Yellow Fever

Description

Yellow fever is a viral disease that is transmitted to humans through the bite of infected mosquitoes. Illness ranges in severity from an influenza-like syndrome to severe hepatitis and hemorrhagic fever. The yellow fever virus is maintained in nature by mosquito-borne transmission between nonhuman primates. Transmission by mosquitoes from one human to another occurs during epidemics of "urban yellow fever."

Occurrence

The disease occurs only in sub-Saharan Africa and tropical South America, where it is endemic and intermittently epidemic. (See Table 4-22 for a list of countries that lie within the endemic zone, which is defined as those areas where there is active yellow fever transmission as well as those in which yellow fever may be more likely to occur because of the presence of the vector and infection in nonhuman primates.) In Africa, where most cases are reported, a variety of vectors are responsible for transmitting the virus. The case-fatality rate is >20%, and infants and children are at greatest risk for infection.

Risk for Travelers

A traveler's risk of acquiring yellow fever is determined by immunization status, location of travel, season, duration of exposure, occupational and recreational activities while traveling, and the local rate of yellow fever virus transmission at the time. Although reported cases of human disease are the principal indicator of disease risk, 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 reported because of the occurrence of the disease in remote areas and lack of specific diagnostic facilities.

¹These countries are not holo-endemic. Please see Map 4-13 and yellow fever vaccine recommendations for details.

During interepidemic periods, low-level transmission may not be detected by public health 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 have estimated an incidence of yellow fever of 1.1-2.4 cases per 1,000 persons and an incidence of death due to yellow fever of 0.2-0.5 deaths per 1,000 persons; both these ranges are less than the threshold of detection of the surveillance systems in place.

The incidence of yellow fever in South America is lower than that in Africa because the mosquitoes that transmit the virus between monkeys in the forest canopy do not often come in contact with humans and because immunity in the indigenous human population is high. Urban epidemic transmission has not occurred in South America for many years, although the risk of introduction of the virus into towns and cities is ever present. For travelers, the risks of illness and death due to yellow fever are probably 10 times greater in rural West Africa than in South America; these 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 risks of illness and of death due to yellow fever in an unvaccinated traveler in endemic areas in Africa are estimated to be 1:1,000 and 1:5,000 per month, respectively. (For a 2-week stay, the risks of illness and death are 1:2,000 and 1:10,000, respectively.) The risks of illness and death to travelers to South America are probably 10 times lower (1:20,000 and 1:100,000, respectively for a two week trip). These estimates are based on risk to indigenous populations and 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. 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.

Prevention

Personal Protection Measures

In addition to vaccination, travelers to areas with yellow fever transmission should be advised to take precautions against exposure to mosquitoes. 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. Permethrin-containing repellents should be applied to clothing. (For further prevention information, see Protection against Mosquitoes and Other Arthropods.)

Vaccine

Yellow fever is preventable by a relatively safe, effective vaccine. To meet international vaccination requirements, yellow fever vaccines must be manufactured under approval by the World Health Organization and administered at an approved yellow fever vaccination center. For all eligible persons, a single injection of 0.5 mL of reconstituted vaccine should be administered subcutaneously. Authorized U.S. vaccination centers can be identified by contacting state or local health departments or by visiting CDC's Travelers' Health website, where there is a listing of current authorized yellow fever vaccination providers in the United States. (http://www2.ncid.cdc.gov/travel/yellowfever/).

Adverse Reactions

General Events

Reactions to yellow fever vaccine are generally mild. Vaccine recipients have reported mild headaches, myalgia, low-grade fevers, or other minor symptoms that may begin within days after vaccination and last 5-10 days after vaccination. In clinical trials, the incidence of mild adverse events has been ∼25%, but many events may have been unrelated, as the trials were not placebo-controlled. 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). Unrecognized allergy to eggs or chicken or to the hydrolyzed gelatin used to stabilize the vaccine may be responsible for hypersensitivity reactions. Persons who have allergies to egg, chicken, or gelatin should be evaluated by an allergist to determine whether they can safely receive yellow fever vaccine.

Yellow Fever Vaccine-Associated Neurologic Disease

Historically, yellow fever vaccine-associated adverse events were seen primarily among infants, and presented as encephalitis. Since 1992, five cases of encephalitis among adult recipients of yellow fever vaccine have been reported to the U.S. Vaccine Adverse Event Reporting System (VAERS). In addition, ten cases of autoimmune neurologic disease have been reported to VAERS, including patients with Guillian-Barré syndrome and acute disseminated encephalomyelitis. All patients with yellow fever vaccine-associated neurologic disease (YEL-AND) had an onset of illness 4-23 days after vaccination. All cases were in first-time vaccine recipients. The risk for vaccine-associated neurologic 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 serious adverse reaction syndrome has recently been described among recipients of yellow fever vaccines produced by several different manufacturers. This syndrome was previously reported as febrile multiple organ system failure and is now called yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Since 1996, nine cases of yellow fever vaccine-associated viscerotropic disease, a disease clinically and pathologically resembling naturally acquired yellow fever, have been reported in the U.S.; an additional 17 cases have been identified worldwide as of October 2004. All U.S. cases required intensive care after experiencing fever, hypotension, respiratory failure, elevated hepatocellular enzymes, hyperbilirubinemia, lymphocytopenia, and thrombocytopenia; eight of the nine also had renal failure, which required hemodialysis. Six (67%) of the U.S. cases have been fatal. In several cases for which tissue samples were available, immunohistochemistry demonstrated viral dissemination throughout the body, including liver, lung, spleen, lymph node, brain, and smooth muscle; however, in many cases, tissue samples were not available for histopathologic review or detection of virus. 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 appears to be higher for persons >60 years of age, as much as 19 cases per million doses distributed.

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 the vaccine only to persons truly at risk for exposure to yellow fever. Additional surveillance to better monitor and quantify wild-type yellow fever activity, as well as 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. 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. 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.

History of Thymus Disease

Recently, a history of thymus disease has been identified as a contraindication to yellow fever vaccine. Four (15%) of the 26 vaccine recipients with YEL-AVD worldwide have had a history of diseases involving the thymus, all of which are extremely rare, suggesting that compromised thymic function may be another independent risk factor for YEL-AVD. One fatal case in the United States occurred in a 67-year-old woman who had a history of thymectomy for a malignant thymoma approximately 2 years before vaccination. A second case in the United States occurred in a 70-year-old man who had a history of hyperthyroidism, myasthenia gravis, and thymectomy for thymoma 20 years before vaccination. This patient survived. A third case was reported from Switzerland and occurred in a 50-year-old man who had a history of thymectomy due to thymoma 8 years prior to vaccination. This patient also survived. Most recently, a fatal case (male, age 44 years) of viscerotropic disease with fulminant hepatic failure temporally associated with yellow fever vaccine was reported from Colombia. This patient had a thymectomy due to benign thymoma 2 years before vaccination.

In addition to concerns about vaccinating elderly travelers, health-care providers should be careful to ask about a history of thymus disorder, including myasthenia gravis, thymoma, or prior thymectomy, when screening a patient before administering yellow fever vaccine. For persons with such a history, alternative means of prevention should be recommended, if travel plans cannot be altered to avoid yellow fever-endemic areas.

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. 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 breastfed infant. When travel of nursing mothers to high-risk yellow fever endemic areas cannot be avoided or postponed, these women may be vaccinated.

Immunosuppression

Infection with yellow fever vaccine virus poses a theoretical risk for travelers with immunosuppression in association with AIDS or other manifestations of HIV infection; leukemia, lymphoma, or generalized malignancy; with a history of thymus disease or thymectomy; or with the administration of corticosteroids, alkylating drugs, antimetabolites, or radiation. There is a single report of a 53 year-old patient with undiagnosed HIV infection who had a low CD4+ count (108 cells/mm³) and who developed YEL-AND and died of meningoencephalitis. Immunosuppressed 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 and intranasal 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 (e.g. CD4+ T lymphocyte cell counts >200/mm³), 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. Family members of immunosuppressed or HIV-infected persons who themselves have no contraindications can receive yellow fever vaccine.

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.

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. However, some egg-sensitive persons are not allergic to cooked eggs and may not know they are susceptible to allergic reactions following raw eggs or egg-containing vaccines. If vaccination of a person with a questionable history of egg or chicken 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 several vaccines, including yellow fever vaccine, and might be the stimulus for some allergic reactions to 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 immune response to yellow fever vaccine is not inhibited by administration of certain other live, attenuated vaccines concurrently or at various intervals of a few days to one month. Smallpox, measles, BCG, and oral (live) typhoid vaccines have been administered in combination with yellow fever vaccines without interference. Additionally, reactions to vaccination are no more severe when these vaccines are administered concurrently. Hepatitis A, hepatitis B, Vi capsular polysaccharide typhoid, meningococcal, inactivated poliovirus, diphtheria-pertussis-tetanus 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.

No data are available on possible interference between yellow fever vaccine and influenza, pneumococcal polysaccharide or conjugate, 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.

International Certificate of Vaccination for Yellow Fever

International regulations require proof of vaccination for travel to and from certain countries. For purposes of international travel, yellow fever vaccine produced by different manufacturers worldwide must be approved by WHO and administered at an approved yellow fever vaccination center. In the United States, state and territorial health departments have authority to designate nonfederal vaccination centers; these can be identified by contacting state or local health departments or by visiting CDC's Travelers' Health website, where there is a listing of current authorized yellow fever vaccination providers (http://www2.ncid.cdc.gov/travel/yellowfever/). 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.

To prevent importation and transmission, a number of countries require a certificate from travelers arriving from infected areas or from countries with infected areas, even if only in transit. Such requirements may be strictly enforced, particularly for persons traveling from Africa or South America to Asia. Some countries in Africa require evidence of vaccination from all entering travelers; others may waive the requirements for travelers coming from nonendemic areas and staying in the country <2 weeks. Travelers with a specific contraindication to yellow fever vaccine should be advised to obtain a waiver before traveling to countries requiring vaccination.

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 4-12 and 4-13 and Table 4-22). The actual areas of yellow fever virus activity can extend beyond the officially reported endemic zones.

An International Certificate of Vaccination must be complete in every detail; if incomplete or inaccurate, it is not valid. Revisions of this certificate dated 9-66, 9-69, 9-71, 1-74, 9-77, 1-82, or 11-91 are acceptable. A copy of the International Certificate of Vaccination, PHS-731, may be purchased for $1.25 ($15.00 per 100) from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402, telephone 1-202-512-1800. The stock number is 017-001-00483-9.

Authorization To Provide Vaccinations and To Validate the International Certificate of Vaccination

A yellow fever vaccination must be given at an official yellow fever vaccination center as designated by respective state health departments or the Division of Global Migration and Quarantine, CDC. The accompanying certificate must be validated by the center that administers the vaccine. The certificate can be validated at most city, county, and state health departments or by vaccinating physicians who possess a "Uniform Stamp." State health departments are responsible for designated nonfederal yellow fever vaccination centers and issuing Uniform Stamps to be used to validate the International Certificate of Vaccination. Information about the location and hours of yellow fever vaccination centers may be obtained by contacting local or state health departments or visiting CDC's Travelers' Health website at http://www2.ncid.cdc.gov/travel/yellowfever/. Health-care providers administering vaccine to travelers should emphasize that an International Certificate of Vaccination must be validated to be acceptable to quarantine authorities. Failure to secure validations can cause a traveler to be revaccinated, quarantined, or denied entry.

The following section should be completed at the time of vaccination:

Persons Authorized To Sign the Certificate

The International Certificate of Vaccination must be signed by a licensed physician or by a person designated by the physician. A signature stamp is not acceptable.

Vaccination Certificate Requirements for Direct Travel from the United States to Other Countries

For direct travel from the United States, only the following countries require an International Certificate of Vaccination against yellow fever.

Table 4-23: Countries that require proof of vaccination against yellow fever

For travel to and between other countries, individual country requirements should be checked. No vaccinations are currently required for return to the United States.

Exemption from Vaccination

Travelers who do not have the required vaccinations or appropriate documentation of a vaccination waiver upon entering a country might be subject to vaccination, medical follow-up, isolation, or quarantine, or a combination of these. In a few countries, unvaccinated travelers are denied entry.

Some countries do not require an International Certificate of Vaccination for infants <6 months of age, <9 months of age, or <1 year of age. Travelers should be advised to check the individual country requirements in Yellow Fever Vaccine Requirements and Information on Malaria Risk and Prophylaxis, by Country.

If a physician concludes that a particular vaccination should not be administered for medical reasons, the traveler should be given a signed and dated statement of the reasons on the physician's letterhead stationary.

No other reasons are acceptable for exemption from vaccination.

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 and the section on Medical Contraindication to Vaccination completed.

Vaccination for Travel on Military Orders

Because military requirements may exceed those indicated in this publication, any person who plans to travel on military orders (civilians and military personnel) should be advised to contact the nearest military medical facility to determine the requirements for the trip.

Treatment

Patients should receive supportive care. In general, no specific treatments or established cures have proven benefit for patients with yellow fever or yellow fever vaccine-related illness.

Bibliography

• Barwick RS, Marfin AA, Cetron MS. Yellow fever vaccine-associated disease [Chapter 3]. In: Scheld WM, Murray BE, Hughes JM, eds. Emerging Infections. 6th ed. Washington, DC: ASM Press, 2004,25-34.
• CDC. Yellow fever Vaccine Information Statement (VIS) http://www.cdc.gov/nip/publications/VIS/vis-yf.pdf
• CDC. Adverse events associated with 17D-derived yellow fever vaccination—United States, 2001-2002. MMWR Morbid Mortal Wkly Rep 2002; 51:989.
• CDC. Yellow fever vaccine; recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep 2002; 51(RR-17):1.
• Chan RC, Penney DJ, Little D, Carter IW, Roberts JA, Rawlinson WD. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet. 2001;358:121-2.
• Martin M, Tsai TF, Cropp B, Chang G-JJ, Holmes DA, et al. Fever and Multisystem organ failure associated with 17D-204 yellow fever vaccination: a report of four cases. Lancet. 2001;358:98-104.
• Monath TP: Yellow fever [Chapter 34]. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia, PA: W.B. Saunders, 2004, p 1095.
• Vasconcelos PF, Luna EJ, Galler R, Silva LJ. Coimbra TL, Barros VL et al. Serious adverse events associated with yellow fever 17DD vaccine in Brazil: a report of two cases. Lancet. 2001;358:91-7.
• Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination. Lancet. 2004; 364 (9438): 936.

- Michelle Russell, Rachel Barwick Eidex, Edward Hayes, Anthony Marfin, Thomas Monath, Dirk Teuwen, Megan Ranney, and Martin Cetron

Announcement

Yellow Fever Vaccine Risk and Updated Yellow Fever Vaccine Information Statement (VIS)

Released: December 3, 2004

According to a September 2004 letter in the journal Lancet , a history of thymic dysfunction may be an independent risk factor for yellow fever vaccine-associated viscerotropic disease (YEL-AVD), a disease that clinically and pathologically resembles naturally acquired yellow fever. As of July 2004, 23 cases of YEL-AVD have been reported worldwide, of which 14 have been fatal. Four (17%) of the 23 patients reported a history of thymectomy due to thymoma.* Before administering yellow fever vaccine, health-care providers are advised to ask travelers about any history of thymus disorder or dysfunction (i.e., myasthenia gravis, thymoma, thymectomy, or DiGeorge syndrome), regardless of the age of the traveler. Persons 60 years of age or older are at increased risk for YEL-AVD, and health-care providers are reminded to consider the risks/benefits of vaccinating such travelers.

CDC has updated the Vaccine Information Statement (VIS) for yellow fever vaccine to include a caution about vaccinating persons with a history of thymic disease (see http://www.cdc.gov/nip/publications/VIS/#yf ).

*As of November 2004, 28 cases of YEL-AVD have been reported worldwide, of which 17 have been fatal.

For a copy of the published letter, see http://www.thelancet.com .

For more information about YEL-AVD, see:

• http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5144a1.htm and
• http://www.cdc.gov/travel/other/yfvaccine-jul2001.htm .

For more information about yellow fever, see http://www.cdc.gov/travel/diseases/yellowfever.htm

Reference

Barwick Eidex R for the Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination [letter]. Lancet. 2004:364:936.