What are hemorrhagic fever viral infections?

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Hemorrhagic fever viral infections (HFVIs) are caused by four distinct families of viruses: arenavirus, bunyavirus, filovirus, and flavivirus. These viruses are round structures with an average diameter of 110 to 130 nanometers (1 billionth of a meter). They are covered with a lipid (fat) membrane. A cross-section view of the viruses shows grainy particles.
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Definition

Hemorrhagic fever viral infections (HFVIs) are caused by four distinct families of viruses: arenavirus, bunyavirus, filovirus, and flavivirus. These viruses are round structures with an average diameter of 110 to 130 nanometers (1 billionth of a meter). They are covered with a lipid (fat) membrane. A cross-section view of the viruses shows grainy particles.

HFVIs are characterized by fever and bleeding disorders, which can progress to shock and death. However, these viruses can also produce a mild infection with little or no symptoms. The viruses are present throughout the globe, and most of them are totally dependent on a host organism, such as a rodent or insect, for replication and survival. This host organism is known as a vector.

Causes

Arenavirus, bunyavirus, filovirus, and flavivirus are all ribonucleic acid (RNA) viruses (RNA is a long chain of nucleotide units). Humans contract one of these viruses through contact with the urine, saliva, or feces of infected rodents. For viruses that have an insect vector, the disease occurs from a bite. Some arenaviruses, such as Machupo and Lassa, can be spread by person-to-person contact. For example, hospital workers caring for infected persons can acquire the infection. Other viruses can enter the body through inhaled airborne particles or by direct contact with broken or abraded (chafed) skin.

Each virus is usually associated with a specific rodent or insect host species, or with a closely related species. These host species (vectors) maintain the virus within their bodies and are not known to exhibit any symptoms of viral illness. Rodents, mosquitoes, and ticks are found in most areas on Earth.

Arenaviruses. These arenaviruses are divided into two groups: the New World or Tacaribe complex and the Old World or Lassa complex. Both groups produce infections in humans. In Africa (Old World), Lassa virus causes Lassa fever; in South America (New World), arenavirus infections are caused by the Machupo virus, which leads to Bolivian hemorrhagic fever; the Guanarito virus, which causes Venezuelan hemorrhagic fever; the Junin virus, which causes Argentine hemorrhagic fever; and the Sabia virus, which causes Brazilian hemorrhagic fever. Infections with the lymphocytic choriomeningitis virus, which causes lymphocytic choriomeningitis, have been reported in the Americas, Australia, Europe, and Japan.

Approximately 400,000 Lassa fever infections occur annually, with a mortality rate of about 20 percent; the disease’s vector is a rat, Mastomys natalensis. Bolivian hemorrhagic fever has a mortality of about 30 percent; its vector is the vesper mouse, Calomys callosus. Venezuelan hemorrhagic fever also has a mortality rate ofabout 30 percent; its vectors are the short-tailed cane mouse ( Zygodontomys brevicauda) and Alston’s cotton rat ( Sigmodon alstoni).

Bunyaviruses. These viruses commonly infect insects and rodents, and some infect humans. Others cause plant diseases. Bunyavirus vectors are mosquitoes, ticks, and sandflies. The only exception is the hantavirus, which is spread through contact with deer mice feces. Transmission of these viruses is usually seasonal. For example, viruses transmitted by mosquitoes are more common in summer. Some of these viruses cause serious illness and death. Two examples are the Crimean-Congo hemorrhagic fever virus and the hantavirus, which causes hantavirus hemorrhagic fever. Crimean-Congo hemorrhagic fever is a tickborne viral infection with a mortality rate of about 30 percent. Hantavirus causes high fever, pulmonary edema (fluid in the lungs), pulmonary failure, and hypotension (dangerously low blood pressure); it has a mortality rate of approximately 55 percent.

Filoviruses. These viruses are the Ebola virus and the Marburg virus. Despite sometimes causing mild illness, they are two of the most virulent (deadly) viruses on the planet. Filoviruses cause a severe viral hemorrhagic fever disease, mainly in sub-Saharan Africa. The vector for the Ebola virus is unknown. However, researchers theorize that a human infection first occurs through contact with an infected animal. This infected human then transmits the infection through contact with blood or secretions from another infected person; thus, family members and health care workers are at increased risk. Mortality rates range from 50 to 90 percent, depending on the particular viral strain.

The Marburg virus is also spread through body fluids. A suspected vector is the Egyptian fruit bat, Rousettus aegyptiacus. Marburg virus infections have a mortality rate of about 25 percent. Recovery may be prolonged in some persons and is complicated by hepatitis (liver inflammation), myelitis (muscle inflammation), orchitis (testicular inflammation), or uveitis (eye inflammation).

Flaviviruses. These viruses cause dengue fever, Kyasanur forest disease, Omsk hemorrhagic fever, and yellow fever. Yellow fever is endemic to tropical regions of Africa and the Americas. The virus primarily affects humans and nonhuman primates (such as monkeys) and is transmitted through the bite of infected Aedes aegypti mosquitoes. It can cause devastating epidemics, which can result in many fatalities. Both in Africa and South America, despite large-scale vaccination campaigns to prevent and control these outbreaks, the risk of major yellow fever epidemics exists, particularly in densely populated, poor, urban settings. Yellow fever is considered to be an emerging, or reemerging, disease of significant importance.

An even greater threat is dengue fever. It is the most prevalent insect-borne virus affecting humans. It is present in more than one hundred countries, and 50 million to 100 million cases occur each year. Dengue fever is transmitted through the bite of an infected A. aegypti or A. albopictus mosquito. Breeding sites for the mosquitoes that transmit dengue virus have increased, partly because of population growth and uncontrolled urbanization in tropical and subtropical countries.

Risk Factors

Taken together, viruses that cause HFVIs are present throughout the globe; however, the overall risk of contracting an infection is low. Furthermore, because each virus is often associated with a specific host, it is usually present only in the area where that host lives. Some viruses are present only in isolated regions; thus, the risk of transmission is extremely low. However, some infections, such as dengue, Lassa, and yellow fevers, are common in certain regions, mainly South America and sub-Saharan Africa. These areas are known as endemic areas for those diseases.

Some infections, such as dengue fever, flare with periodic outbreaks; thus, travel to a region during an epidemic increases the risk of infection. The risk of infection in an endemic area is greater if one hikes or camps in the countryside rather than staying in a hotel and taking guided tours. Infection from a virus outside the endemic area is possible because of air travel or because of bioterrorism.

The risk of a rodent-borne infection increases in rodent-infested buildings, by living in the country, or by living near an area where rodents congregate (such as trash storage areas). The risk of insect-borne infection increases by being outdoors with exposed areas of skin, particularly at night.

The following persons are at increased risk: hospital workers ranging from health care professionals to janitorial staff, laboratory workers, and researchers studying these viruses. For example, hospital personnel in Africa caring for patients with Ebola frequently contract the disease.

Symptoms

Infected humans may remain healthy and exhibit no symptoms. If symptoms occur, they often begin with a gradual onset of flulike symptoms (fever, muscular aches, and cough). If the disease progresses during the next few days, infected persons often experience a sore throat, headache, chest pain, abdominal pain, vomiting, and diarrhea. Further progression leads to bleeding from the gums, the intestinal tract, and other internal organs; next occurs facial swelling and conjunctivitis (inflammation and swelling of the eyelids and portions of the eyeballs). At this stage, hematuria (blood in the urine) commonly occurs. With further progression comes temporary or permanent hearing loss, pulmonary edema (fluid in the lungs), and encephalitis (brain inflammation). Late stages of the disease can lead to shock, seizures, coma, and death.

Severe multisystem disease occurs in about 20 percent of cases. Hemorrhage and tissue damage occurs in the liver, spleen, and kidneys. The mortality rate for these cases ranges from 15 to 100 percent.

Screening and Diagnosis

In the early stages of infection, the symptoms are similar to those of many other viral infections: fever, muscular aches, and cough. Early diagnosis is essential for treatment; however, the similarity of the symptoms to a much less virulent viral infection hampers an early diagnosis. Despite this, researchers are developing and evaluating accurate and uncomplicated diagnostic tests for hemorrhagic fever infections. A definite diagnosis can be made in a highly specialized laboratory only, one that can detect the presence of a virus or antibodies to it. Antibodies are gammaglobulin proteins that are present in blood or other bodily fluids; they are used by the immune system to identify and inactivate foreign organisms, such as bacteria and viruses. A test known as an enzyme-linked immunosorbent assay (ELISA) test is used; this biochemical technique can detect the presence of an antibody or an antigen in a sample. Specific ELISA tests are required for each virus.

Treatment and Therapy

No established drug treatments or cures exist for most HFVIs. The antiviral drug ribavirin is effective for Lassa fever if given early in the course of the disease. However, it might cause birth defects, so women taking the medication should avoid pregnancy at that time.

Treatment for HFVIs consists mainly of supportive care, such as the replacement of fluid loss, blood and blood product (platelet) transfusions, and the maintenance of blood pressure. This supportive care keeps the infected person in a reasonable state of health, which allows the body time to develop antibodies to the virus. These antibodies attack and inactivate the virus. If this occurs, the infected person regains his or her health and is immune to further attacks from the virus.

Complicating the immune response to these viruses is their ability to mutate (evolve) into different, and sometimes more virulent, strains of the virus. If a significant difference exists between the original and mutated strains, the immune system will not recognize the virus and repeat illness is possible. For example, dengue viruses have evolved rapidly as they have spread worldwide; more virulent strains have spread across Asia and the Americas.

Research into HFVIs is focused on vector (rodents and mosquitoes) control and on developing vaccines and antiviral medications. Researchers are looking for an appropriate animal model for vaccine testing. Nonhuman primate models can most reliably mimic human disease; however, less costly and more readily available rodent models are also being studied. Genetic inhibitors of these viruses are being identified in genetics laboratories. The antiviral activity of the natural human hormones, dehydroepiandrosterone and epiandrosterone, and sixteen synthetic derivatives are under investigation.

Prevention and Outcomes

Vaccines are present for yellow fever and Argentine hemorrhagic fever. These vaccines are about 96 percent effective in preventing infection; however, they have a significant level (30 to 35 percent) of adverse effects. Essentially, these vaccines produce a mild case of the viral disease. The side effects of the vaccines include headache, fever, nausea and vomiting, weakness, myalgia (muscle pain), retroocular pain (pain behind the eyeballs), dizziness, low back pain, exanthema (widespread rash), mildly decreased blood cell and platelet counts, and microhematuria (blood in the urine that is visible microscopically).

The best prevention is to avoid contact with the rodent and insect vectors. For rodent control, garbage should be placed in rodent-proof containers. As a further precaution, these containers should be placed as far from a home as possible. Placement of traps and pesticides in attics and other areas can control the rodent population. The risk of mosquito bites can be reduced by staying indoors at night, applying insect repellants, and wearing full-length clothing. Window screens should be placed to prevent entrance of mosquitoes into a home. If entrance cannot be completely prevented, sleeping nets should be placed over beds. Spraying with pesticides will also reduce the insect population. Prevention includes avoiding mosquito bites and promoting a clean community environment to discourage rodents from entering homes. In recent years, vector control programs have been eliminated, often because of lack of government funding. This increases the risk of infection.

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. Infection control techniques include isolating infected persons and wearing protective clothing. Other infection control recommendations include proper use, disinfection, and disposal of instruments and equipment (such as needles and thermometers) used in treating or caring for persons with these infections.

Researchers are focused on developing strategies for these diseases in the following areas: containment, treatment, and vaccines. Furthermore, they are attempting to develop methods for earlier diagnosis of these diseases.

Bibliography

Berger, Stephan A., Charles H. Calisher, and Jay S. Keystone. Exotic Viral Diseases: A Global Guide. Lewiston, N.Y.: B. C. Dekker, 2003. A guide to viral diseases written primarily, but not solely, for the clinician. Examines the epidemiology, signs, symptoms, and treatments of all unusual viral infections of humans.

Centers for Disease Control and Prevention. “What Are Viral Hemorrhagic Fevers?” Available at http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/vhf.htm. A look at HFVIs, provided by the CDC’sspecial pathogens branch.

Grady, D. Deadly Invaders: Virus Outbreaks Around the World, from Marburg Fever to Avian Flu. Boston: Kingfisher, 2006. A readable introductory student text covering viral epidemics. The book begins with an account of the author’s trip to Angola to cover an outbreak of Marburg fever. Other viral diseases are covered in subsequent chapters and include avian flu, human immunodeficiency virus infection, SARS, and West Nile virus.

Howard, Colin R., ed. Viral Haemorrhagic Fevers. Boston: Elsevier, 2005. Part of the Perspectives in Medical Virology series, this book is an informative introductory guide to hemorrhagic fevers for students and general readers.

Parker, J., and P. Parker. The Official Patient’s Sourcebook on Viral Hemorrhagic Fevers. San Diego, Calif.: Icon Health, 2003. Although this book is mostly useful to doctors, caregivers, and other health professionals, it also provides guidance for general readers onfinding information on viral hemorrhagic fevers, from the essentials to the most advanced areas of research.

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