Yellow Fever

• Yellow fever is a viral hemorrhagic infection transmitted by mosquitoes of the Aedes genus.
• Yellow fever has and continues to affect the equatorial tropics and is believed to have been imported to the Americas with the West African slave trade. As early as the 1600s, the Mayans recorded a yellow fever epidemic in the Yucatan and Guadalupe. Throughout the next 200 years, yellow fever epidemics plagued the tropics and coasts of the Americas and Caribbean. The first major yellow fever epidemic struck the U.S. in Philadelphia in July 1793. At the time, Philadelphia was home to over 2,000 free blacks, and white refugees where fleeing from Santo Domingo colony in the Caribbean after a slave uprising. By the end of the epidemic in the winter, of a population of 45,000, 5,000 had died and 17,000 left the city.
• Benjamin Rush, one of the original signers of the Declaration of Independence, gained renown as a physician who tirelessly offered heroic treatments, including mercury and bloodletting, during the epidemic. At the time, yellow fever was not well understood to be a an infectious disease spread by mosquitoes, and one of his efforts to enlist blacks to care for the sick failed, because he mistakenly believed them to be immune.
• In contradiction to the then prevalent view of disease spreading by "bad air" or rotting materials, American physician Josiah Clark Nott in 1848 and Cuban physician Carlos Finlay in 1881 proposed that a vector was spreading yellow fever. Dr. Finlay is remembered for his pioneering work to identify the Aedes mosquito as the vector of yellow fever, and he first proposed mosquito control to control the spread of yellow fever.
• Yellow fever hindered American efforts during the 1898 Spanish American War, killing more infantry than the fighting, and completion of the Panama Canal was nearly halted as 10% of workers died. The U.S. Army established the Yellow Fever Commission in Cuba to study the problem, and Army physician Major General Walter Reed, experienced in the study of tropical diseases, was appointed head. Crediting and building on Finlay's work, his experiments proved that yellow fever was spread by the bite of the Aedes mosquito. From this point, mosquito-control measures permitted completion of the Panama Canal in 1903.
• Up to 50% of severely affected people will die from yellow fever without treatment.
• Yellow fever cases are rising since the 1990s because of multiple factors, including declining population antibodies, urbanization and human encroachment into wilderness, and expanding mosquito habitats due to global warming and climate change.
• One of the hallmarks that gives yellow fever its name is jaundice, or yellowing of the skin and sclerae in more severe disease. Eighty-five percent of cases of yellow fever present as a flu-like illness, with fevers, chills, headache, backache, and nausea and vomiting. Serious illness arises in 15% of those infected within 24 hours after initial resolution. High fever, abdominal pain, nausea and vomiting, and jaundice occur, progressing to typical "hemorrhagic fever" with kidney failure and bloody stools, bleeding from orifices, and vomiting ("black vomit"). Half of victims with the hemorrhagic fever stage recover, and half die within 14 days.
• Treatment is directed at reducing the symptoms until the illness completes its course. There is no specific treatment for yellow fever. Because the illness may be very similar to malaria, hepatitis, leptospirosis, and other viral hemorrhagic fevers that may also exist in the geographic area, it can only be definitively diagnosed by specialized antibody testing or postmortem. Yellow fever vaccine is a major prevention tool, and one dose provides lifelong protection against yellow fever for people who live in endemic areas. Some travelers have contraindications to yellow fever vaccine that outweigh the benefit of the vaccine. In addition, some countries require proof of yellow fever vaccination in travelers arriving from endemic areas, even if only stopping to connect to another flight.

Yellow fever virus in an arbovirus in the genus Flavivirus. Arbo derives from the Latin word for "tree" and indicates the tropical forest habitat that favors yellow fever and its vector. Several mosquitoes, including Aedes and Haemogogus, may transmit yellow fever and other tropical infections depending on the habitat. Yellow fever survives and spreads via three cycles: sylvatic (forest or jungle), urban, or intermediate (somewhere in between).

Sylvatic yellow fever cycles among primate hosts bitten by mosquitoes; only occasionally is a human an accidental host when entering the jungle, such as with logging operations. Urban yellow fever is transmitted by Aedes mosquitoes in areas of dense population, and epidemics occur when population immunity wanes. Intermediate yellow fever is the commonest pattern of transmission in Africa, where mosquitoes that breed in both primate and human habitats can transmit infection within and among villages. In all cases, the lower the population immunity, the more extensive the outbreaks and the more severe the illness.

Yellow fever is not contagious or transmitted directly from person to person, however, since it is difficult to distinguish yellow fever from contagious illnesses that may circulate in endemic areas (for example, other viral hemorrhagic fevers such as Ebola), early precautions are wise depending on the availability of isolation garb and facilities. In U.S. health-care facilities, Contact and Droplet Precautions would apply to any patient with suspected viral hemorrhagic fever, based on U.S. Centers for Disease Control and Prevention (CDC) guidance.

The incubation period between infection with yellow fever by a mosquito bite and initial symptoms may range from three to six days, followed by one or two stages of illness.

Initial symptoms of yellow fever may be indistinguishable from those of malaria, dengue fever, or other viral hemorrhagic fevers. Sudden high fever and chills occur, with prominent backache and headache, appetite loss, and nausea or vomiting. Occasionally, Faget's sign may be observed as bradycardia (slowed heartbeat) in relation to the elevated body temperature.

After three or four days, viremia (presence of virus in the bloodstream) resolves. Fifteen percent of individuals will develop a second, more severe, stage of illness within the next two to 48 hours, with high fever, abdominal pain, nausea and vomiting, and development of jaundice. The symptoms of this stage may overlap with the signs and symptoms of leptospirosis or viral hepatitis if presenting at this point for medical care. Spontaneous bruises and hemorrhage due to abnormal blood coagulation may occur from the eyes, nose, mouth, needle puncture sites, as well as upper and lower gastrointestinal tract with blood in vomit and stool. Abnormal blood levels of liver enzymes, as well as kidney failure, may occur.

Aside from being a resident of an endemic area, risk factors include a recent history of travel to an area in which yellow fever is common or endemic, and lack of vaccination against yellow fever. It is not so likely that a nonresident will travel to an endemic area without yellow fever vaccination; several countries along the usual routes between endemic areas will not admit travelers who do not have a yellow fever vaccination card, even if only to change planes at the airport.

If you have traveled to a tropical area and develop a high fever and muscle aches, you should seek urgent medical evaluation at a hospital's emergency department. Some facilities may lack diagnostic testing for travelers' illnesses, and once stabilized, you may need to be transferred to a higher level facility where these tests can be promptly performed and infectious disease subspecialists can advise on care. The most critical concern will be the prompt diagnosis and treatment of malaria, hepatitis, or other viral hemorrhagic fevers.

Certain individuals are at high risk for complications from both yellow fever and yellow fever vaccine, especially those who are immunosuppressed due to HIV infection or due to immunosuppressant medications. These individuals must weigh the fact that they cannot receive yellow fever vaccine with the necessity of traveling to an endemic area at all. If the need to travel outweighs the risk, these individuals may be permitted to travel with documentation of medical exemption by a health-care professional. This is further detailed under the section on Yellow Fever Prevention and Vaccine.

Many diseases cause fever in the tropical and subtropical world, including malaria, typhoid, dengue, leptospirosis, and others. Most of these require different management, some more urgent than others, and an ill individual may have more than one infection. Thus, it is very important to make a specific diagnosis, but early in care, diagnoses are often presumptive and based on travel and exposure history.

Yellow fever is diagnosed by laboratory tests, including IgM-capture ELISA, MIA (microsphere-based immunoassay) and IgG ELISA, performed on blood sampled during acute illness. Tissues may be tested postmortem with transcription-polymerase chain (PCR) reaction testing (which detects viral RNA), immunohistochemical stains, and viral culture. These tests are highly specialized and not available in the U.S., except in some state laboratories and the CDC Arbovirus Diagnostic Laboratory. Usually, results may be obtained from the CDC within two weeks. The CDC Yellow Fever Diagnostic Testing page contains links to instructions for submission of specimens. Health-care professionals should contact their local public-health department for assistance with these arrangements and evaluations.

Even though there is no specific treatment for yellow fever, supportive care at home is not advised where resources permit access to health care. Any nonresident traveler to areas endemic for yellow fever is also at risk for other life-threatening conditions and should seek urgent evaluation at an emergency department if fever develops. Aside from yellow fever, malaria may manifest even up to one year later, regardless of preventive treatment. There are no effective home remedies for yellow fever, and individuals must seek urgent medical care and follow all medical instructions carefully.

Yellow fever treatment is directed at support of vital functions such as blood pressure and heartbeat and medications for pain and fever control in the first stage of illness. If progression to the second stage occurs, supportive medical management at a tertiary care facility may be necessary. Clinicians can telephone the CDC for advice on diagnosis and treatment of the disease (http://www.cdc.gov).

Yellow fever is a potentially fatal illness. People planning to travel to an area endemic for yellow fever should see their physician before travel, preferably at least six weeks before departure; preventive measures for other serious illnesses are also very important. Travelers should use mosquito-bite precautions, including wearing light, protective clothing and using window screens and bed nets when available. Insect repellants should be used and should contain DEET, picaridin, IR3535, or oil of lemon eucalyptus. Room sprays and insecticides may be used to reduce the mosquito population in sleeping areas.

Yellow fever vaccine is given at least 10 days prior to departure, is highly effective, and generally provides 10 years of immunity, after which a booster should be given in the setting of recurrent or ongoing exposure. Areas of risk may be found in the CDC Yellow Book chapter 3, under Viral Hemorrhagic Diseases (Figure 1 and Figure 2).

Yellow fever vaccine is recommended for all individuals over 9 months of age who reside or will be traveling in endemic areas of Latin America and Africa, as well as for entry into certain countries. Contraindications include age under 6 months, severe allergy to any of the vaccine components, or history of severe reaction to a dose of yellow fever vaccine.

Generally, yellow fever vaccine is well tolerated with only mild flu-like symptoms as a side effect. However, because yellow fever vaccine is a live attenuated virus vaccine, there is potential for infection from the vaccine itself in some populations. Conditions where risk versus benefit of the vaccine should be carefully weighed include people with HIV or other immunocompromised states such as thymus disorders, malignancy, transplantation, or treatment with corticosteroids, chemotherapy, and other immunosuppressants. Others include pregnancy, breastfeeding, age over 59, and age 6-8 months. Note that yellow fever vaccine virus is not shed by the recipient and poses no threat to others.

Adults 60 or over may be at increased risk of serious disease or death after yellow fever vaccine, especially with a first yellow fever vaccination. These individuals must discuss risks, itineraries, and other preventive measures above with their health-care professional.

In women of childbearing age, vaccination during pregnancy is unlikely to be a risk to the fetus but poses a theoretical risk of infection to the mother the closer she is to the third trimester, when her immunity is lowest. While birth defects have not been observed, out of caution most experts suggest a minimum two-week period of avoiding conception before receiving the yellow fever vaccination.

Yellow fever vaccine is given at least 10 days prior to departure and generally provides 10 years of immunity, after which a booster should be given in the setting of recurrent or ongoing exposure. In the U.S., yellow fever vaccine is given only in designated yellow fever vaccination centers. Travelers receive a yellow International Certificate of Vaccination card validated by the vaccination center and valid for 10 years. This card is required for entry to certain countries, even if only to change planes at the airport.

Eighty-five percent of individuals recover fully from the first stage of illness, with no further consequences, and have lifelong immunity to yellow fever. Of the 15% who will progress to severe disease, half will also recover fully with lifelong immunity. Half of these will die within 10-14 days of onset of initial symptoms and signs.

Long-term effects are uncommon, even in those who recover from severe disease. Delays in diagnosis may occur if the disease is rarely seen and is therefore not initially considered by the treating physician. Delays increase the risk of serious complications or death due to inadequate support or because of unrecognized concurrent diseases, such as malaria.

The World Health Organization and U.S. Centers for Disease Control maintain extensive and updated yellow fever information for health-care professionals, as well as travelers, including specific guidance for travel precautions based on type of trip.

World Health Organization
http://www.who.int/topics/yellow_fever/en/

U.S. Centers for Disease Control
http://www.cdc.gov/yellowfever/