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Hemorrhagic Fever Syndrome (HFS) refers to a variety of RNA viruses which can cause mild or potentially severe disease with hemorrhagic manifestations. The most common viruses responsible for Hemorrhagic Fever (HF) can be categorized according to their Family.

South American Hemorrhagic Fever. This includes Argentine HF due to the Junin virus; Bolivian HF due to the Machupo Virus; and Venezuelan HF due to the Guanarito virus.

Hemorrhagic Fever with Renal Syndrome (HFRS), due to Hantaan virus, Seoul virus, etc.

Overall, the risk is very low. The majority of HF viruses occur in areas not frequented by travellers. Crimean- Congo HF may be a risk for campers or hikers in endemic areas. Field biologists, missionaries, and volunteers in rural areas are at small theoretical risk of acquiring Arenavirus type HF such as South American HF. Hantavirus pulmonary syndrome (HPS) is generally associated with exposure to rodent excreta, especially deer mice, so activities such as staying in dwellings inhabited by rodents or disturbing rodent-infested areas while hiking or camping can be a risk to the traveller.

With increasing international travel, Yellow fever and Dengue HF are an increasing concern. Since 1996 Yellow Fever cases have been reported in American and European travellers to endemic areas of Africa and South America. None of these tourists had received Yellow Fever vaccine. It has been reported that Dengue is an increasing risk for the traveller, especially in the Caribbean, Central America, and South America.

Lassa fever occurs in West Africa, in particular in Sierra Leone, Liberia, Guinea, and Nigeria.

South American HF is found mainly in focal rural areas of Argentina, Bolivia, Venezuela, and Brazil.

Rift Valley fever is found in sub-Saharan Africa and has shown recent spread to Saudi Arabia. .

Crimean-Congo HF occurs in Africa, the Middle East, the Balkans, central Asia, and southern Soviet Union.

HPS is found, in particular, in the western United States (Arizona, New Mexico, Colorado, and Utah) as well as in western Canada, Central and South America.

Marburg was first detected among laboratory workers in Marburg, Germany, after exposure to African green monkeys. Rare cases of Marburg virus infection have been reported in Zimbabwe, Kenya, and South Africa.

Kyasanur Forest disease is found in a limited area of Karnataka state, India.

Yellow fever is endemic in the tropical areas of equatorial sub-Saharan Africa and tropical South America between latitudes 15 degrees north and 10 degrees south. It does not occur in Asia. Approximately 90 percent of Yellow Fever occurs in Africa and 10 % in the Americas. Urban transmission is a major concern in Africa.

Dengue HF occurs in the tropics and subtropics worldwide with endemic areas in Asia, Polynesia, Micronesia, East and West Africa, South America, and the Caribbean. In recent years, there has been an increase of dengue in South and Central America, the Caribbean and India. There has been increasing concern about the expanding areas of Dengue HF over the past few decades. This will continue to be of concern for future travellers. The following map shows the change in distribution of Dengue HF in the Americas.

American countries with laboratory-confirmed Dengue hemorrhagic fever (red shaded areas), prior to 1981 and from 1981 to 1997.

Lassa fever is transmitted to humans by a chronically infected rat, Mastomys, which tends to live close to human dwellings. Rodent contamination of food and drink, inhalation of aerosolized rodent secretions, or contact with rodent excreta through skin abrasions as well as human-to-human infection by contact with infected secretions are possible. Of note, Lassa fever is the most commonly exported HF.

South American HF is acquired primarily by inhalation of infectious aerosols of rodent excreta, or less often by person-to person transmission through contact with infected body fluids. Argentine HF occurs mainly in the fall season in male farm workers.

Rift Valley fever is acquired by humans by mosquito bite (Culicine spp); by contact with the blood of infected sheep, cattle, or goats; and by aerosols from the blood of infected domestic animals. Transmission is increased in the rainy season.

Crimean- Congo HF is transmitted to humans by Ixodid (tick) bites, crushed ticks, and through contact with infected body fluids from animals or humans. It is more common in sheep or cattle handlers.

Hemorrhagic fever with renal syndrome (HFRS) is transmitted by aerosols and direct contact with infected rodent urine or other excreta and occasionally by rodent bites.

Marburg –Ebola has an unknown mode of primary transmission in nature. Secondary infection is by nosocomial infection, especially from blood and tissue fluids. Person -to- person transmission occurs primarily through contaminated needles and contact with infected individuals.

Yellow fever has both a sylvatic (forest) and urban cycle. Sylvatic transmission is due to the bite of an infectious Haemagogus mosquito with the monkey acting as the main reservoir. Urban yellow fever is transmitted from human -to- human by the bite of an infectious Aedes aegypti mosquito, generally at altitudes up to 2500 metres.

Dengue HF is transmitted from person-to-person by the bite of an infectious Aedes aegypti mosquito, which is a daytime biter. Dengue HF generally requires previous exposure to another serotype of Dengue and will, therefore, be more likely to occur in the local population (especially children) or long term expatriates who have had previous exposure to Dengue.

Kyasanur Forest disease is transmitted to humans by Haemaphysalis ticks which generally feed on rodents, birds, cattle and flying squirrels.

Clinical presentations vary with the different viral agents. Initially, symptoms generally include headache, fever, malaise, and myalgias which can develop over several hours to 3-4 days and which can be followed by severe sore throat and abdominal pain (Lassa HF), rash (Dengue, Ebola, and Marburg), and gastrointestinal bleeding. Signs range from non-specific, such as fever, flushing, conjunctival injection, and periorbital edema, to specific signs indicating the onset of hemorrhage, for example, epistaxis, bleeding gums, petechiae, and purpura. In severe disease, intractable hypotension, electrolyte imbalance, and renal, lung, and liver failure may occur. Neurological impairment due to encephalitis is also seen. Hearing loss is common in Lassa fever. Jaundice and albuminuria are common in Yellow fever.

An important clinical test in Dengue HF is the Tourniquet Test. This is performed by inflating a blood pressure cuff midway between the systolic and diastolic pressures and looking for onset of petechiae > 20 per square inch by 5 minutes.

The WHO definition of DHF/DSS (Dengue Hemorrhagic Fever / Dengue Shock Syndrome) requires all of the following criteria:

1 .Fever.

2. Hemorrhagic manifestations or a positive tourniquet test.

3. Platelets less than 100,000.

4. Evidence of increased plasma leakage (pleural effusion, ascites, hematocrit increased by 20% or decreased by 20% with hydration, or hypoproteinemia).

The majority of travellers will not come into contact with the different vectors and reservoirs of hemorrhagic fevers. Prevention can include avoidance of contact with the host species (eg. not sleeping in local dwellings potentially contaminated with rodents, not handling or feeding rodents, keeping food areas clean, encouraging safe clean up of rodent droppings, and avoiding newly slaughtered animals). In addition, medical and nursing personnel should be reminded to use universal precautions and barrier nursing care when exposed, in particular, to Crimean-Congo HF, Lassa fever, and Ebola and Marburg.

At this time, the majority of hemorrhagic fevers do not have an effective vaccine.

One important exception is the live attenuated vaccine for Yellow fever (YF-VAX), produced by Aventis Pasteur and prepared in chick embryos.

Yellow Fever vaccine is recommended for all travelers ≥ 9 months of age passing through or living in countries in Africa, Central America and South America where Yellow Fever infection is officially reported or immunization is required. Immunization is also advised in non-urban areas in countries that do not report YF but are in the YF endemic zones.

The vaccine is contraindicated in infants < 4 months of age due to the risk of encephalitis and should be given to infants between 4-9 months of age only if they are traveling to high risk areas and a high level of protection against mosquito exposure is not possible. It is generally recommended to avoid the vaccine in pregnant women and immunocompromised individuals. There is increasing evidence, however, that individuals with asymptomatic HIV whose CD4 T cell count is greater than 200 may safely receive the vaccine. An individual risk assessment should be done for individuals >65 years of age due to recent reports of possible increased adverse effects.

The vaccine should not be given to individuals with known anaphylactic hypersensitivity to eggs.

If other live vaccines are not given at the same time, it is essential to wait at least 4 weeks. Inactivated parenteral cholera vaccine (no longer used in Canada) must be given three weeks or more from the administration of Yellow Fever vaccine. It is also advisable to avoid the vaccine in an ill patient.

The YF vaccine is given as a 0.5 ml s/c injection with booster doses every 10 years as required, however, it is believed that immunity may actually persist for life.

The vaccine should be stored in a freezer (5 to -30°C) until reconstituted by the addition of diluent. Any unused reconstituted vaccine must be kept refrigerated and discarded one hour after reconstitution.

The International Certificate from a designated Yellow Fever Vaccination Centre is valid for 10 years, beginning 10 days after vaccination. Of note, exemption should be provided for those travelers requiring a Certificate but for whom the yellow fever vaccine is contraindicated.

Adverse reactions to the vaccine include local reactions, with 2% to 5% incidence of mild headache, myalgia, and low-grade fever 5 to 10 days after immunization. Of note, seven cases of sepsis -like illness have been reported since 1996. Studies are in progress in order to better define the risk factors for these rare adverse events.

Other types of hemorrhagic fever vaccines used in endemic areas include a safe, effective vaccine for high-risk residents of endemic areas of Argentine HF and a limited supply of vaccine for Rift Valley fever, mainly advised for veterinarians and virology workers in sub-Saharan Africa. Kyasanur Forest disease also has its own local Indian vaccine.

This varies according to the specific etiological agent. It is important to remember that precautions appropriate to each virus must be taken to prevent infection while processing samples. Investigations should be carried out in a high-security lab if a diagnosis of a HF with the potential for nosocomial spread is suspected. Diagnostic expertise and consultation is essential.

Generally, evaluation for neutralizing antibodies in acute and convalescent sera, detection of IgM or viral antigen, or viral isolation are performed.

The following Reference table is a general overview of the diagnostic tests available.

Primarily supportive care with careful monitoring of fluids and electrolytes and avoidance of NSAIDS. Specific measures include an infusion of convalescent phase plasma during the first 8 days of illness in Argentine HF (reduces mortality from 15-30 % to <1 %).

Ribavirin, an antiviral agent, is effective in reducing mortality in Lassa fever and should be used in higher risk patients, eg, if AST >150. Ribavirin should also be used in other Arenavirus infections such as South American HF and has been found to have some benefit in HFRS and possibly in Rift Valley fever and Crimean-Congo HF.

Disease	I.P. in days	Case Infection	Case Fatality
Lassa fever	5-16	<10%	15%
South American HF	7-14	>50%	10 -15 %
Rift Valley fever	2-5	1%	50%
Crimean - Congo HF	3-12	20-100%	15-30 %
Hemorrhagic fever with renal syndrome HPS	9-35 7-30	4-80% >80%	5-15% 40-50%
Ebola and Marburg	3-16	>75%	25-90 %
Yellow Fever	3-6	80-95%	20 %
Dengue HF	3-15	0.007-1%	1%-20%
Kyasanur Forest HF Omsk HF	3-8	variable	0.5-10 %

Disease	Acute Serum Ag+ ELISA	Acute Serum RT-PCR	Acute Serum Virus Isolation
Lassa fever	Usually positive, if negative, IgM is usually +.	Has been used.	Usually + if still ill.
South American HF	Usually +.	Has been used.	Usually +.
Rift Valley Fever	In severe cases +.	Has been used.	Isolated in first few days.
Crimean-Congo HF	In severe cases +.	Useful.	Usually + if ill.
HFRS	Negative. IgM is test of choice.	May be +.	Difficult to isolate.
HPS	Negative. IgM is test of choice.	Usually + in first few days.	Difficult to isolate.
Marburg HF	Experimental.	+	Readily isolated.
Ebola HF	Usually +. IgM may be present later.	+	Usually readily isolated.
Yellow fever	Variable. IgM is test of choice.	Experimental.	Readily isolated in first 4 days.
Dengue HF	Variable. IgM is test of choice.	+	Usually readily isolated.
Kyasanur Omsk HF	No experience.	No experience.	Usually isolated in the acute hemorrhagic phase.