Yellow Fever

• Sporadic cases resulting from forest (or sylvatic or jungle) cycle of transmission occur in both South America and Africa. Wild mosquitoes acquire the infection from infected monkeys and then spread it to humans living or working in the tropical rainforest.
• The intermediate cycle of transmission occurs in the moist savannah zones of Africa only, when semi-domestic mosquitoes infect both monkeys and humans and may cause small epidemics in rural villages.
• Urban cycle transmission can occur when immigrants bring the virus into cities, spreading it via the bites of the Ae. aegypti mosquito. No monkey transmission is involved. Large epidemics can develop in unvaccinated populations.

Yellow Fever is endemic in 10 countries in South America and over 30 countries in sub-Saharan Africa. It is thought that there is a great degree of under-reporting of this disease. The World Health Organisation estimates that there are approximately 200,000 cases of yellow fever per year, with 30,000 deaths.¹ Over the last 20 years, there has been a re-emergence of yellow fever, with more epidemics and a wider spread of countries reporting cases.²

Changes in the world's environment, such as deforestation and urbanisation, climate change and increasing international travel may have a role in increasing contact with the mosquito/virus. Until the beginning of the twentieth century, yellow fever outbreaks also occurred in Europe, Central and North America. Whilst the virus is not felt to be present in these areas now, they must still be considered at risk for future yellow fever epidemics.³

Yellow fever is rare in travellers and, since 1996, there have been just 6 fatal imported cases in European and US travellers. All fatal cases were in unvaccinated travellers.⁴

Risk is related to geography (being present in an endemic area) and receiving mosquito bites.

• The incubation period, following a bite from an infected mosquito, is 3-6 days.
• The clinical manifestation is an acute followed by a toxic phase.
• The acute phase is characterised by:
  • Fever
  • Myalgia, especially back pain
  • Headache
  • Shivering
  • Anorexia, nausea and vomiting
• During the acute phase, an individual is viraemic and, if bitten by a mosquito, will potentially transmit the disease onwards.
• In the acute phase the fever may be very high but the pulse is slow, in contrast to expectations.
• After 3-4 days the symptoms usually abate.
• Within 24 hours of this, around 15% enter the toxic phase:
  • Fever returns, jaundice (usually not severe), abdominal pain and vomiting occur.
  • Bleeding, due to decreased production of clotting factors and/or disseminated intravascular coagulation, can occur from the mouth, nose, eyes and stomach.
  • Renal function deteriorates with albuminuria, and acute renal failure may ensue with compete anuria. The renal failure may be pre-renal from dehydration but glomerulonephritis and interstitial nephritis may also occur.
  • Of those who suffer the toxic phase, up to half will die within 10-14 days developing shock and multi-organ failure and the rest will recover without persisting organ damage.

• FBC may show haemoconcentration due to dehydration or dilution after haemorrhage. Leucopenia is common. Platelets are low if there is a consumptive coagulopathy. This will also produce fibrin degradation products.
• Prothrombin time is elevated.
• Dehydration and renal failure will affect U & Es and creatinine.
• Bilirubin is elevated and liver enzymes are markedly elevated. Albumin may be low from reduced synthesis, albuminuria and extravasation through permeable endothelium. This may cause oedema as in nephrotic syndrome. Liver failure may induce hypoglycaemia.
• Antiviral titres should show at least a 4-fold increase over the course of the disease. A single level may be used if IgM is detected but it does not form for 10 days.
• Rapid detection methods are also now available based on enzyme-linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR).
• ECG may be useful to detect myocarditis.
• Liver biopsy should be avoided because of the risk of bleeding.

• Falciparum malaria
• Dengue fever
• Typhoid
• Rickettsial diseases
• Viral haemorrhagic fevers, Lassa, Marburg and Ebola fever
• Leptospirosis
• Other causes of viral hepatitis
• Poisoning with carbon tetrachloride

There is no specific anti-viral treatment. Management is supportive:

• Oral rehydration fluid may be required along with non-hepatotoxic antipyretics, cooling blankets and tepid sponging.
• Late in the disease gradual rewarming may be needed to correct hypothermia.
• Intensive care is necessary for severe cases and may improve outcome where it is available.⁶
• Fresh frozen plasma has been suggested, to maintain the prothrombin time at 25-30 seconds.
• If renal failure does not resolve rapidly, dialysis may be used.
• Avoid centrally-acting drugs that may precipitate or aggravate encephalopathy.

• Liver and renal failure
• Myocarditis
• Secondary bacterial infection
• Encephalitis

Around 15% enter the toxic phase. Of these, half die, giving a mortality rate of about 7.5%. Those who do not die tend to recover with no long-term problems.

See also article on Yellow Fever Vaccination.

• The most important factor is vaccination, both of exposed and susceptible indigenous populations and of travellers to affected regions. The live attenuated vaccine (Yellow Fever 17D) has been available for many years; it is highly effective, producing neutralising antibodies in over 99% with immunity that is long-lasting (at least 10 years). A vaccination certificate is needed for international travel to and from many countries with endemic yellow fever.
• Control of mosquitoes is of secondary importance.
• General measures include insecticide-impregnated mosquito nets, insect repellant and protective clothing.
• Strict quarantine precautions in countries with no disease but which possess the mosquitoes capable of carriage and transmission, e.g. Australia (whose coastal regions of Queensland are home to Ae. aegypti).
• Public health measures including improved surveillance and epidemic preparedness.

1. World Health Organisation; Yellow Fever
2. Robertson SE, Hull BP, Tomori O, et al; Yellow fever: a decade of reemergence. JAMA. 1996 Oct 9;276(14):1157-62. [abstract]
3. Gubler DJ; The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle? Comp Immunol Microbiol Infect Dis. 2004 Sep;27(5):319-30. [abstract]
4. Health Protection Agency; Yellow Fever
5. Reader GD; Yellow Fever; emedicine. April 2009
6. Boulos M, Segurado AA, Shiroma M; Severe yellow fever with 23-day survival. Trop Geogr Med. 1988 Oct;40(4):356-8. [abstract]

• Norrby E; Yellow fever and Max Theiler: the only Nobel Prize for a virus vaccine. J Exp Med. 2007 Nov 26;204(12):2779-84. [abstract]
• Staples JE, Monath TP; Yellow fever: 100 years of discovery. JAMA. 2008 Aug 27;300(8):960-2.