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Hemorrhagic Fevers

Hemorrhagic Fevers

Definition

Hemorrhagic fevers are caused by viruses that exist throughout the world. However, they are most common in tropical areas. Early symptoms, such as muscle aches and fever, can progress to a mild illness or to a more debilitating, potentially fatal disease. In severe cases, a prominent symptom is bleeding, or hemorrhaging, from orifices and internal organs.

Description

Although hemorrhagic fevers are regarded as emerging diseases, they probably have existed for many years. This designation isn't meant to imply that they are newly developing, but rather that human exposure to the causative viruses is increasing to the point of concern.

These viruses are maintained in nature in arthropod (insects, spiders and other invertebrates with external hard skeletons) or animal populationsso-called disease reservoirs. Individuals within these populations become infected with a virus but do not die from it. In many cases, they don't even develop symptoms. Then the viruses are transmitted from a reservoir population to humans by vectorseither members of the reservoir population or an intervening species, such as mosquitoes.

Hemorrhagic fevers are generally either endemic or linked to specific locations. If many people reside in an endemic area, the number of cases may soar. For example, dengue fever, a type of hemorrhagic fever, affects approximately 100 million people annually. A large percentage of those infected live in densely populated southeast Asia; an area in which the disease vector, a mosquito, thrives. Some hemorrhagic fevers are exceedingly rare, because people very infrequently encounter the virus. Marburg hemorrhagic fever, which has affected fewer than 40 people since its discovery in 1967, provides one such example. Fatality rates are also variable. In cases of dengue hemorrhagic fever-dengue shock syndrome, 1-5% of the victims perish. On the other end of the spectrum is Ebola, an African hemorrhagic fever, that kills 30-90% of those infected.

The onset of hemorrhagic fevers may be sudden or gradual, but all of them are linked by the potential for hemorrhaging. However, not all cases progress to this very serious symptom. Hemorrhaging may be attributable to the destruction of blood coagulating factors or to increased permeability of body tissues. The severity of bleeding ranges from petechiae, which are pin-point hemorrhages under the skin surface, to distinct bleeding from such body orifices as the nose or vagina.

Causes and symptoms

The viruses that cause hemorrhagic fevers are found most commonly in tropical locations; however, some are found in cooler climates. Typical disease vectors include rodents, ticks, or mosquitoes, but person-to-person transmission in health care settings or through sexual contact can also occur.

Filoviruses

Ebola is the most famous of the Filoviridae, a virus family that also includes the Marburg virus. Ebola is endemic to Africa, particularly the Republic of the Congo and Sudan; the Marburg virus is found in sub-Saharan Africa. The natural reservoir of filoviruses is unknown. The incubation period, or time between infection and appearance of symptoms, is thought to last three to eight days, possibly longer.

Symptoms appear suddenly, and include severe headache, fever, chills, muscle aches, malaise, and appetite loss. These symptoms may be accompanied by nausea, vomiting, diarrhea, and abdominal pain. Victims become apathetic and disoriented. Severe bleeding commonly occurs from the gastrointestinal tract, nose and throat, and vagina. Other bleeding symptoms include petechiae and oozing from injection sites. Ebola is fatal in 30-90% of cases.

Arenaviruses

Viruses of the Arenaviridae family cause the Argentinian, Brazilian, Bolivian, and Venezuelan hemorrhagic fevers. Lassa fever, which occurs in west Africa, also arises from an arenavirus. Infected rodents, the natural reservoir, shed virus particles in their urine and saliva, which humans may inhale or otherwise come in contact with.

Fever, muscle aches, malaise, and appetite loss gradually appear one to two weeks after infection with the South American viruses. Initial symptoms are followed by headache, back pain, dizziness, and gastrointestinal upset. The face and chest appear flushed and the gums begin to bleed. In about 30% of cases, the disease progresses to bleeding under the skin and from the mucous membranes, and/or to effects on the nervous system, such as delirium, coma, and convulsions. Untreated, South American hemorrhagic fevers have a 10-30% fatality rate.

Lassa fever also begins gradually, following an 8-14 day incubation. Initial symptoms resemble those of the South American hemorrhagic fevers, followed by a sore throat, muscle and joint pain, severe headache, pain above the stomach, and a dry cough. The face and neck become swollen, and fluid may accumulate in the lungs. Bleeding occurs in 15-20% of infected individuals, mostly from the gums and nose. Overall, the fatality rate is lower than 2%, but hospitals may encounter 20% fatality rates, treating typically the most serious of cases.

Flaviviruses

The Flaviviridae family includes the viruses that cause yellow and dengue fevers.

Yellow fever occurs in tropical areas of the Americas and Africa and is transmitted from monkeys to humans by mosquitoes. The virus may produce a mild, possibly unnoticed illness, but some individuals are suddenly stricken with a fever, weakness, low back pain, muscle pain, nausea, and vomiting. This phase lasts one to seven days, after which the symptoms recede for one to two days. Symptoms then return with greater intensity, along with jaundice, delirium, seizures, stupor, and coma. Bleeding occurs from the mucous membranes and under the skin surface, and dark blood appears in stools and vomit.

Mosquitoes also transmit the dengue virus. Dengue fever is endemic in southeast Asia and areas of the Americas. Cases have also been reported in the Caribbean, Saudi Arabia, and northern Australia. In 2004 several cases were reported along the border between Texas and Mexico in the southwestern United States. This virus causes either the mild dengue fever or the more serious dengue hemorrhagic feverdengue shock syndrome (DHF-DSS).

In children, dengue fever is characterized by a sore throat, runny nose, slight cough, and a fever lasting for a week or less. Older children and adults experience more severe symptoms: fever, headache, muscle and joint pain, loss of appetite, and a rash. The skin appears flushed, and intense pain occurs in the bones and limbs. After nearly a week, the fever subsides for one to two days before returning. Minor hemorrhaging, such as from the gums, or more serious gastrointestinal bleeding may occur.

DHF-DSS primarily affects children younger than 15 years. The symptoms initially resemble those of dengue fever in adults, without the bone and limb pain. As the fever begins to abate, the individual's condition worsens and hemorrhaging occurs from the nose, gums, and injection sites. Bleeding is also seen from the gastrointestinal, genitourinary, and respiratory tracts.

Bunyaviruses

The Bunyaviridae family includes several hundred viruses but only a few are responsible for hemorrhagic fevers in humans.

Rift Valley fever is caused by the phlebovirus, found in sub-Saharan Africa and the Nile delta. Natural reservoirs are wild and domestic animals, and transmission occurs through contact with infected animals or through mosquito bites. The incubation period lasts 3-12 days. Most cases of Rift Valley fever are mild and may be symptomless. If symptoms develop, they include fever, backache, muscle and joint pain, and headache. Hemorrhagic symptoms occur rarely; while death, which occurs in fewer than 3% of cases, is attributable to massive liver damage.

Crimean-Congo hemorrhagic fever is caused by nairovirus and occurs in central and southern Africa, Asia, Eurasia, and the Middle East. The virus is found in hares, birds, ticks, and domestic animals and may be transmitted by ticks or by contact with infected animals. The nairovirus incubation period is three to 12 days; after which an individual experiences fever, chills, headache, severe muscle pain, pain above the stomach, nausea, vomiting, and appetite loss. Bleeding under the skin and gastrointestinal and vaginal bleeding may develop in the most severe cases. Death rates range from 10% in southern Russia to 50% in parts of Asia.

Hemorrhagic fever with renal (kidney) syndrome is caused by the hantaviruses: Hantaan, Seoul, Puumala, and Dobrava. Hantaan virus occurs in northern Asia, the Far East, and the Balkans; Seoul virus is found worldwide; Puumala virus is found in Scandinavia and northern Europe; while Dobrava virus occurs in the Balkans. Wild rodents are the natural reservoirs and transmit the virus via their excrement or body fluids or through direct contact. Initial symptoms develop within 10-40 days and include fever, headache, muscle pain, and dizziness. Other symptoms are blurry vision, abdominal and back pain, nausea, and vomiting. High levels of protein in the urine signal kidney damage; hemorrhaging may also occur. Death rates range from 0-10%.

Diagnosis

Since the hemorrhagic fevers share symptoms with many other diseases, positive identification of the disease relies on evidence of the viruses in the bloodstreamsuch as detection of antigens and antibodiesor isolation of the virus from the body. Disruptions in the normal levels of bloodstream components may be helpful in determining some, but not all, hemorrhagic fevers.

Treatment

Lassa fever, and possibly other hemorrhagic fevers, respond to ribavirin, an antiviral medication. However, most of the hemorrhagic fever viruses can only be treated with supportive care. Interferon is not useful and may in fact complicate management. Such care centers around maintaining correct fluid and electrolyte balances in the body and protecting the patient against secondary infections. Heparin and vitamin K administration, coagulation factor replacement, and blood transfusions may be effective in lessening or stopping hemorrhage in some cases.

Some researchers are investigating the possibility of targeting tissue factor (TF) as a way of treating viral hemorrhagic fevers. TF is a protein that activates the coagulation process in these illnesses, and experimental models suggest that a blockade of tissue factor assists the body's immune response to hemorrhagic fever viruses.

Prognosis

Recovery from some hemorrhagic fevers is more certain than from others. The filoviruses are among the most lethal; fatality rates for Ebola range from 30-90%, while DHF-DSS cases result in a 1-5% fatality rate. Whether a case occurs during an epidemic or as an isolated case also has a bearing on the outcome. For example, isolated cases of yellow fever have a 5% mortality rate, but 20-50% of epidemic cases may be fatal.

Permanent disability can occur with some types of hemorrhagic fever. About 10% of severely ill Rift Valley fever victims suffer retina damage and may be permanently blind, and 25% of South American hemorrhagic fever victims suffer potentially permanent deafness.

Proper treatment is vital. In cases of DHF-DSS, fatality can be reduced from 40-50% to less than 2% with adequate medical care. For individuals who survive hemorrhagic fevers, prolonged convalescence is usually inevitable. However, survivors seem to gain lifelong immunity against the virus that made them ill.

Prevention

Hemorrhagic fevers can be prevented through vector control and personal protection measures. Attempts have been made in urban and settled areas to destroy mosquito and rodent populations. In areas where such measures are impossible, individuals can use insect repellents, mosquito netting, and other methods to minimize exposure.

KEY TERMS

Antibody A molecule created by the body's immune system to combat a specific infectious agent, such as a virus or bacteria.

Antigen A specific feature, such as a protein, on an infectious agent. Antibodies use this feature as a means of identifying infectious intruders.

Coagulating factors Components within the blood that help form clots.

Endemic Referring to a specific geographic area in which a disease may occur.

Hemorrhage As a noun, this refers to the point at which blood is released. As a verb, this refers to bleeding.

Incubation The time period between exposure to an infectious agent, such as a virus or bacteria, and the appearance of symptoms of illness.

Petechiae Pinpoint hemorrhages that appear as reddish dots beneath the surface of the skin.

Reservoir A population in which a virus is maintained without causing serious illness to the infected individuals.

Ribavirin A drug that is used to combat viral infections.

Tissue factor A glycoprotein involved in blood coagulation.

Vector A member of the reservoir population or an intervening species that can transmit a virus to a susceptible victim. Mosquitoes are common vectors, as are ticks and rodents.

Vaccines have been developed against yellow fever, Argentinian hemorrhagic fever, and Crimean-Congo hemorrhagic fever. Vaccines against other hemorrhagic fevers are being researched. Another possible preventive measure is increasing the number of natural killer (NK) cells in the body. These cells appear to be an important innate source of protection against Ebola and other filoviruses.

Prevention of epidemics of hemorrhagic fevers has acquired a new importance in the early 2000s from concern that the causative viruses might be used as weapons of bioterrorism. These viruses can be transmitted in aerosol form as well as having a high mortality rate.

Resources

BOOKS

Beers, Mark H., MD, and Robert Berkow, MD., editors. "Viral Diseases." Section 13, Chapter 162 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

PERIODICALS

Izadi, S., K. H. Naieni, S. R. Madjdzadeh, and A. Nadim. "Crimean-Congo Hemorrhagic Fever in Sistan and Baluchestan Province of Iran, A Case-Control Study on Epidemiological Characteristics." International Journal of Infectious Diseases 8 (September 2004): 299-306.

Mahanty, S., and M. Bray. "Pathogenesis of Filoviral Haemorrhagic Fevers." Lancet Infectious Diseases 4 (August 2004): 487-498.

Ruf, W. "Emerging Roles of Tissue Factor in Viral Hemorrhagic Fever." Trends in Immunology 25 (September 2004): 461-464.

Salvaggio, M. R., and J. W. Baddley. "Other Viral Bioweapons: Ebola and Marburg Hemorrhagic Fever." Dermatologic Clinics 22 (July 2004): 291-302.

Setlick, R. F., D. Ouellette, J. Morgan, et al. "Pulmonary Hemorrhage Syndrome Associated with an Autochthonous Case of Dengue Hemorrhagic Fever." Southern Medical Journal 97 (July 2004): 688-691.

Warfield, K. L., J. G. Perkins, D. L. Swenson, et al. "Role of Natural Killer Cells in Innate Protection against Lethal Ebola Virus Infection." Journal of Experimental Medicine 200 (July 19, 2004): 169-179.

ORGANIZATIONS

Centers for Disease Control and Prevention. 1600 Clifton Rd., NE, Atlanta, GA 30333. (800) 311-3435, (404) 639-3311. http://www.cdc.gov.

Infectious Diseases Society of America (IDSA). 66 Canal Center Plaza, Suite 600, Alexandria, VA 22314. (703) 299-0200. Fax: (703) 299-0204. http://www.idsociety.org.

World Health Organization (WHO). http://www.who.int/en/.

OTHER

Centers for Disease Control and Prevention, Special Pathogens Branch. "Ebola Hemorrhagic Fever," August 23, 2004. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/ebola.htm.

Centers for Disease Control and Prevention, Special Pathogens Branch. "Marburg Hemorrhagic Fever," August 23, 2004. http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/marburg.htm.

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Hemorrhagic Fevers

HEMORRHAGIC FEVERS

DEFINITION


Hemorrhagic fevers (pronounced heh-meh-RA-jik) are a group of diseases caused by viruses. They occur throughout the world, but are most common in tropical areas. Early symptoms include muscle aches and fevers. The disease can progress to a more serious condition and, in many cases, can be fatal. A prominent symptom in late stages is hemorrhaging (rapid or heavy bleeding) from body openings and internal organs.

DESCRIPTION


Hemorrhagic fevers are a growing concern throughout the world. They are not new diseases, but they are affecting much larger numbers of people every year.

The viruses that cause hemorrhagic fevers live in a great variety of animals, such as arthropods and mammals. Arthropods are insects, spiders, and other animals with hard external skeletons. These animals are called the natural reservoir for the disease. In many cases, these animals do not become ill when infected by the viruses. They do, however, carry the viruses in their body.

Viruses are transferred from these animals to humans by vectors. A vector is an organism that carries a disease from one animal to another. Mosquitoes are common vectors. When they bite an animal, they suck in some of its blood. If the animal is infected with a virus, the blood also contains that virus. When the vector bites a human, it leaves some of its saliva in the wound. Some of the virus may also be left behind. The human becomes infected with the virus.

Hemorrhagic fevers are often endemic. An endemic disease is one that affects many people in a given area over long periods of time. Dengue fever (pronounced DEN-gay) is an example. It affects about 100 million people annually. Most of these people live in southeast Asia. The area is very crowded. People often live in close contact with each other. The disease is transmitted easily from one person to another. In addition, the mosquito that carries dengue fever thrives in southeast Asia.

Hemorrhagic Fevers: Words to Know

Disease reservoir:
A population of animals in which a virus lives without causing serious illness among the animals.
Endemic:
The widespread occurrence of a disease over a given area that lasts for an extended period of time.
Hemorrhage:
Heavy or uncontrollable bleeding.
Ribavirin:
A drug used to treat viral infections.
Vector:
An animal that transmits an infectious agent, such as a virus, from one animal to another animal.

Some hemorrhagic fevers are very rare. An example is Marburg hemorrhagic fever. It was first discovered in 1967. In the next thirty years after that, fewer than forty people were diagnosed with the disease.

The rate of fatalities (deaths) varies among the different forms of hemorrhagic fever. In the case of dengue fever, the death rate is about 1 to 5 percent. At the other extreme, ebola (pronounced ee-BO-la), an African hemorrhagic fever, kills 50 to 90 percent of those infected.

The onset (beginning) of hemorrhagic fevers may be sudden or gradual. They all have one characteristic in common, however. They all have the potential to result in hemorrhaging. The seriousness of the hemorrhaging also varies. In some cases, it involves no more than tiny pinpoints of bleeding under the skin. In other cases, the patient may bleed extensively from the mouth, nose, and other body openings.

CAUSES AND SYMPTOMS


Many different kinds of hemorrhagic fevers are known. The viruses that cause these diseases are usually found in tropical locations, but some are also found in cooler climates. Typical disease vectors include rodents (mice and rats), ticks, and mosquitoes. The virus can also be passed from person to person through sexual contact or other means.

Filoviruses

Ebola (pronounced ee-BO-la) is the most famous of the filoviruses (pronounced fi-lo-VI-russ-ez). It is endemic to Africa, especially to the Republic of the Congo and to Sudan. Scientists have not discovered the natural reservoir for the filoviruses.

Symptoms of a filovirus infection appear suddenly. They include severe headache, fever, chills, muscle aches, and loss of appetite. These symptoms may be accompanied by nausea, vomiting, diarrhea, and abdominal pain. A person with the infection may become listless and disoriented. Severe bleeding occurs from the stomach and intestines, nose, throat, and vagina. Ebola is fatal in 50 to 90 percent of all cases.

Arenaviruses

Arenavirus (pronounced uh-RE-nuh-virus) infections occur most often in parts of South America and west Africa. In west Africa they cause a disease known as lassa fever. The disease is spread by rodents. The virus is transmitted when humans come in contact with the urine and saliva of rats and mice. Symptoms differ somewhat between South American and west African forms of the disease.

The first symptoms of South American arenavirus infection are fever, muscle ache, weakness, and loss of appetite. Later, patients experience dizziness, headache, back pain, and upset stomach. The face and chest become red, and the gums begin to bleed. In about 30 percent of all cases, hemorrhaging occurs. Bleeding occurs under the skin and in the mucous membranes, the moist tissues that line body openings. In late stages, the nervous system is affected. A person experiences delirium and convulsions and may go into a coma. About 10 to 30 percent of patients die of the disease.

The symptoms of lassa fever are somewhat similar to those of South American infections, but the death rate is usually much lower, about 2 percent.

Flaviviruses

The two best known diseases caused by flaviviruses (pronounced fla-vih-VI-russ-ez) are yellow fever and dengue fever.

Yellow fever occurs in tropical areas of the Americas and Africa. It is transmitted from monkeys to humans by mosquitoes. Some people experience only a mild form of the disease. They may not even realize that they

have been infected. In more serious cases, a patient experiences fever, weakness, low back pain, muscle pain, nausea, and vomiting. After about a week, these symptoms nearly disappear. Then they come back stronger than before. They develop into delirium (a form of madness), seizures, numbness, and coma. Bleeding occurs under the skin and in the mucous membranes. Blood also appears in stools and vomit.

Bunyaviruses

Bunyaviruses (pronounced BUN-yuh-vi-russ-ez) cause a number of hemorrhagic fevers, including Rift Valley fever and Crimean-Congo hemorrhagic fever. Rift Valley fever occurs in southern Africa and the Nile delta. The disease is transferred from wild and domestic animals to humans by

bites of infected animals or through mosquito bites. The death rate is less than 3 percent.

Crimean-Congo hemorrhagic fever is found throughout much of Africa, Asia, and the Middle East. It is found in rabbits, birds, ticks, and domestic animals. Humans contract the disease after being bitten by an infected animal or by infected ticks. Death rates range from 10 to 50 percent. The symptoms of both Rift Valley and Crimean-Congo fevers are similar to those of other hemorrhagic fevers.

DIAGNOSIS


The symptoms of hemorrhagic fevers are similar to those of other diseases. Diagnosis depends on blood tests that show the presence of the virus.

TREATMENT


There are few drugs for the treatment of viral infections. Ribavirin (pronounced RI-buh-vih-rin) is one such drug. It is sometimes used to treat lassa fever and other hemorrhagic fevers. Treatment of these diseases is generally aimed at making patients more comfortable. Patients are often given fluids to replace those lost by vomiting and diarrhea. They may be given antibiotics to protect against other infections. Vitamin K is sometimes given to help stop bleeding. Blood transfusions may also be used to restore blood lost during hemorrhaging.

In many parts of the world, patients with hemorrhagic fevers receive no treatment at all. There are not enough medical or financial resources to treat everyone with the disease. People are left to recover or die on their own.

PROGNOSIS


The prognosis for various forms of hemorrhagic fever vary widely. The death rate for ebola can be as high as 90 percent. For some forms of dengue fever, it can be as low as 1 percent.

Some types of hemorrhagic fever can cause permanent disability. For example, about 10 percent of those who develop Rift Valley fever will suffer eye damage. They may become permanently blind. About 25 percent of patients with South American hemorrhagic fever become permanently deaf.

Proper treatment is very important. It can reduce the death rate dramatically. In some forms of dengue fever, lack of treatment results in a death rate of 40 to 50 percent. With adequate treatment, the death rate drops to less than 2 percent.

PREVENTION


The best way to prevent hemorrhagic fevers is to eliminate the vectors that carry the diseases. For example, efforts have been made to wipe out mosquito or rodent populations in some areas. These efforts are sometimes successful in big cities in developed nations. They are less successful in large rural areas in developing nations. In these cases, the best hope may be personal protection. People should use mosquito netting, insect repellents, and other devices to protect themselves against vectors.

Vaccines have also been developed against some hemorrhagic fevers, including yellow fever, Argentinean hemorrhagic fever, and Crimean-Congo fever. People who plan to travel in areas where these diseases occur should

be vaccinated against them. The vaccines are costly, however, and many local populations cannot afford them.

FOR MORE INFORMATION


Books

Garrett, Laurie. The Coming Plague: Newly Emerging Diseases in a World Out of Balance. New York: Farrar, Strauss, and Giroux, 1994.

Henig, Robin Marantz. A Dancing Matrix: How Science Confronts Emerging Viruses. New York: Vintage Books, 1994.

Regis, Edward. Virus Ground Zero: Stalking the Killer Viruses With the Centers for Disease Control. New York: Pocket Books, 1996.

Ryan, Frank. Virus X: Tracking the New Killer Plagues Out of the Present and into the Future. Boston: Little Brown & Company, 1997.

Periodicals

LeGuenno, Bernard, "Emerging Viruses," Scientific American (October 1995): pp. 56+.

Web sites

Outbreak (An on-line information service about emerging diseases) http://www.outbreak.org (accessed October 25, 1999).

National Center for Infectious Diseases. Viral Hemorrhagic Fever. http://www.cdc.gov/ncidod/diseases/virlfvr/virlfvr.htm (accessed October 25, 1999).

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