Yellow Fever

Clinical Description

Identification

Acute infectious viral disease of short duration and varying severity. The mildest cases may be clinically indeterminate; typical attacks are characterized by sudden onset of fever, chills, headache, backache, generalized muscle pain, prostration, nausea and vomiting. The pulse may be slow and weak out of proportion to the elevated temperature (Faget sign). Leukopenia appears early and is most pronounced about the fifth day. Most infections resolve at this stage. Approximately 15% of cases progress after a brief remission of hours to a day into the ominous stage of intoxication, manifested by jaundice and hemorrhagic symptoms including epistaxis, gingival bleeding, hematemesis (coffee-ground or black), and melaena. Elevated liver enzymes, abnormalities in clotting factors, albuminuria, and anuria may occur as a result of liver and renal failure. The overall case-fatality rate is 20%–50%.

Infectious Agent

The virus of yellow fever, of the genus Flavivirus and family Flaviviridae.


Diagnosis

Laboratory diagnosis is through isolation of virus from blood by inoculation (suckling mice, mosquitoes or cell cultures); through demonstration of viral antigen in the blood by ELISA or in tissues, especially liver, by use of labeled specific antibodies; and through demonstration of viral RNA in blood and tissue by PCR or hybridization probes. PCR or hybridization probes can also be used to distinguish acute infections with yellow fever virus from recent vaccination. Serological diagnosis includes demonstrating specific IgM in early sera or a rise in titer of specific antibodies in paired acute and convalescent sera. Demonstration of a rise in IgM level in the 2nd serum is also preferable. Serological cross-reactions occur with other flaviviruses.


Epidemiology

Mode of Transmission

In urban and certain rural areas, the bite of infective Aedes spp. mosquitoes. In South American forests, the bite of several species of forest mosquitoes, Haemagogus spp. and Sabethes spp. In Africa, Ae. africanus is the principal vector in the monkey population, while semi-domestic Aedes spp., such as Ae. furcifer, Ae. luteocephalus, and Ae. simpsoni complex, transmit the virus from monkeys to humans. Ae. simpsoni was also believed to be responsible as the person-to-person vector during large epidemics in Ethiopia. While Ae. albopictus is a relatively inefficient vector for yellow fever transmission, its recent territorial expansion raises concern about this species as a potential bridging vector for sylvatic and urban cycles of yellow fever.

Incubation Period

From 3 to 6 days.

Period of Communicability

Blood of patients is infective for mosquitoes shortly before onset of fever and for the first 3–5 days of illness; however the virus has been found in the blood up to 17 days after illness onset. The disease is highly communicable where many susceptible people and abundant vector mosquitoes coexist; it is not communicable through contact or common vehicles. The extrinsic incubation period in Ae. aegypti is 9–12 days at the usual tropical temperatures. Once infected, mosquitoes remain so for life.

Reservoir

In urban areas, humans and Aedes mosquitoes; in forest areas, vertebrates other than humans, mainly nonhuman primates and possibly marsupials, and forest mosquitoes. Trans-ovarian transmission of the infection in mosquitoes has been documented, but its contribution to maintenance of infection is unknown. Humans have no essential role in transmission of jungle yellow fever, but are the primary amplifying host in the urban cycle.

Susceptibility

Recovery from yellow fever is followed by lasting immunity; second attacks are unknown. Mild unapparent infections are common in endemic areas. Transient passive immunity in infants born to immune mothers may persist for up to 6 months. In natural infections, antibodies appear in the blood within the first week.

Occurrence

Yellow fever has three transmission cycles: a sylvatic or jungle cycle that involves Aedes or Haemagogus mosquitoes and nonhuman primates; an intermediate cycle involving humans and various Aedes spp in savannah regions of Africa; and an urban cycle involving humans and mainly Aedes aegypti mosquitoes. Sylvatic transmission is restricted to tropical regions of Africa and Latin America, where a few hundred cases occur annually, most often among occupationally exposed young adult males in forested or transitional areas. The intermediate transmission cycle involves humans in humid or semi-humid areas of Africa, where infected mosquitoes feed on both monkeys and humans, resulting in small-scale epidemics. Historically, urban yellow fever occurred in many cities of the Americas, causing large epidemics. At time of writing in early 2008, a large urban outbreak of yellow fever has not been seen in over 50 years in the Americas—though a small urban outbreak was believed to occur in Bolivia during 1999. In Africa, urban outbreaks still occur. Re-infestation with Ae. aegypti may put many cities at risk of renewed urban yellow fever transmission.

In Africa, the endemic zone is located between 15°N and 10°S latitude, and encompasses 33 countries with a combined population of over 500 million. Nine countries in the tropical region of South America and the Caribbean islands also have endemic disease. While no recent cases have been identified, yellow fever disease and transmission has been documented previously in Europe and North and Central America. There is no evidence that yellow fever has ever been present in Asia.


Prevention and Control

1)    Preventive measures:

a)    Institute a program for active immunization of all people 9 months or older who are at risk of becoming infected due to residence, occupation or travel. A single subcutaneous injection of a vaccine containing viable attenuated yellow fever 17D strain virus, cultivated in chick embryo, is effective in >95% of recipients. Antibodies appear 7–10 days after immunization and may persist for at least 30–35 years, though immunization or re-immunization within 10 years is required by the International Health Regulations for travel from endemic areas.

Of the 44 countries identified as having endemic yellow fever, 33 are using yellow fever vaccine in national immunization schedules, with 43% coverage. Since 1989, WHO has recommended that at-risk countries in the endemic-epidemic belt of Africa incorporate yellow fever vaccine into their routine childhood immunization programs (EPI). Of the 33 at-risk African countries, 22 have introduced YF in EPI; overall yellow fever EPI immunization coverage was 66% (range of 30% to 95%) in 2006, up from 22% in 2002. The vaccine can be given any time after 6 months of age, and can be administered with other antigens such as measles vaccine. The vaccine is contraindicated in the first 4 months of life, and should be considered for those aged 4–9 months only if the risk of exposure is judged to exceed the risk of vaccineassociated encephalitis, the main complication in this age group. The vaccine is not recommended during pregnancy or breastfeeding unless the risk of disease is believed to be higher than the theoretical risk to the fetus or infant. There is no evidence of major malformations occurring in the fetus secondary to the vaccine. However, one study observed lower rates of maternal seroconversion; checking antibody titers or re-immunizing women after delivery or termination may therefore be warranted. There is insufficient evidence to permit a definitive statement on whether the vaccine would pose a risk for humans infected with HIV. Limited data suggest the vaccine may be tolerated in individuals with asymptomatic disease, but the vaccine is not currently recommended for individuals with symptomatic HIV, and a waiver clause therefore applies.

Severe adverse events have been observed following yellow fever vaccination, including anaphylaxis, neurotropic disease, and viscerotropic disease. With the later two conditions, the vaccine virus replicates either in the brain or other organs, such as the liver, to cause disease. Two possible risk factors for developing a severe reaction are advanced age and diseases of the thymus gland. Proper surveillance and support for adverse events following immunization should be part of any standard vaccine program or large vaccination campaign.

b)    For urban yellow fever eradicate or control the vector; immunization when indicated.

c)    Sylvan or jungle yellow fever, transmitted by Haemagogus and forest species of Aedes, is best controlled through immunization, which is recommended for all people in rural communities whose occupation brings them into forests in yellow fever areas, and for people who intend to visit those areas. Protective clothing, bednets and repellents are advised for those not immunized.

2)    Control of patient, contacts and the immediate environment:

a)    Report to local health authority: Events involving yellow fever cases are required to be assessed at the national level for potential notification to WHO under the International Health Regulations.

b)    Isolation: Blood and body fluid precautions. Prevent access of mosquitoes to patient for at least 5 days after onset, by screening the sickroom, spraying quarters with residual insecticide, and using insecticide-treated bednets.

c)    Concurrent disinfection: The homes of patients and all houses in the vicinity should be sprayed promptly with an effective insecticide.

d)    Quarantine: Not applicable.

e)    Immunization of contacts: Family and other contacts and neighbors not previously immunized should be immunized promptly.

f)    Investigation of contacts and source of infection: Inquire about all contacts and all places, including forested areas, visited by the patient 3–6 days before onset, to locate focus of yellow fever; observe all people visiting that focus. Search patient's premises and places of work or visits over the preceding several days for mosquitoes capable of transmitting infection; apply effective insecticide. Investigate mild febrile illnesses and unexplained deaths suggesting yellow fever.

g)    Specific treatment: None.

3)    Epidemic measures:

a)    Urban or Ae. aegypti-transmitted yellow fever:

i)    Mass immunization, beginning with people most exposed and those living in Ae. aegypti-infested areas who have not been vaccinated against yellow fever in the last 10 years.

ii)    Eliminate or treat all actual and potential breeding places.

iii)    Spraying the inside of all houses in the community with insecticides has shown promise for controlling urban epidemics.

b)    Jungle or sylvan yellow fever:

i)    Immediately immunize all people living in or near forested areas or entering such areas.

ii)    Ensure that non-immunized individuals avoid those tracts of forest where infection has been localized, and that those just immunized avoid those areas for 7–10 days after immunization.

c)    In regions where yellow fever may occur, a diagnostic post-mortem examination service should be organized to collect small specimens of tissues, especially liver, from fatal febrile illnesses of 10 days duration or less, provided biological safety can be ensured. Facilities for viral isolation or serological confirmation are necessary to establish diagnosis, since histopathological changes in the liver are not pathognomonic.

d)    In Central and South America, confirmed deaths of howler and spider monkeys in the forest are presumptive evidence of the presence of yellow fever. Confirmation by the histopathological examination of livers of moribund or recently dead monkeys, or by virus isolation, is highly desirable. In Africa, monkeys are rarely symptomatic and rarely die from infections with yellow fever virus, and thus cannot be used to indicate the presence of yellow fever.

e)    Immunity surveys through neutralization tests of wild primates captured in forested areas are useful in defining enzootic areas. Serological surveys of human populations are not useful where yellow fever vaccine has been widely used, and can be difficult to interpret in places with other endemic flaviviruses.

4)    Disaster implications:

Mass vaccination may be considered if an epidemic is feared.

5)    International measures:

a)    Yellow fever cases are no longer required to be reported to the WHO under the newly updated International Health Regulations (IHR, 2005). However, if a case of yellow fever is felt to constitute a public health emergency, it should be reported to the WHO within 24 hours, by the most efficient means of communication available. To be considered a public health emergency, the event should meet at least two of the following criteria:

i)    Public health impact of the event is serious.

ii)    The event is unusual or unexpected.

iii)    There is a significant risk of international spread.

iv)    There is a significant risk of international travel or trade restrictions.

b)    Measures applicable to ships, aircraft and land transport arriving from areas with ongoing yellow fever transmission are no longer specified in the IHR (2005). There are, however, applicable guidelines listed in the IHR for any areas with ongoing disease transmission.

c)    Animal quarantine: Due to the risk of nonhuman primates carrying zoonotic pathogens, such as yellow fever, the World Organisation of Animal Health (OIE) recommends in the Terrestrial Animal Health Code (2007) that in captive-bred nonhuman primates be held in quarantine for 30 days, and nonhuman primates captured from the wild be held in quarantine for 12 weeks.

d)    International travel: A valid international certificate of immunization against yellow fever is required by many countries for entry of travelers coming from or going to recognized yellow fever zones of Africa and South America; otherwise, quarantine measures are applicable for up to 6 days. WHO recommends immunization for all travelers to areas other than major cities in countries where the disease occurs in humans or is assumed to be present in nonhuman primates. The International Certificate of Vaccination against Yellow Fever is valid for 10 years from 10 days after date of immunization; if re-immunization occurs within that period, it is valid 10 years from date of re-immunization.
 

Source: Heymann (Ed.). (2008). Control of Communicable Diseases Manual, 19th edition. Washington, DC: American Public Health Association.
 


Available Vaccines

WHO-Prequalified Yellow Fever Vaccines

 
Common Disease Taxonomy: