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 populations—so-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 vectors—either 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 fever—dengue 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 bloodstream—such as detection of antigens and antibodies—or 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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fever /fe·ver/ (fe´ver)

1. pyrexia; elevation of body temperature above the normal (37°C).

2. any disease characterized by elevation of body temperature.

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blackwater fever  a dangerous complication of falciparum malaria, with passage of dark red to black urine, severe toxicity, and high mortality.

boutonneuse fever  a tickborne disease endemic in the Mediterranean area, Crimea, Africa, and India, due to infection with Rickettsia conorii, with chills, fever, primary skin lesion (tache noire), and rash appearing on the second to fourth day.

cat-scratch fever  see under disease.

central fever  sustained fever resulting from damage to the thermoregulatory centers of the hypothalamus.

childbed fever  puerperal septicemia.

Colorado tick fever  a tickborne, nonexanthematous, febrile, viral disease caused by an arenavirus and seen in the Rocky Mountain area of the United States.

continued fever  one that varies only slightly in 24 hours.

Crimean-Congo hemorrhagic fever  a hemorrhagic fever caused by the Crimean-Congo hemorrhagic fever virus, transmitted by ticks and by contact with blood, secretions, or fluids from infected animals or humans; it occurs in the Crimea, Central Asia, and regions of Africa.

drug fever  febrile reaction to a therapeutic agent, such as a vaccine, antineoplastic, or antibiotic.

elephantoid fever  a recurrent acute febrile condition occurring with filariasis; it may be associated with elephantiasis or lymphangitis.

enteric fever  any of a group of febrile illnesses associated with enteric symptoms caused by salmonellae, especially typhoid fever and paratyphoid fever.

epidemic hemorrhagic fever  an acute infectious disease characterized by fever, purpura, peripheral vascular collapse, and acute renal failure, caused by viruses of the genus Hantavirus, thought to be transmitted to humans by contact with saliva and excreta of infected rodents.

familial Mediterranean fever  a hereditary disease usually seen in Armenians and Sephardic Jews, with short recurrent attacks of fever, pain in the abdomen, chest, or joints, and erythema like that of erysipelas; it may be complicated by amyloidosis.

Haverhill fever  the bacillary form of rat-bite fever, due to Streptobacillus moniliformis, and transmitted through contaminated raw milk and its products.

hay fever  a seasonal form of allergic rhinitis, with acute conjunctivitis, lacrimation, itching, swelling of the nasal mucosa, nasal catarrh, and attacks of sneezing, an anaphylactic or allergic reaction excited by a specific allergen (such as pollen).

hemorrhagic fevers  a group of diverse, severe viral infections seen around the world but mainly in the tropics, usually transmitted to humans by arthropod bites or contact with virus-infected rodents; they all have certain common features, including fever, hemorrhagic manifestations, thrombocytopenia, shock, and neurologic disturbances.

humidifier fever  malaise, fever, cough, and myalgia caused by inhalation of air that has been passed through humidifiers, dehumidifiers, or air conditioners contaminated by fungi, amebas, or thermophilic actinomycetes.

intermittent fever  an attack of malaria or other fever, with recurring fever episodes separated by times of normal temperature.

Katayama fever  fever associated with severe schistosomal infections, accompanied by hepatosplenomegaly and by eosinophilia.

Lassa fever  a highly fatal, acute, febrile disease seen in West Africa, caused by a virulent arenavirus and characterized by increasing prostration, sore throat, ulcerations of the mouth or throat, rash, and general aching.

metal fume fever  a disease of welders and others working with volatilized metals, marked by sudden thirst, metallic taste in the mouth, high fever with chills, sweating, and leukocytosis.

mud fever  a type of leptospirosis seen in workers in flooded fields and swamps in Germany and Russia.

nonseasonal hay fever , hay fever, perennial nonseasonal allergic rhinitis.

Oroya fever  see Carrión's disease.

paratyphoid fever  paratyphoid.

parenteric fever  a disease clinically resembling typhoid fever and paratyphoid, but not caused by Salmonella.

parrot fever  psittacosis.

pharyngoconjunctival fever  an epidemic disease due to an adenovirus, seen mainly in school children, with fever, pharyngitis, conjunctivitis, rhinitis, and enlarged cervical lymph nodes.

phlebotomus fever  a febrile viral disease of short duration, transmitted by the sandfly Phlebotomus papatasi, with dengue-like symptoms, seen in Mediterranean and Middle Eastern countries.

Pontiac fever  a self-limited disease marked by fever, cough, muscle aches, chills, headache, chest pain, confusion, and pleuritis, caused by a strain of Legionella pneumophila.

pretibial fever  an infection due to a serovar of Leptospira interrogans, marked by a rash on the pretibial region, with lumbar and postorbital pain, malaise, coryza, and fever.

puerperal fever  septicemia accompanied by fever, in which the focus of infection is a lesion of the mucous membrane of the parturient canal due to trauma during childbirth; usually due to a streptococcus.

Q fever  a febrile rickettsial infection, usually respiratory, first described in Australia, caused by Coxiella burnetii.

rat-bite fever  either of two clinically similar acute infectious diseases, usually transmitted through a rat bite, one form (bacillary) of which is caused by Streptobacillus moniliformis and the other form (spirillary) by Spirillum minor.

recurrent fever 

1. relapsing f.

2. recurrent paroxysmal fever occurring in various diseases, such as malaria.

relapsing fever  any of a group of infectious diseases due to various species of Borrelia, marked by alternating periods of fever and apyrexia, each lasting from five to seven days.

remittent fever  one that shows significant variations in 24 hours but without return to normal temperature.

rheumatic fever  a febrile disease occurring as a sequela to Group A hemolytic streptococcal infections, characterized by multiple focal inflammatory lesions of connective tissue structures, especially of the heart, blood vessels, and joints, and by Aschoff bodies in the myocardium and skin.

Rift Valley fever  a zoonotic febrile disease with dengue-like symptoms, due to an arbovirus, transmitted to humans by mosquitoes or by contact with diseased animals; first observed in the Rift Valley, Kenya.

Rocky Mountain spotted fever  infection with Rickettsia rickettsii, transmitted by ticks, marked by fever, muscle pain, and weakness followed by a macular petechial eruption that begins on the hands and feet and spreads to the trunk and face, with other symptoms in the central nervous system and elsewhere.

rose fever  a form of hay fever caused by grass pollens released while roses or other flowers are blooming.

scarlet fever  an acute disease caused by Group A β-hemolytic streptococci, marked by pharyngotonsillitis and a skin rash caused by an erythrogenic toxin produced by the organism; the rash is a diffuse, bright red erythema, and desquamation of the skin begins as fine scaling with eventual peeling of the palms and soles.

Sennetsu fever  a febrile disease seen in Japan and Malaysia and caused by Ehrlichia sennetsu, characterized by headache, nausea, lymphocytosis, and lymphadenopathy.

septic fever  fever due to septicemia.

South African tickbite fever  boutonneuse f.

trench fever  a louse-borne rickettsial disease due to Bartonella quintana, transmitted by the body louse, Pediculus humanus corporis, and characterized by intermittent fever, generalized aches and pains, particularly severe in the shins, chills, sweating, vertigo, malaise, typhus-like rash, and multiple relapses.

typhoid fever  infection by Salmonella typhi chiefly involving the lymphoid follicles of the ileum, with chills, fever, headache, cough, prostration, abdominal distention, splenomegaly, and a maculopapular rash; perforation of the bowel may occur in untreated cases.

fever of unknown origin  (FUO) a febrile illness of at least three weeks' duration (some authorities permit a shorter duration), with a temperature of at least 38.3°C on at least three occasions and failure to establish a diagnosis in spite of intensive inpatient or outpatient evaluation (three outpatient visits or three days' hospitalization).

West Nile fever  see under encephalitis.

yellow fever  an acute, infectious, mosquito-borne viral disease, endemic primarily in tropical South America and Africa, marked by fever, jaundice due to necrosis of the liver, and albuminuria.