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.
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.
Table 3–20.
Yellow fever vaccine dosage
Primary: 1 |
0.5 mL |
|
Booster |
0.5 mL |
1 dose every 10 years |
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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
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