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All you need to know about... yellow fever

Alexandra Jordan
MSc RGN BSc(Hons)
Nurse Adviser

Hilary Simons
MSc RGN RSCN
Nurse Adviser
National Travel Health Network and Centre (NaTHNaC)

Yellow fever virus is a single-stranded RNA virus of the genus flavivirus in the family Flaviviridae.(1) Dengue fever and Japanese encephalitis are also flaviviruses.(2)
Yellow fever is only transmitted in tropical areas of sub-Saharan Africa and parts of South and Central America (see Figure 1). Endemic areas are defined as countries where "the virus is present in mosquitoes and nonhuman primates and where there is a potential risk of infection for humans."(3) The extent of the endemic areas has recently been redefined and maps are available.(4)

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There are two main transmission cycles of yellow fever; sylvatic (forest) and urban. The virus is transmitted by the bite of an infected female Aedes spp. mosquito. In the forest, the virus is also transmitted by other closely related species that breed in tree holes (eg, Haemogogus sp. and Sabethes sp. in South America).(1) Mosquitoes that transmit yellow fever virus require a blood meal in order to reproduce and are most active in the daytime.(5) Once infected, the mosquito remains so for life.(6)
In the sylvatic cycle, the virus is maintained between nonhuman primates (monkeys) and mosquitoes. Humans may become infected when they live in or visit the forest, or when infected nonhuman primates move out of the forest and infect mosquitoes living on the perimeter.(1)
Urban yellow fever is maintained between humans and mosquitoes and occurs when infected humans enter urban areas where the mosquito vector is present. Aedes aegypti, a domestic mosquito that has successfully adapted to live in urban areas, is the exclusive vector in this cycle. In both Africa and South America, the potential for urban outbreaks exists due to an increase in human mobility between rural and urban areas and infestation or reinfestation of urban areas by the Aedes mosquito.(1,7)
In order to meet the requirements of the International Health Regulations (IHRs),(8) countries are required to report cases of yellow fever to the World Health Organization (WHO). However, surveillance and reporting systems are often inadequate and the true number of cases has been estimated to be between three and 250 times higher than the number reported.(9)

Signs and symptoms
The incubation period for yellow fever is between three and six days. Following a bite from an infected mosquito the virus is present in the bloodstream before fever develops and for the first three to five days of the illness.(6) During this time the infection can be transmitted to a noninfected mosquito, but is not transmissible from person to person. Infected persons should be nursed away from mosquitoes in order to prevent further spread of the disease.
An estimated 15-50% of those who are infected develop clinical symptoms.(1) In symptomatic infection the patient appears acutely unwell with sudden onset of a high fever of 39°C or above together with chills, malaise, nausea, headache, myalgias and dizziness. A period of remission may follow, lasting 24 hours.(2) The majority of patients go on to full recovery; however, progression to a more severe form may occur.(2) At this stage jaundice, renal failure and haemorrhage may occur together with hepatic and renal failure, haematological/clotting abnormalities and cardiac and central nervous system involvement.(1) Death occurs in nearly 20-50% of these cases seven to 10 days after onset.(2,10)
Recovery leads to lifelong immunity and there are no reported cases of reinfection.(7,11)
Yellow fever is a disease that is rarely seen outside of the tropics. Diagnosis may be difficult as symptoms are similar to many other febrile illnesses, including malaria, hepatitis E and other haemorrhagic fevers. Serology is the most important test and yellow fever virus-specific IgM enzyme-linked immunosorbent assay (ELISA) is the most commonly used. In fatal cases diagnosis postmortem includes characteristic liver and tissue changes.(1,6
There is no specific antiviral treatment for yellow fever. Management involves supportive care to alleviate symptoms.(4)

Vaccine
Vaccination is the most effective method of prevention of yellow fever. Yellow fever vaccine (YEL) derived from the 17D virus and produced in chick embryos, has been available since the 1930s. Globally over 400 million doses have been given and the vaccine has a good safety profile.(12) The only vaccine currently available in the UK is Stamaril™ (Sanofi Pasteur MSD).(13)
Following vaccination more than 95% of vaccinees have neutralising antibodies to the virus within seven to 14 days.(14) A "Certificate of Vaccination or Prophylaxis" does not become valid until 10 days after receipt of yellow fever vaccine.(8) Although immunity from the vaccine is thought to last for longer than 10 years and may be lifelong, vaccination is given every 10 years to those at continued risk, in order to comply with international certificate requirements.(11,14)
The vaccine is generally well tolerated, but local reactions to the vaccine occur in approximately 16% of recipients.(13) These are usually mild and of short duration. Cases of anaphylaxis are rare - one case per 130,000-250,000 doses of vaccine.(15)
YEL is contraindicated in the following circumstances:

  • Current febrile illness.
  • History of anaphylactic reaction to egg, egg product or any other component of the vaccine.
  • Babies aged less than six months.
  • Immunocompromisation, either by disease or treatment.
  • History of thymic dysfunction including thymoma, thymectomy and myasthenia gravis.

In addition, special caution should be observed when considering YEL in certain individuals including:

  • Pregnant women.
  • Babies aged six to nine months.
  • HIV-positive individuals.
  • People aged 60 years and over.

Specific contraindications and special cautions should be reviewed in the Summary of Product Characteristics (SmPC).(13)
In recent years there have been increasingly frequent reports of two serious postvaccination syndromes; yellow fever vaccine-associated viscerotropic disease (YEL-AVD) and yellow fever vaccine-associated neurotropic (or neurologic) disease (YEL-AND).(16) The risk of such rare adverse events occurring in the general population has been estimated to be five cases per million doses of vaccine administered.(17) To date, these rare adverse events have only occurred in first-time vaccinees.(16)
It is known that very young infants are at risk of postvaccine encephalitis.(13) A separate neurotropic syndrome YEL-AND, occurring mostly in adults, has been reported in the literature.(1,18) Symptoms typically occur four to 23 days postvaccination and include severe headache, confusion and aphasia. The majority completely recover, although two deaths have been reported.(14,19)
Cases of YEL-AVD were first described in the literature in 2001.(20,21) Following enhanced surveillance further cases have been identified, including some deaths.(11,22) Symptoms typically occur two to eight days postvaccination and include elevated liver enzymes, abnormal renal function, lymphocytopenia and thrombocytopenia. YEL-AVD may result in multiple organ failure.
Analysis of the data relating to postvaccine adverse events found certain persons to be at higher risk from YEL-AND or YFV-AVD.(16,18,23) One study identified thymic dysfunction as an independent risk factor for YEL-AVD and a history of thymoma, thymectomy or other thymus disease, including myasthenia gravis, is now an absolute contraindication to vaccination with YEL.(16)
In addition, persons over the age of 60 years appear to be at an increased risk of both YEL-AND and YEL-AVD.  For these individuals, the risk is estimated at 25 cases per million doses of vaccine administered.(17) YEL should therefore only be given to those visiting endemic areas and at high risk of disease.
Further studies are being undertaken in order to determine the risk of YEL adverse reactions. Healthcare professionals are encouraged to report postvaccination adverse events to the Medicines and Healthcare Products Regulatory Agency (MHRA) via the yellow card system and to the vaccine manufacturer.(16,23-25)

Advising travellers
For all travellers, it is essential to weigh the risk of yellow fever disease at the destination against the risk of adverse events from the vaccine in the recipient, ensuring that only those who are at risk of disease are vaccinated.
Unless there are medical contraindications, vaccine should be offered to all travellers over the age of nine months who are travelling to endemic areas and who are therefore at risk from the disease.  Travellers should also be counselled about the rare risk of adverse events following YEL and encouraged to make an informed choice regarding vaccination.
Travel to yellow fever endemic areas without protection by vaccination should be discouraged. There may be circumstances in which it is necessary to consider providing a medical exemption letter.(26) This should be discussed on an individual basis with the healthcare professional. Medical exemption letters are not a guarantee of passage and do not provide protection from the disease.
The Aedes mosquito is most active during daylight hours. Insect bite precautions are very important in order to reduce the risk of disease, particularly for those not able to receive the vaccine.(27)

International Health Regulations (IHRs)
Yellow fever vaccine is only available at centres registered under the IHRs.(8) The IHRs are a public health measure to prevent worldwide spread of the disease and to protect populations in endemic and vulnerable countries (ie, those which have the vector mosquito but not the disease). Under the IHRs travellers are obliged to meet the certificate requirements of different countries, which are published by WHO.(3) Healthcare professionals should check these requirements as part of the pretravel consultation.
In the UK the National Travel Health Network and Centre (NaTHNaC) is charged with the administration of registered yellow fever vaccination centres (YFVCs). See Resources for more information about registering as a YFVC.

Conclusion
Risk assessment for travellers to yellow fever endemic areas should be a key feature of the pretravel consultation. Travelling unprotected to endemic areas should be discouraged. Healthcare professionals should discuss the risks from the disease and the vaccine in order that travellers may make an informed decision regarding vaccination.

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References:

  1. Marfin A, Barwick Eidex R, Monath T. Yellow fever. In Guerrant R, Walker D, Weller P, editors. Tropical infectious diseases; principles, pathogens and practice. 2nd ed. Philadelphia: Elsevier; 2006.
  2. Broom A, Smith D, Hall R, et al. Arbovirus infections. In Cook G, Zumla A, editors. Manson's tropical diseases. Edinburgh: Saunders; 2003.
  3. WHO. International travel and health. Geneva: WHO; 2006. Available from: http://www.who.int/ith/en/
  4. Arguin P, Kozarsky P, Navin A. Health information for overseas travel 2005-2006. Chapter 4: Yellow fever. Centers for Disease Control and Prevention. Atlanta: Mosby; 2005. Available from: http://www2.ncid.cdc.gov/travel/yb/utils/ybGet.asp?section=dis&obj=yello...
  5. White G. Medical acarology and entomology. In Cook G, Zumla A, editors. Manson's tropical diseases. Edinburgh: Saunders; 2003.
  6. Heyman D. Control of communicable diseases manual. 18th ed. Washington: American Public Health Association; 2004.
  7. WHO. Increased risk of urban yellow fever outbreaks in Africa. Geneva: WHO; 2007. Available from: http://www.who.int/csr/disease/yellowfev/urbanoutbreaks/en/print.html
  8. WHO. International health regulations. Geneva: WHO; 2005. Available from: http://www.who.int/csr/ihr/en/
  9. WHO. Yellow fever - factsheet 100. Geneva: WHO; 2001. Available from: http://www.who.int/mediacentre/factsheets/fs100/en/
  10. Monath TP. Yellow fever: an update. Lancet Infect Dis 2001;1:11-20.
  11. Centers for Disease Control and Prevention. Yellow fever vaccine recommendations of the advisory committee on immunization practices (ACIP). MMWR 2002;51(RR-17):1-11. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5117a1.htm
  12. Yellow fever vaccine - WHO position paper. Weekly Epidemiological Record 2003;3 October:349-59. Available from: http://www.who.int/wer/2003/en/wer7840.pdf
  13. Summary of Product Characteristics. Stamaril. Electronic Medicines Compendium. 11 December 2006. Available from: http://emc.medicines.org.uk/emc/industry/default.asp?page=displaydoc.asp...
  14. Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia: Saunders; 2004.
  15. Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. J Allergy Clin Immunol 1999;103:698-701.
  16. Khromava AY, Barwick Eidex R, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23:3256-63.
  17. NaTHNaC. Health Information Sheet. Yellow fever - Information for travellers receiving vaccine. 2006. Available from: http://www.nathnac.org/pro/factsheets/documents/YFvaccineinfofortravelle...
  18. McMahon A, Barwick Eidex R, Marfin A, et al. Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 2007;25:1727-34.
  19. Kengsakul K, Sathirapongsasuti K, Punyagupta S. Fatal myeloencephaltis following yellow fever vaccination in a case with HIV infection. J Med Assoc Thai 2002;85:131-4.
  20. Martin M, Tsai T, Cropp B, et al. Fever and multisystem organ failure associated with 17D-204 yellow fever vaccine: a report of four cases. Lancet 2001;358:90-104.
  21. Chan R, Penney D, Little D, et al. Hepatitis and death following vaccination with 17D-204 yellow fever vaccine. Lancet 2001;358:121-2.
  22. Kitchener S. Viscerotropic and neurotropic disease following vaccination with the 17D yellow fever vaccine, Arilvax. Vaccine 2004;22:2103-5.
  23. Barwick Eidex R. History of thymoma and yellow fever vaccination. Lancet 2004;364:936.
  24. Medicines and Healthcare Products Regulatory Agency. Reporting safety problems. Available from: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=285
  25. Sanofi Pasteur MSD. Available from: http://www.apmsd.co.uk/
  26. NaTHNaC. Designation of yellow fever vaccination centres; information pack. Revision 3. January 2007. Available from: http://www.nathnac.org/pro/documents/YFInfoPackRevision3Jan2007.pdf
  27. NaTHNaC. Health information sheet. Insect bite avoidance. April 2005. Available from: http://www.nathnac.org/pro/factsheets/iba.htm

Resources:
NaTHNaC Resources for Yellow Fever Vaccination Centres
W: http://www.nathnac.org/pro/Yellow_Fever_Vaccination_Centre_Information.htm
NaTHNaC Health Information Sheet - Yellow Fever. August 2005
W: http://www.nathnac.org/pro/factsheets/yellow.htm

Further reading
Salisbury D, Ramsay M, Noakes K, editors. Yellow fever - chapter 5. Immunisation against infectious disease. London: Department of Health; 2006. Available from: http://www.dh.gov.uk/asset
Root/04/14/13/56/04141356.pdf