruses in serum, although 100% efficacy in inactivating these viruses should not be assumed. For tests in which the validity is affected by the presence of a detergent in the serum, heat inactivation alone may be of some benefit in reducing infectivity.
 * Blood smears (e.g., for malaria) are not infectious for VHF after fixation in solvents.
 * Attempts to isolate or cultivate the virus should not be part of routine clinical laboratory diagnosis when VHF is suspected. If such procedures are done on specimens where VHF is suspected, biosafety level 4 facilities and procedures are required.
 * Routine cleaning and disinfecting procedures can be used for automated analyzers; analyzers should be disinfected after use as recommended by the manufacturer or with a 500 parts per million solution (1:100 dilution) of sodium hypochlorite (1/4 cup of household bleach to 1 gallon water).

Environmental Infection Control Procedures:


 * Environmental surfaces or inanimate objects contaminated with blood, other body fluids, secretions, or excretions should be cleaned and disinfected using standard procedures (See See: Guideline for Environmental Infection Control in Healthcare Facilities).
 * Disinfection can be accomplished using a U.S. Environmental Protection Agency (EPA)-registered hospital disinfectant or a 1:100 dilution of household bleach (1/4 cup bleach to 1 gallon water). For grossly soiled surfaces, (e.g., vomitus or stool), use a 1:10 dilution of household bleach.
 * Soiled linens should be placed in clearly labeled leak-proof bags at the site of use, transported directly to the laundry area, and laundered following routine healthcare laundry procedures.
 * Liquid medical waste such as feces and vomitus can be disposed of in the sanitary sewer following local sewage disposal requirements (www.cdc.gov/ncidod/hip/enviro/guide.htm). Care should be taken to avoid splashing when disposing of these materials.
 * When discarding solid medical waste (e.g., needles, syringes, and tubing) contaminated with blood or other body fluids from VHF patients, contain the waste with minimal agitation during handling. Properly contained wastes should be managed according to existing local and state regulations for ensuring health and environmental safety during medical waste treatment and disposal. On-site treatment of the waste in an incinerator or a gravity-displacement autoclave for decontamination purposes will help to minimize handling of contaminated waste. Alternatively, off-site medical waste treatment resources may be used.

Secondary Prevention
In conjunction with the World Health Organization, CDC has developed practical, hospital-based guidelines, titled Infection Control for Viral Haemorrhagic Fevers In the African Health Care Setting. The manual can help health-care facilities recognize cases and prevent further hospital-based disease transmission using locally available materials and few financial resources.

Future or Investigational Therapies
Scientists and researchers are challenged with developing containment, treatment, and vaccine strategies for these diseases. Another goal is to develop immunologic and molecular tools for more rapid disease diagnosis, and to study how the viruses are transmitted and exactly how the disease affects the body (pathogenesis). A third goal is to understand the ecology of these viruses and their hosts in order to offer preventive public health advice for avoiding infection.

Notable VHF outbreaks

 * Mékambo in Gabon is the site of several outbreaks of Ebola hemorrhagic fever.
 * Orientale, Congo villages of Durba and Watsa were the epicenter of the 1998–2000 outbreak of Marburg hemorrhagic fever.
 * Uige Province in Angola is the site of world's worst hemorrhagic fever epidemic, which occurred in 2005.
 * The ongoing 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 the Ebola virus.
 * Some experts believe that the Black Death of the Middle Ages may have been caused by a VHF and not by the [[bubonic plague.

Additional Resources

 * Health Protection Agency
 * This article includes information that originally came from US Government publications and websites and is in the public domain.

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