Yellow Fever

Description

Yellow fever is a mosquito-borne viral disease. Illness ranges in severity from an influenza-like syndrome to severe hepatitis and hemorrhagic fever. Yellow fever is caused by a zoonotic virus that is maintained in nature by transmission between nonhuman primates and mosquito vectors. In some situations, humans may serve as the primary host in the transmission cycle (“urban yellow fever”).

Occurrence

The disease occurs only in sub-Saharan Africa and tropical South America (see Maps 3–9 and 3–10), where it is endemic and intermittently epidemic. In Africa, a variety of vectors are responsible for the disease, and it is in Africa where most cases are reported. The case-fatality rate is >20%, and infants and children are at greatest risk for infection. In South America, cases occur most frequently in young men who have occupational exposure to mosquito vectors in forested or transitional areas of Bolivia, Brazil, Colombia, Ecuador, Venezuela, and Peru.

Risk for Travelers

The risk of a traveler's acquiring yellow fever is determined by immunization status, geographic location, season, duration of exposure, occupational and recreational activities while traveling, and the rate of yellow fever virus transmission at the time. Although reported cases of human disease are the principal guide to the level of transmission, they may be absent (because of a high level of immunity in the population) or not detected as a result of poor surveillance. Only a small proportion of yellow fever cases are officially notified, because of the occurrence of the disease in remote areas and lack of specific diagnostic facilities. Indeed, the majority of cases during outbreaks in Africa are missed despite an extraordinarily high incidence of infection and disease.

During interepidemic periods, the incidence of overt disease is below the threshold of detection by existing surveillance. Such interepidemic conditions may last years or even decades in certain countries or regions. This “epidemiologic silence” may provide a sense of false security and lead to travel without the benefit of vaccination. Surveys in rural West Africa during “silent” periods indicate that the incidence of yellow fever illness is 1.1–2.4 cases per 1,000 persons and that the incidence of death due to yellow fever is 0.2–0.5 deaths per 1,000 persons; both these ranges are less than the threshold of detection of the existing means of surveillance.

The incidence of yellow fever in South America is lower than that in Africa because virus transmission between monkeys and mosquitoes occurs in the canopy of the forest, isolated from human contact, and because immunity in the indigenous human population is high. The risks of illness and death are probably 10 times lower in South America than they are in rural West Africa, but the risks vary greatly according to specific location and season. In West Africa, the most dangerous time of year is during the late rainy and early dry seasons (July–October). Virus transmission is highest during the rainy season (January–March) in Brazil.

The low incidence of yellow fever, generally a few hundred cases per year, has led to complacency among travelers. In Brazil, for example, where the majority of the population lives in coastal regions outside the endemic zone, unvaccinated recreational or vocational travelers to the interior are the usual victims of yellow fever. Four of the five cases from the United States and Europe in 1996–2002 were among travelers who were exposed in South America. All five cases were fatal. Although not as dramatic as the situation in Africa, the 1990s represented a period of increased enzootic and epizootic yellow fever transmission in South America. Brazil and Peru are currently experiencing an expansion of yellow fever virus activity, and the risk to travelers is higher than usual.

The risks of illness and of death due to yellow fever in an unvaccinated traveler are estimated to be 1:1,000 and 1:5,000 per month, respectively. (For a 2-week journey, the risks of illness and death are 1:2,000 and 1:10,000, respectively.) These estimates, which are based on risk to indigenous populations, may overestimate the risk to travelers, who may have a different immunity profile, take precautions against getting bitten by mosquitoes, and have less outdoor exposure than do indigenous residents. Based on data for U.S. travelers, the risk for illness in a traveler due to yellow fever has been estimated to be 0.4–4.3 cases per million travelers to yellow fever-endemic areas.

Map 3–9. Yellow fever-endemic zones in Africa, 2003 View enlarged map

Map 3-10. Yellow fever-endemic zones in the Americas, 2003 View enlarged map

Prevention

Personal Protection Measures

In addition to vaccination, travelers should be advised to take precautions against exposure to mosquitoes when traveling in areas with yellow fever transmission. Staying in air-conditioned or well-screened quarters and wearing long-sleeved shirts and long pants will help to prevent mosquito bites. Insect repellents containing DEET should be used on exposed skin only. Permethrin-containing repellents should be applied to clothing. Travelers to rural areas should bring mosquito nets and aerosol insecticides or mosquito coils. (For further prevention information, see Protection against Mosquitoes and Other Arthropod Vectors.)

Vaccine

Yellow fever is preventable by a relatively safe, effective vaccine (see Table 3–20 for dosage information). International regulations require proof of vaccination for travel to and from certain countries. For purposes of international travel, vaccines produced by different manufacturers worldwide must be approved by the World Health Organization and administered at an approved yellow fever vaccination center. State and territorial health departments have authority to designate nonfederal vaccination centers; these can be identified by contacting state or local health departments. Vaccinees should receive a completed International Certificate of Vaccination, signed and validated with the center's stamp where the vaccine was given. This certificate is valid 10 days after vaccination and for a subsequent period of 10 years.

A number of countries require a certificate from travelers arriving from infected areas or from countries with infected areas. Some countries in Africa require evidence of vaccination from all entering travelers; others may waive the requirements for travelers coming from noninfected areas and staying in the country <2 weeks. (Yellow Fever Vaccine Requirements and Information on Malaria Risk and Prophylaxis, by Country) Vaccination is also recommended for travel to countries that do not officially report the disease but lie in the yellow fever-endemic zone (see Maps 3–9 and 3–10). The actual areas of yellow fever virus activity can extend beyond the officially reported infected zones.

Some countries require a traveler, even if only in transit, to have a valid international certificate of vaccination if he or she has visited any country either known or thought to have yellow fever virus. Such requirements may be strictly enforced, particularly for persons traveling from Africa or South America to Asia. Travelers with a specific contraindication to yellow fever vaccine should be advised to obtain a waiver before traveling to countries requiring vaccination. (See “Vaccination Certificate Requirements.”)

Adverse Reactions

General Events. Reactions to yellow fever vaccine are generally mild. After vaccination, vaccinees have reported mild headaches, myalgia, low-grade fevers, or other minor symptoms 5–10 days after vaccination. In clinical trials, the incidence of mild adverse events has been ~25%. Approximately 1% of vaccinees find it necessary to curtail regular activities. Immediate hypersensitivity reactions, characterized by rash, urticaria, or asthma or a combination of these, are uncommon (incidence <1 case per 131,000 vaccinees) and occur principally in persons with histories of egg allergy.

Yellow Fever Vaccine-Associated Neurotropic Disease. Historically, yellow fever vaccine-associated neurotropic disease was seen primarily among infants. Recently, nine cases of encephalitis have been reported among adult recipients of yellow fever vaccine with onset of illness 4–23 days after vaccination. All cases were in first-time vaccine recipients. The risk for vaccine-associated neurotropic disease does not appear to be limited to infants, and crude estimates in the United States of the reported frequency range from 4 to 6 cases per 1,000,000 doses distributed.

Yellow Fever Vaccine-Associated Viscerotropic Disease. A new serious adverse reaction syndrome has recently been described among recipients of yellow fever vaccines. This syndrome was previously reported as febrile multiple organ system failure and is now called yellow fever vaccine-associated viscerotropic disease. In July 2001, the first seven case reports of this syndrome were published. These cases occurred during 1996–2001 and the reports described patients with severe multiple organ system failure. All seven persons required intensive care after experiencing fever, hypotension, respiratory failure, elevated hepatocellular enzymes, hyperbilirubinemia, lymphocytopenia, and thrombocytopenia; six of the seven also had renal failure, which required hemodialysis. Six of the seven died. Subsequently, retrospective and prospective case finding has identified seven additional cases. These additional cases demonstrate that this serious adverse reaction probably occurs as a clinical spectrum of disease severity, from moderate illness with focal organ dysfunction to severe disease with overt multiple organ system failure and death. All cases reported thus far have occurred in primary vaccinees. Yellow fever vaccines must be considered as a possible, but rare, cause of yellow fever vaccine-associated viscerotropic disease that is similar to fulminant yellow fever caused by wild-type yellow fever virus. Accurately measuring the incidence of vaccine-associated viscerotropic disease is currently precluded by lack of adequate prospective data; however, crude estimates in the United States of the reported frequency range from 3 to 5 cases per 1,000,000 doses distributed. This frequency may be higher for persons >60 years of age.

Because of recent reports of deaths from yellow fever among unvaccinated travelers to areas endemic for yellow fever and of these reports of vaccine-associated viscerotropic disease, yellow fever vaccination of travelers to high-risk areas should be encouraged as a key prevention strategy, however, physicians should be careful to administer yellow fever vaccine only to persons truly at risk for exposure to yellow fever. Additional surveillance to better monitor and quantify yellow fever vaccine-specific adverse outcomes should be established. Studies are being conducted to clarify the cause and risk factors for these rare adverse events associated with the yellow fever vaccines.

Precautions and Contraindications

Age. The risk for adverse reactions appears to be age related. Infants <6 months of age should not be vaccinated because they are more susceptible to the serious adverse reaction of yellow fever vaccine-associated neurotropic disease (also known as postvaccinal encephalitis) than are older children. Immunization should be delayed until an infant is at least 9 months of age. (See “Vaccine Recommendations for Infants and Children,” “Yellow Fever Vaccine,”, for a discussion of yellow fever immunization for infants and children.) In unusual circumstances, physicians considering vaccinating infants aged < 9 months should contact the Division of Vector-Borne Infectious Diseases (970-221-6400) or the Division of Global Migration and Quarantine (404-498-1600) at CDC for advice.

A recent analysis of adverse events passively reported to the Vaccine Adverse Event Reporting System (VAERS) during 1990–2002 indicates that persons >60 years of age may be at increased risk for systemic adverse events following vaccination compared with younger persons. Retrospective and prospective case finding has resulted in the identification of a total of eight cases of this adverse event in the United States. Travelers aged >60 years should discuss with their physicians the risks and benefits of vaccination in the context of their destination-specific risk for exposure to yellow fever virus.

Pregnancy. The safety of yellow fever vaccination during pregnancy has not been established, and the vaccine should be administered only if travel to an endemic area is unavoidable and if an increased risk for exposure exists. If international travel requirements, rather than an increased risk for infection, are the only reason to vaccinate a pregnant woman, efforts should be made to obtain a waiver letter from the traveler's physician. Pregnant women who must travel to areas where the risk for yellow fever infection is high should be vaccinated and, despite the apparent safety of this vaccine, infants born to these women should be monitored closely for evidence of congenital infection and other possible adverse effects resulting from yellow fever vaccination. If vaccination of a pregnant woman is deemed necessary, serologic testing to document an immune response to the vaccine can be considered, because the seroconversion rate for pregnant women in a developing nation has been reported to be substantially lower than that observed for other healthy adults and children. To discuss the need for serologic testing, the appropriate state health department or CDC's Division of Vector-Borne Infectious Diseases at 970-221-6400 or Division of Global Migration and Quarantine at 404-498-1600 should be contacted for more information.

Lactation. Whether this vaccine is excreted in breast milk is not known. There have been no reports of adverse events or transmission of the vaccine viruses from nursing mother to infant. As a precautionary measure, vaccination of nursing mothers should be avoided, because of the theoretical risk of the transmission of virus to the breast-fed infant. When travel of nursing mothers to high-risk yellow fever endemic areas cannot be avoided or postponed, such women may be vaccinated.

Immunosuppression. Infection with yellow fever virus poses a theoretical risk for travelers with immunosuppression in association with AIDS or other manifestations of HIV infection; leukemia, lymphoma, or generalized malignancy; or with the administration of corticosteroids, alkylating drugs, antimetabolites, or radiation. Such patients should not be vaccinated. If travel to a yellow fever-infected zone is necessary, patients should be advised of the risks posed by such travel, instructed in methods for avoiding vector mosquitoes, and supplied with vaccination waiver letters by their physicians. Low-dose (i.e., 20-mg prednisone or equivalent/day), short-term (i.e., <2 weeks) systemic corticosteroid therapy or intra-articular, bursal, or tendon injections with corticosteroids should not be sufficiently immunosuppressive to constitute an increased hazard to recipients of yellow fever vaccine.

Persons who are HIV-infected but do not have AIDS or other symptomatic manifestations of HIV infection, who have established laboratory verification of adequate immune system function, and who cannot avoid potential exposure to yellow fever virus should be offered the choice of vaccination. If international travel requirements are the only reason to vaccinate an asymptomatic HIV-infected person, rather than an increased risk for infection, efforts should be made to obtain a waiver letter from the traveler's physician. Asymptomatic HIV-infected persons who must travel to areas where the risk for yellow fever infection is high should be offered the choice of vaccination and monitored closely for possible adverse effects.

Data regarding seroconversion rates after yellow fever vaccination among asymptomatic HIV-infected persons are limited, but they do indicate that the seroconversion rate among such persons is reduced. Because vaccination of asymptomatic HIV-infected persons might be less effective than that of persons not infected with HIV, measurement of the neutralizing antibody response to vaccination should be considered before travel. Physicians should consult the applicable state health department or CDC's Division of Vector-Borne Infectious Diseases at 970-221-6400 or Division of Global Migration and Quarantine at 404-498-1600, for more information.

Family members of immunosuppressed or HIV-infected persons who themselves have no contraindications can receive yellow fever vaccine.

Hypersensitivity. Live yellow fever vaccine is produced in chick embryos and should not be given to persons hypersensitive to eggs. Generally, persons who are able to eat eggs or egg products may receive the vaccine. If vaccination of a person with a questionable history of egg hypersensitivity is considered essential because of high risk for exposure, an intradermal test dose may be administered under close medical supervision. Specific directions for skin testing are found in the package insert. In some instances, small test doses for vaccine administered intradermally have led to an antibody response. Gelatin is used as a stabilizer in different vaccines, including yellow fever vaccine. Gelatin has been implicated as a cause of allergic reaction related to other vaccines and, therefore, may do the same regarding yellow fever vaccine. If international travel regulations are the only reason to vaccinate a traveler hypersensitive to eggs or gelatin, efforts should be made to obtain a waiver.

Simultaneous Administration of Other Vaccines and Drugs. Studies have shown that the seroimmune response to yellow fever vaccine is not inhibited by administration of certain other vaccines concurrently or at various intervals of a few days to one month. Measles and Bacille Calmette-Guerin (BCG) have been administered in combination with yellow fever vaccines without interference. Additionally, the severity of reactions to vaccination has not been amplified by concurrent administration of yellow fever and measles vaccines. Hepatitis A, hepatitis B, Vi capsular polysaccharide typhoid, meningococcal, inactivated poliovirus, and yellow fever vaccines may be given concurrently. If live virus vaccines are not given concurrently, 4 weeks should be allowed to elapse between sequential vaccinations.

There are no data on possible interference between yellow fever vaccine and rabies or Japanese encephalitis vaccines.

A prospective study of persons given yellow fever vaccine along with 5 mL of commercially available immune globulin showed no alteration of the immunologic response to yellow fever vaccine when compared with controls. Although chloroquine inhibits replication of yellow fever virus in vitro, it does not adversely affect antibody responses to yellow fever vaccine in persons receiving the drug as antimalarial prophylaxis.

Waiver Letters from Physicians

A physician's letter clearly stating the contraindications to vaccination is acceptable to some governments. Ideally, it should be written on letterhead stationery and bear the stamp used by health department and official immunization centers to validate the international certificate of vaccination. Under these conditions, it is also useful for the traveler to obtain specific and authoritative advice from the embassy or consulate of the country or countries he or she plans to visit. Waivers of requirements obtained from embassies or consulates should be documented by appropriate letters and retained for presentation with the International Certificate of Vaccination.

— Rachel Barwick, Martin Cetron, Anthony Marfin, Thomas Monath