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Copyright 2004 Tara K. Harper.  All rights reserved.

TKH Virology Notes:
Yellow Fever

•  Description      •  Mechanism      •  Outbreaks
•  Location      •  Incubation Period      •  Vaccine
•  Vector      •  Symptoms      •  Odds 'n' Ends
     •  Diagnosis      •  Links
     •  Mortality Rates
     •  Treatment

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Science and Technical  References for Writers

NOTE:  This file is for information only.  It is not intended for diagnosis.

Yellow Fever

Description.   An acute, infectious, hemorrhagic viral disease.  It is characterized by sudden onset of fever, bradycardia, and headache;  with jaundice and hemorrhaging occuring in severe cases.  

Yellow-fever, a flavivirus and member of the Arbovirus family, is an enveloped virus.  It contains three structural proteins; the envelope (E) protein is the major component of the virion surface.   The antigenic elements of this envelope protein inhibit red blood cell clotting, while other elements recognize and bind to host-cell receptors.  

The yellow fever isolates appear to be genetically stable.  Genetic drift occurs within each genotype; the envelope gene appears to mutate randomly at a rate of 2.2 bases per year,  

Yellow fever is often called a classic hemorrhagic fever whose history is the history of the New World.  Epidemics of yellow fever followed the trade ships from Africa to the Americas, and centuries of disease resulted.  It is thought that the virus was brought to the New World via water casks and water barrels in which infected mosquitoes had laid their eggs. 

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     •  West and Central Africa in the moist savanna zones, occasionally in urban African areas, and more uncommonly in jungle regions.
     •  South and Central American - the occasional outbreaks occur almost exclusively among wood cutters and agricultural workers in sylvan settings.

There are no reported cases of yellow fever in Asia.  It is suspected that the high incidence of dengue fever helps confer protection against yellow fever, and that the Asian mosquito strains are not as competent as vectors of the disease.

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Vector.   Aedes mosquitoes, including A. aegypti, A. africanus, A. simpsoni, A. furcifer, A. luteocephalus, and A. albopictus (Asian tiger mosquito).  Urban yellow fever is transmitted by the Aedes aegypti mosquito.   A. aegypti becomes infectious 2 weeks after feeding on a viremic host.  Jungle, or sylvatic, yellow fever is transmitted by Haemagogus and other mosquitoes (such as Masoni africana) of the forest canopy (tree-hole breeding mosquitoes).  These mosquitoes acquire the virus from viremic primates.  The yellow-fever virus can also be passed from one mosquito generation to another via the mosquito eggs.

Yellow fever virus has been isolated from other insect vectors, such as:  phlebotomine flies, horse mosquitoes (Brazil), common ticks (Amblyomma variegatum) in West Africa, and other parasitic arthropods.

A secondary vector is nosocomial transmission in laboratories and hospitals.

The natural yellow-fever cycle is mosquito-monkey-mosquito.  The virus is taken up by the mosquito which feeds on viremic monkeys.  When the mosquito bites another host, the virus is transferred to the new host via the mosquito's saliva.  The shift from jungle yellow fever to urban yellow fever is thought to be the result of humans entering the sylvan setting and becoming part of the yellow-fever cycle:  Initially, wood cutters and other forest workers were bitten by forest-canopy mosquitoes carrying the yellow-fever virus.  The humans then returned to the urban settings.  The A. aegypti mosquito, which breeds in standing water such as water barrels, shallow basins, and so on; lived in the urban setting and fed on viremic humans in towns and villages.  A. aegypti then became a vector for the transmission of yellow fever within urban populations.  However, Haemagogus mosquitoes have also been discovered biting humans inside dwellings near forests.

Because of mosquito breeding cycles, yellow fever occurs most often during months with high rainfall, humidity, and temperature.  In Africa, the incidence of disease is greatest at the end of the rainy season and early into the dry season.

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Mechanism.  Not yet available.

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Incubation Period:  Usually 3-6 days.  There are usually no prodromal or premontive symptoms during incubation of the disease.

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Symptoms.   Sudden onset of fever, slow pulse, and headache.  Severe cases progress to intense albuminuria (excessive amounts of the protein albumin in the urine), jaundice, and hemorrhage--in particular, hematemesis, or a "black" vomit of blood.

After the incubation period, there are three main stages to yellow fever:
1. Invasion or Infection.   This stage lasts 2 to 5 days, and is characterized by sudden onset of a fever of 102 to 104 F.  The patient's pulse is initially rapid, but by the second day, becomes slow (Faget's sign).  This syndrome lasts approximately 3 days.  At this time, the virus if present in the patient's blood.  Other symptoms include:  flushed face, injected eyes, nausea, vomiting, constipation, epigastric distress, headache, muscle pains (especially in the neck, back, and legs), severe prostration, restlessness, and irritability.  Mild cases of yellow fever usually end at this stage after 1 to 3 days of symptoms.   .
2. Remission.   For moderate to severe cases, the fever falls abruptly (by crisis) 2 to 5 days after onset.  This remission lasts from several hours to several days.  .
 . 3. Intoxication.   This stage, in which the fever and bradycardia recurs, lasts from 3 to 9 days.  It is characterized by the three distinct symptoms of yellow fever:  jaundice, extreme albuminuria (90% of cases), and hematemesis--the vomiting of blood.  Other symptoms include mucosal hemorrhages, petechiae and/or ecchymoses, renal dysfunction and scanty or absent urination, dehydration, apathy, confusion, and dullness.  The patient may pass dark, tarry stools (melena) or bleed abnormally from the uterus.  During this phase, viremia is usually absent, and viral antibodies appear.  In terminal cases, the disease progresses to delirium, convusions, coma, and finally death.  Terminal signs include:  hypothermia, agitated delirium, intractable hiccups, hypoglycemia, stupor, and coma.  .  .

Convalescence is usually of short duration, except in the most severe cases.  There is no known sequelae.  However, there is evidence that yellow fever can cause, in some cases, persistent neuronal infection.

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Diagnosis.   Mild cases of yellow fever are nonspecific enough that they cannot be distinguished from a variety of other conditions.  Severe cases can still be confused with other diseases which cause jaundice, such as:  viral hepatitis, falciparum malaria, Rift Valley fever, typhoid, Q fever, typhus, adn so on.  Specific diagnosis can be confirmed by isolating the virus or demonstrating the viral antigen or a specific antibody response.  The virus is best isolated from serum taken during the first 4 days of illness.  However, the virus can still be detected from serum obtained up to 14 days after onset of symptoms.

Diagnostic tests for yellow fever include:
     •  HI, CF, and neutralization tests for antibodies.  The HI and neutralization antibodies appear with 7 days of onset of symptoms; the CF antibodies appear later in the course of the disease.
     •  Indicrect immunofluorescence
     •  ELISA, which is sensitive enough that it may be able to detect antigen even in poorly handled or contaminated samples.
     •  PCR, which can detect the viral genome in serum

In the intoxication stage, diagnosis is confirmed by isolating the virus from the blood or by detection of rising antibody titer.  An autopsy will show midzonal liver cell necrosis.   In addition, lab results can indicate:
     •  Extreme albuminuria by the 3rd day.  In extreme cases, the albumin level can reach 20 gm/L.
     •  Low white blood count, which usually drops to 1500 to 2500 by the 5th day.
     •  Decreased synthesis of vitaim K-dependent coagulation factors.
     •  Disseminated intravascular coagulation (DIC).
     •  Altered platelet function.
     •  Thrombocytopenia.
     •  Prolonged clotting times and prothrombin times.
     •  Slightly elevated bilirubin and serum transaminase levels.

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Mortality Rates.  Approximately 10% of clinical cases.  However, the actual mortality rate may be lower because of undiagnosed mild or inapparent infections.  During epidemics, case fatality rates have reached as high as 50%.

Previous exposure to or infection with dengue appears to confer some protection against yellow fever.

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Treatment.   Supportive.  Treatment consists of complete bed rest--including sedatives if necessary;  a high-protein, high-carbohydrates liquid diet;  analgesics for headache;  and antipyretics and tepid sponge baths to reduce fever.  Fluids must be carefully monitored for adequate blood volume; transfusions may be required.  In severe cases, patients may receive calcium gluconate to help counteract hemorrhaging.  

Ribavirin trials with infected monkeys were unsuccessful.  In other monkey trials, gamma-interferon delayed onset of viremia and symptoms, but did not affect survival rates.

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Outbreaks and History of Infection.   Yellow fever epidemics occurred in almost every major port on the East Coast of the U.S. for three and a half centuries, as a result of ship trade between epidemic areas and the Americas.  Cities as far north as New York, Philadelphia, and Boston were hit with epidemics.  In one epidemic in 1793 in Philadelphia, uncounted people were infected, half the population of the city fled the epidemic, and over 4,500 died.  Yellow fever epidemics also broke out in the 1700s in Italy, France, Spain, and England.  

There are between 50 and 300 cases of yellow fever reported annually in the Americas.  Up to 5,000 cases are reported annually in Africa.  However, epidemics are increasing in both size and frequency, and the actual number of cases in Africa can be as high as hundreds of thousands in a single year.

Some notable outbreaks:
   - 1648, Yucatan (Mexico), and Havana, Cuba, first epidemics in the Americas
   - 1905, port cities, southern U.S.:  5,000 infected; with 1,000 dead.
   - 1949, Panama, epidemic which spread north through Costa Rica, Guatemala, and Mexico.
   - 1950's, equatorial Africa:  five separate epidemics.
   - 1959, Zaire, epidemic
   - 1960-1962, Ethiopia:  100,000 infected, with over 30,000 dead.
   - 1986 to present, Nigeria:  the virus was introduced from a sylvan source and continues to be spread by mosquitoes and viremic travelers.  Case fatality rates are over 50%, and there is a population of 20 million at risk in the endemic area.  A single outbreak from April to July, 1991, resulted in over 600 deaths.
   - 1992-1993, Kenya:  first epidemic in over 25 years.
   - 1990, Cameroon; spread of the virus from the Nigerian epidemic.  20,000 cases and 1,000 deaths.
   - 1993, Ghana

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Vaccine.   The 17D strain of live, attenuated yellow-fever vaccine, which confers immunity for approximately 10 years.  Adverse reactions are experienced by approximately 5% of vaccinees.  Side effects include:  mild headache, muscle pain, or other minor symptoms.  

In general, the vaccine should not be given to the following persons:
Infants under 6 months of age (never), because of the risk of developing viral encephalitis.  In most cases, infants should be 1 year of age before receiving the vaccine.  .
Pregnant women, because the fetus might become infected with yellow fever from the live-virus vaccine.  .
 . People who are hypersensitive to eggs.  (As with many other vaccines, the yellow-fever vaccine is prepared in embryonated eggs.)  .  .
People who are already immunocompromised as a consequence of AIDS, HIV, leukemia, lymphoma, radiation therapy, drugs, or other condition or treatment. .

Studies have shown that previous immunization from infection with Wesselsbron, Zika, and dengue viruses have resulted in less viremia in monkeys infected with yellow fever.

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Odds 'n' Ends.
Yellow fever was the first human microbial disease discovered to be caused by an agent which could be filtered and yet was smaller than any known bacteria.  .  .
 . Many institutes around the world produce yellow-fever vaccines that are contaminated with avian leukosis virus.  However, the avian leukosis viris has not yet been associated with human leukemia, lymphoma, or other cancer.  .  .  .

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     •  Fact Sheet:  CDC general information

Copyright 2004 Tara K. Harper

All rights reserved.  It is illegal to reproduce or transmit in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, any part of this copyrighted file without permission in writing from Tara K. Harper.  Permission to download this file for personal use only is hereby granted by Tara K. Harper.

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