Epidemiology

Yellow fever is endemic in 10 countries in South America and in 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 Organization estimates that there are approximately 200,000 cases of yellow fever per year, with 30,000 deaths.^[1] Over a 20-year period, there has been a re-emergence of yellow fever, with more epidemics and a wider spread of countries reporting cases. Those is rural areas are at the greatest risk.

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. Yellow fever has never been reported in Asia. 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.

Yellow fever is rare in travellers and, since 1996, there have been just six fatal imported cases in European and US travellers. All fatal cases were in unvaccinated travellers.^[2]

Risk factors

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

Presentation^[3]

Symptoms very from nonspecific self-limiting symptoms of fever, malaise, photophobia and headaches to sudden-onset illness with fever and vomiting. It can progress to jaundice and haemorrhage.

• The incubation period, following a bite from an infected mosquito, is usually 3-6 days although it can be longer.
• 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 (DIC), 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 7-10 days, developing shock and multi-organ failure and the rest will recover without persisting organ damage.

Investigations^[3]

• FBC may show haemoconcentration due to dehydration or dilution after haemorrhage. Leukopenia is common. Platelets are low if there is a consumptive coagulopathy.
• 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. This may cause oedema, as in nephrotic syndrome. Liver failure may induce hypoglycaemia.
• Antiviral titres should show at least a four-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.

Differential diagnosis

• 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.

Management

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.
• n actively bleeding patients, fresh frozen plasma is administered to maintain 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.

Complications

These are varied and may include:

• Liver and renal failure
• Myocarditis
• Secondary bacterial infections
• Pulmonary oedema
• Haemorrhage and DIC
• Encephalitis

Prognosis

In local populations in endemic areas, the overall fatality rate is around 5%. Infancy and age older than 50 years is associated with increased severity of illness and increased mortality.

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.

Prevention

See also separate article 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 95-100% with immunity that probably persists for life, but re-vaccination is advised after 10 years for those who are at risk of contracting the disease.
• 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, eg Australia (whose coastal regions of Queensland are home to Ae. aegypti).
• Public health measures including improved surveillance and epidemic preparedness.