hemorrhagic

Viral Hemorrhagic Fevers

Primary Distribution: Hemorrhagic fevers (HFs) are found in numerous areas of the world, with variants noted below under vectors and agents.

Agents and Vectors: Viruses are transmitted by:

Zoonosis or transmission of a disease of animals directly to humans from the animal host (especially rodents in the case of hemorrhagic fevers): HF with renal syndrome secondary to Hantaan virus infection: Europe, East China, and Korea (In Europe includes Puumala virus, Scandinavia; Belgrade virus, Yugoslavia; Dobrava virus, Balkan area. These three tend to cause milder infections); Hantavirus pulmonary syndrome: North America (especially Southern), South America (especially Andes); Junin HF, Argentina; Machupo HF, Bolivia; Lassa HF, West Africa; Ebola and Marburg HFs: Central Africa (vector not known).
Tick: Omsk HF: Russia, especially Siberia; Kyasanur Forest hemorrhagic fever: India; Crimean-Congo HF: Africa, Middle East, Eastern Europe, Russia, Western China.
Mosquito: Chikungunya HF: Africa and East Asia; dengue fever: worldwide; yellow fever: tropical Africa and South America; Rift Valley fever: Africa, especially Central, Egypt.

The viral HFs are are considered by the CDC to be Category A biological warfare (BW) agents (CDC, 2000). See bioterror box below.

Incubation: Because the index of suspicion is increased with travel in an endemic area + hemorrhagic manifestations occurring within the incubation period, endemic areas and incubation periods are given in discussions of specific HFs. The range of incubation for HFs is 3-28 days.

Clinical Findings and Treatment

Note: The most important HFs are discussed separately in this site and summarized in this file. These include dengue fever, yellow fever, Lassa fever, and the Ebola and Marburg fevers). Those of lesser importance, i.e., lower incidence or virulence are summarized in this file. These include hemorrhagic fever with renal syndrome caused by hantavirus, hantavirus pulmonary syndrome, South American HFs, Kyasanur Forest HF, Omsk HF, Crimean-Congo HF, Chikungunya HF, and Rift Valley HF. The U.S. Centers for Disease Control groups Crimean-Congo, Lassa, Ebola, and Marburg hemorrhagic fevers together as causing viral hemorrhagic fevers (VHFs) and in some cases, presents management as of VHF as a unified concept (CDC, 1995). The Marburg and Ebola hemorrhagic fevers (both from Filoviruses) are characterized by easy transmissability, high mortality, lack of effective vaccine, and lack of effective treatment.

General Signs and Symptoms: The viral hemorrhagic syndrome (VHS) results from widespread increased permeability of microvasculature. Depending on the severity of vascular instability and decrease in platelet function, presentation may range from mild to severe illness; and hemorrhagic manifestations are not always apparent. A common course of illness begins with an abrupt onset of fever, myalgia, cutaneous flushing, and conjunctival suffusion. Within several days, the patient's condition worsens to include syncope, photophobia, headache, hyperesthesia, abdominal pain, nausea/vomiting, anorexia, and prostration.

Bioterror Considerations

The viral HFs (Lassa, Junin and related) are considered by the CDC to be Category A biological warfare agents as they pose a risk to national security because they "can be easily disseminated or transmitted from person to person; cause high mortality, with potential for major public health impact; might cause public panic and social disruption; and require special action for public health preparedness" (CDC, 2000, p. 5). Though Iraq is not known to have produced weaponized viral HFs (Shoham, 2000), "all are potentially infectious by the aerosol route and most are stable as respirable aerosols (Cieslak & Eitzen, 2000, p. 28). Treatment is supportive, hence very challenging in a mass casualty situation.

Specific Signs and Symptoms

Hemorrhagic fever with renal syndrome caused by hantavirus (Europe, Russia, East China, and Korea): Incubation ranges from 9-35 days. Severity of the illness varies, with mild or subclinical infections common. More severe cases are characterized by a febrile stage lasting 3-5 days with abrupt onset of fever, headache, photophobia, blurred vision, facial flushing extending to neck and shoulders, conjunctival petechiae, periorbital edema, pharyngeal injection and/or petechiae, axillary petechiae, lumbar back pain and CVA tenderness lasting 3-5 days. The illness may gradually resolve after this febrile stage or a hypotensive stage may begin as the temperature falls. The hypotensive stage is characterized by decreased blood pressure, tachycardia, and sometimes shock. Thrombocytopenia, leukocytosis, proteinuria, and oliguria occur, as does renal failure in some cases. Renal function returns as the oliguric phase resolves and the polyuric phase ensues. Electrolyte imbalances and dehydration may occur in the polyuric phase. Disseminated intravascular coagulation may occur relatively early in the course of illness. Treatment is supportive as discussed below.
Hantavirus pulmonary syndrome (North America, especially Southern; South America, especially Andes): Incubation ranges from 7-28 days. Hantavirus infection is thought to occur through inhalation of infected rodent droppings dust. Hantaviruses cause HFs as described above and in Latin America and the U.S., the hantavirus pulmonary syndrome (HPS). HPS is characterized by a flu-like febrile illness that rapidly progresses to shock and adult respiratory distress syndrome with thrombocytopenia, hemoconcentration, and leukocytosis. Treatment is supportive as discussed below. Ventilation may be necessary within 24 hours of onset.
Junin HF (Argentina), Machupo HF (Bolivia), and other South American HFs: Incubation in South American HFs ranges from 7-14 days. South American HFs are characterized by the gradual onset of fever, myalgia, and signs and symptoms as described above under general signs and symptoms. Thrombocytopenia, bleeding, and neurological dysfunction (confusion, tremors, and cerebellar signs) are common in South American HFs. Treatment is supportive and also includes ribavirin as discussed below.
Lassa HF (West Africa, including Nigeria) is discussed in greater detail in a full discussion file. Incubation of Lassa fever ranges from 7-21 days. Presentation of Lassa fever varies. Common early symptoms are gradual onset of fever, malaise, headache, and abdominal pain. Other symptoms are conjunctivitis, facial swelling, sore throat, non-productive cough, retrosternal pain, nausea, vomiting, diarrhea, back pain, and myalgia. Respiratory rate, temperature, pulse rate are increased and blood pressure decreased. Neurological symptoms may also occur, including hearing loss, tremors, and encephalitis. Hemorrhagic manifestations (not usually evident) may include mucosal bleeding and, less frequently, conjunctival, gastrointestinal, or vaginal bleeding. Severe infections produce hemorrhagic manifestations, pleural effusions, and shock. Pregnant women are more likely to die than are others. Some degree of deafness occurs in about 30% of patients. See full discussion. Treatment is supportive and also includes ribavirin as discussed below.
Ebola and Marburg HFs: See full discussion (Central Africa): Incubation of Ebola and Marburg HFs ranges from 3-16 days. Both Ebola and Marburg HFs are characterized by sudden onset of fever, chills, severe headache, and myalgia. On about the fifth day of illness, a maculopapular rash may appear - most prominently on the trunk (the rash may eventually desquamate). Other manifestations occurring at about the same time include sore throat/pharyngitis, chest pain, abdominal pain, nausea, vomiting, diarrhea, and hemorrhagic symptoms, e.g., bleeding mucosal membranes. Symptoms may increase in severity and include jaundice, pancreatic inflammation, rapid weight loss, prostration, delirium, shock, hepatic failure, massive hemorrhaging, and multi-organ failure. Case fatality rates for Marburg HF are around 25% and for Ebola HF range from 50% to 90% (in Africa). See full discussion. Treatment is supportive as discussed below.
Kyasanur Forest HF (India): Incubation is 3-8 days. Kyasanur Forest HF is caused by a tick-borne flavivirus and currently is found only in the Mysore State of India. The illness is characterized by sudden onset fever and headache, followed by back and extremity pain, bradycardia, lymphadenopathy, conjunctival injection, palantine injection, petechiae, and other hemorrhagic signs. Meningoencephalitis is relatively common. Treatment is supportive as discussed below.
Omsk HF (Russia): Except for geographic location, Omsk HF is similar to Kyasanur Forest HF.
Crimean-Congo HF (Africa, Middle East, Eastern Europe, Russia, Western China): Incubation is 3-12 days. Crimean-Congo HF is transmitted by the bite or crushing of infected ticks, or by contact with live or dead infected mammals. The clinical picture is similar to that described above under General Signs and Symptoms, except that in Crimean-Congo HF there are significant liver abnormalities (>AST, >phosphokinase, >bilirubin, leukocytosis, and signs of disseminated intravascular coagulation. Though treatment is not definitive, more severe cases are often successfully treated with IV ribavirin as described below.
Chikungunya fever (Topical areas, especially urban, of Asia, India, and East Africa): Chikungunya fever is an arboviral infection transmitted by the Aedes aegypti mosquito. Incubation is 2-4 days and the illness is self-limiting with acute symptoms (abrupt onset fever, headache, arthralgias, nausea, vomiting, abdominal pain, sore throat, lymphadenopathy, rash at defervescence, and malaise) lasting 3-10 days. Arthralgias remain a problem for weeks to several months after the acute phase. Febrile convulsions may occur in young children. Treatment is supportive for fever and pain.
Dengue: See full discussion (East and West Africa, Southeast and East Asia, Pacific Islands, Eastern Australia, Central and South America, Mexico, South Texas, Caribbean Islands - with distribution increasing, especially in urban areas) Incubation is 7-10 days. Dengue fever and HF are transmitted by mosquitos, and there is increasing incidence and prevalence of cocirculation of multiple serotypes. Dengue is usually a self-limited illness characterized by abrupt onset high (biphasic) fever, chills, headache, rash, signs of bleeding, changes in taste, sore throat, nausea, vomiting, diarrhea, anorexia, severe aching myalgia and arthralgia (hence "bone-break" fever), and depression. Complications include meningoencephalitis, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Treatment is supportive and convalescence tends to be lengthy. See full discussion.
Rift Valley fever (Africa, especially Central, Egypt): Incubation is 3-5 days. The Rift Valley fever (RVF) virus is transmitted by mosquito or perhaps other blood-sucking insect bite; and by exposure to body fluids or meat of infected animals. Most people with RVF have no symptoms or a mild febrile illness with liver abnormalities. Others, however, develop a classic HF with weakness, fatigue, back pain, dizziness, and rapid weight loss. Retinal vasculitis occurs in about 10% of cases, and encephalitis may also occur in a few patients. Though definitive research on treatment is lacking, treatment of severe cases may include the use of IV ribavirin as described below.

Complications: Shock, multifocal hemorrhage, encephalopathy, seizures, convulsions, and/or coma may occur in more serious infections. Renal failure is a complication of HF with renal syndrome. Case mortality rates vary with the causative virus and level of care. For example, the mortality rate for patients with dengue HF who receive supportive care is less than 1%, while the mortality rate for patients with hantavirus pulmonary syndrome is 30-50%. The mortality rate for patients with Ebola HF ranges from 50-90%.

Laboratory Findings: Increased AST, leukopenia, proteinuria, hemoconcentration, thromboctopenia, and at least in the case of Crimean-Congo HF, also increased creatinine phosphokinase, bilirubin, leukocytosis, and signs of disseminated intravascular coagulation.

Diagnosis: Hemorrhagic manifestations + travel to an endemic area. Except for the presence of the rash, dengue fever is difficult to distinguish from other febrile illnesses (e.g., malaria, yellow fever, influenza) or arboviral disease with dengue-like courses (Colorado tick fever, Rift Valley fever, Ross River fever, sandfly fever). For this reason, an initial diagnosis may be "dengue-like disease." Serologic diagnosis is on the basis of a fourfold or greater increase in antibody titer in paired sera by hemagglutination inhibition, complement fixation, enzyme immunoassay, or neutralization test. Standardized immunoglobulin (Ig) M- and IgG-capture enzyme immunoassay are used to identify acute-phase antibodies. Samples are collected no earlier than five days, nor later than six weeks after onset. Viral RNA can be detected by specific complementary DNA probes or amplified first by polymerase chain reaction.

Differential Diagnosis: Rickettsial diseases (typhus, Q fever, trench fever, spotted fevers such as Rocky Mountain or Boutonneuse), meningococcemia, malaria, shigellosis, leptospirosis.

Treatment: Treatment is supportive with acetaminophen rather than aspirin for fever and pain relief, bed rest, fluid replacement, and gradual convalescence. Increased capillary permeability limits the extent of fluid replacement. Pressors may be required to maintain blood pressure. Renal failure requires dialysis. Lassa fever, South American HFs, and possibly Crimean-Congo HF and Rift Valley HF may be treated with a slow infusion of IV ribavirin 32 mg/kg; followed by 16 mg/kg qid for 4 days; and this by 8 mg/kg tid for 6 days. Dengue hemorrhagic fever and shock syndrome are medical emergencies treated in intensive care settings.

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References

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