Yellow Fever

Yellow Fever is a viral disease that is transmitted by several species of mosquito. It is caused by the yellow fever virus, which belongs to the genus flavivirus. The disease can be recognised from historical texts dating back over 400 years but it is believed to have been transported to the New World from Africa in the 18th and 19th centuries.

Humans and monkeys are the principle reservoirs for the virus. The commonest types of mosquito that transmit the virus are Aedes aegypti and Haemagogus species but the latter is found only in South America. Yellow fever is not transmitted directly from person to person.

There are three main transmission cycles:

• Sporadic cases resulting from forest cycle (also known as sylvatic or jungle cycle) of transmission occur in both South America and Africa.
• The intermediate cycle of transmission occurs in the moist savannah zones of Africa only, when mosquitoes infect both animals and humans and may cause small epidemics in rural villages.
• Urban cycle transmission can occur where the virus is introduced into urban areas and the Aedes aegypti mosquito is present. This can lead to large epidemics in unvaccinated populations.

It 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 underreporting of this disease. The World Health Organization estimates that there are approximately 200,000 cases of yellow fever per year, with 30,000 deaths. Over the last 20 years numbers have been increasing.¹

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

Risks are being unvaccinated in an endemic area and bites from mosquitoes. Yellow fever vaccine is extremely effective.

• After a bite from an infected mosquito the incubation period is 3 to 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. This is the stage of viraemia during which a mosquito that bites will become infected from the human.
• In the acute phase the fever may be very high but the pulse is slow, in contrast to expectations.
• After 3 or 4 days the symptoms usually abate.
• Within 24 hours of this around 15% enter the toxic phase. The fever returns and jaundice follows; hence the name yellow fever (although the jaundice is usually not severe). There is abdominal pain and vomiting.
• Bleeding can occur from the mouth, nose, eyes and stomach. Renal function deteriorates with albuminuria and acute renal failure may ensue with compete anuria. Bleeding results from decreased production of clotting factors but there may also be disseminated intravascular coagulation. 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 to 14 days and the rest will recover without persisting organ damage.

• FBC may show a high Hb due to haemoconcentration in dehydration or dilution after haemorrhage. Leukopenia 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&E and creatinine.
• Liver failure may induce hypoglycaemia. 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.
• 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.
• ECG may be useful to detect myocarditis.
• Liver biopsy should not be used because of the risk of bleeding.

• Malaria
• 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 chemotherapeutic agent against the virus.
• Oral rehydration fluid may be required along with a non-hepatotoxic antipyretics, alongside cooling blankets and tepid sponging.
• Late in the disease gradual rewarming may be need to correct hypothermia.
• Intensive care may improve outcome where it is available.²
• Fresh frozen plasma has been suggested, to maintain the prothrombin time at 25 to 30 seconds.
• If renal failure does not resolve rapidly, dialysis may be used.
• Avoid centrally acting drugs that may precipitate or aggravate encephalopathy.

• Myocarditis may cause cardiac failure.
• Secondary bacterial infection may occur and need appropriate treatment.
• Encephalitis is rare.

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

• The most important factor is vaccination.
• 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 who possess the mosquitoes capable of carriage and transmission (e.g. Australia whose coastal regions of Queensland are home to Ae. aegypti).

There is considerable promise in new applications of yellow fever 17D virus. This is the live, attenuated vaccine. It may be used as a vector for foreign genes as a means of developing new vaccines against other viruses, and possibly against cancers.³

• Yellow fever has probably always been enzoonotic in Africa in forest monkeys, who do not suffer recognisable disease, and probably spread to America with the Ae. aegypti mosquito via the slave trade, where it is also enzoonotic in forest monkeys. From these hosts it has spread to man, both in endemic and periodically epidemic fashion.
• Descriptions of yellow fever date back 400 years, to 1648 in the Yukatan Peninsula, Mexico, although the best early account is credited to the writer Mathew Carey (1760-1839), published in his Philadelphia Journal of the Medical and Physical Sciences in 1793, describing the epidemic of that year in Philadelphia.
• Carlos Finlay (1833-1915), born of a Scottish father and French mother in Cuba, was the first to suggest that yellow fever was transmitted by the bite of a mosquito, although the theory when published in 1881, was ignored for many years. He was awarded the Legion of Honour by the French government in 1908, nominated for the Nobel Prize, and given a state funeral in Cuba. His name lives on in the biennial UNESCO Carlos J Finlay Prize for Microbiology.
• It was left to Walter Reed (1851-1902), leading a US medical commission to Cuba in 1900, to prove the theory, although he ignored Finlay's contribution (he even supplied the mosquitoes). A gifted student, Reed entered the University of Virginia aged 16 by special dispensation, and after requesting to study medicine a year later, passed his exams and graduated 9 months later aged 18, gaining his MD a year later, and entering the US Army Medical Corps in 1875. His grave at Arlington is inscribed: "He gave to man control over that dreadful scourge - Yellow Fever".
• Theiler and Smith, working on a strain of yellow fever originally from one Asibi, a native of the Gold Coast, used by Stokes, Bauer, and Hudson in 1927 to infect rhesus monkeys, developed the attenuated 17D vaccine in 1937. The original strain had not proved benign and several deaths in laboratory workers were attributed to it. Recent reports suggest the rare occurence of an acute yellow fever-like illness with high mortality following vaccination, but there is no substitute vaccine yet available.
• Max Theiler (1899-1972), a South African of a Swiss father, was a graduate of St Thomas' Hospital and the London School of Tropical Medicine, working in Havard and the Rockefeller Foundation in New York, was awarded the Nobel Prize in 1951 for his discoveries (his team had proved in 1927 that the cause was a virus) concerning yellow fever and how to combat it.