Yellow fever is a viral illness transmitted between primates by several species of mosquito. It is not transmitted directly from person to person. The pathogen is an RNA virus belonging to the genus flavivirus and it affects only primates (including humans) and certain mosquito species of which the main vector is the yellow fever mosquito (Aedes aegyptii). Other mosquitoes such as the tiger mosquito (Aedes albopictus), native to Southeast Asia, can act as a vector. Infection causes a wide spectrum of disease, from mild symptoms to severe illness, and death, and can include jaundice (which gives the condition its name). There is evidence of yellow fever in historical texts dating back over 400 years.
Humans and monkeys are the principal reservoirs for the virus. It has probably always been enzoonotic in Africa in forest monkeys, who do not suffer recognisable disease. It spread to America with the A. aegypti mosquito via the slave trade. It is also spread via Haemagogus species, which are only found in South America. The virus is taken up by a feeding female mosquito from an infected primate. The virus replicates in the mosquito's stomach then is haematogenously transferred to the salivary glands, enabling injection into the bloodstream of the next bitten person. Female mosquitos can also pass the virus vertically to their eggs and larvae.
There are three main transmission cycles:
- The sylvatic, or jungle, cycle causes sporadic cases in both South America and Africa. Wild mosquitoes acquire the infection from infected primates and then spread it to humans living or working in the forest.The sylvatic cycle is the only route of transmission in South America.
- The intermediate cycle 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. This cycle is now the source of most African infections.
- Urban cycle transmission can occur when immigrants bring the virus into cities, where it is only spread via the bites of the A. aegypti mosquito. (This mosquito also transmits other viral haemorrhagic fevers such as dengue and chikungunya). No monkey transmission is involved. Large epidemics can develop in unvaccinated populations. This cycle has been confined to Africa since the Millennium.
Yellow fever is endemic in 10 countries in South America and in over 30 countries in sub-Saharan Africa. There is believed to be a great degree of under-reporting of cases. The World Health Organization (WHO) estimates that there are approximately 200,000 cases of yellow fever per year, with 30,000 deaths.
Yellow fever is rare in travellers. Since 1996 there have been six fatal imported cases in European and USA travellers. All fatal cases were in unvaccinated travellers.
Forty-four endemic countries in Africa and Latin America, with a combined population of over 900 million, are at risk: in Africa, an estimated 508 million people live in 31 countries at risk. The other 13 countries are in Latin America, with Bolivia, Brazil, Colombia, Ecuador and Peru at greatest risk.
Until the beginning of the twentieth century, yellow fever outbreaks also occurred in Europe and Central and North America. Yellow fever has never been reported in Asia.
In the last 20 years there has been a re-emergence of yellow fever, with more epidemics and a wider spread of countries reporting cases. Those in 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.
Small numbers of imported cases occur in countries free of yellow fever. Although the disease has never been reported in Asia, the region is at risk because the conditions required for transmission are present there. In the seventeenth to nineteenth centuries, outbreaks of yellow fever were reported in North America (Charleston, New Orleans, New York, Philadelphia, etc) and Europe (England, France, Ireland, Italy, Portugal and Spain).
Yellow fever is one of the many causes of viral haemorrhagic fever. After transmission, viral replication initially takes place in the lymphatic system. It infects, amongst others, monocytes, macrophages and dendritic cells and from there reaches the liver to infect hepatocytes. This leads to cell breakdown with potentially massive cytokine release. Shock and multiple organ failure may result.
Risk is related to geography (being present in an endemic area) and receiving mosquito bites.
Yellow fever is difficult to diagnose, especially during the early stages. It can be confused with severe malaria, viral haemorrhagic fevers, leptospirosis, viral hepatitis (especially the fulminating forms of hepatitis B and D) and other diseases, as well as poisoning. Diagnosis is clinical, with symptoms of fever, pain, nausea and vomiting occurring 6-10 days after leaving an affected area. Most cases are mild but even mild cases should be confirmed virologically because of the risk of outbreak.
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 lasts 3-4 days and is characterised by:
- Myalgia, especially back pain.
- Anorexia, nausea and vomiting.
- Fever may be very high but the pulse is typically slow
- The individual is viraemic and, if bitten by a mosquito, will potentially transmit the disease onwards.
- Within 24 hours, around 15% enter the toxic phase:
- The toxic phase is characterised by:
- Recurrence of fever.
- Jaundice (usually not severe), abdominal pain and vomiting.
- Bleeding from the mouth, nose, eyes and stomach, due to decreased production of clotting factors and/or disseminated intravascular coagulation (DIC).
- Deterioration of renal function, which may lead to acute kidney injury. This may be pre-renal (dehydration) or due to glomerulonephritis and interstitial nephritis.
- Around half will die from shock and multi-organ failure in 7-10 days. The remaining half will recover without persisting organ damage.
- 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 show at least a four-fold increase in IgG-titre over the course of the disease. A single level may be diagnostic if IgM is detected but it does not form for 10 days. However, these tests can cross-react with other flaviviruses such as dengue.
- 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.
- Rickettsial diseases.
- Viral haemorrhagic fevers.
- Lassa, Marburg and Ebola fever.
- Other causes of viral hepatitis.
- Poisoning with carbon tetrachloride.
There is no specific antiviral 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.
- In actively bleeding patients, fresh frozen plasma is administered to maintain prothrombin time at 25-30 seconds.
- If renal insufficiency does not resolve rapidly, dialysis may be required.
- Centrally-acting drugs that may precipitate or aggravate encephalopathy must be avoided.
These are varied and may include:
- Hepatorenal failure.
- Secondary bacterial infections.
- Pulmonary oedema.
- Haemorrhage and DIC.
- Infancy and age older than 50 years is associated with increased severity of illness and increased mortality.
- Overall around 15% enter the toxic phase. This phase has a 50% mortality. Those who do not die tend to recover with no long-term problems.
- In local populations in endemic areas, the overall fatality rate is slightly lower - around 5% rather than 7.5%.
Personal prevention of yellow fever includes vaccination, as well as avoidance of mosquito bites in areas where yellow fever is endemic.
Institutional measures for prevention of yellow fever include vaccination programmes and measures of controlling mosquitoes. Programmes for distribution of mosquito nets for use in homes are providing reductions in cases of both malaria and yellow fever.
Prompt detection of yellow fever and rapid response through emergency vaccination campaigns are essential for controlling outbreaks. The WHO recommends that every at-risk country has at least one national laboratory where basic yellow fever blood tests can be performed. One confirmed case of yellow fever in an unvaccinated population could be considered an outbreak[1, 3].
Yellow fever vaccination
Dr Sarah Jarvis, 25th April 2019.
The Medicines and Healthcare products Regulatory Agency (MHRA) has issued a new warning about the use of yellow fever vaccination following two fatal adverse reactions.
Yellow fever vaccination must not be given to patients with immunosuppression or a medical history of thymus dysfunction. Patients over 60 are also at significantly increased risk of severe adverse reactions, and immunisation of people in this age group should be conducted with extreme caution and only after a comprehensive risk assessment.
Yellow fever vaccination is not available on the NHS and is given by registered Yellow Fever Centres.
- The 17D live attenuated vaccine was developed in 1936 by Max Theiler and his team and became widely available in 1951. It has been one of the most successful antiviral vaccines to date and over 540 million doses have been used worldwide.
- Wherever high vaccination rates (>80%) have been achieved the incidence of yellow fever has declined. However, whilst the majority of countries with endemic yellow fever do have vaccination programmes, few achieve vaccination coverage of more than half of their population.
- Expansion of travel to these areas has increased demand for the vaccine and every year there are shortages.
Purpose of yellow fever vaccination
Yellow fever vaccination is carried out with three different purposes:
- To protect populations in areas exposed to epidemic and endemic disease.
- To protect individual travellers from the disease when they may be exposed to it: the risk of transmission is dependent on the presence, in the country of the disease, in humans, mosquitos or other animals. The vaccine is recommended for all travellers aged 9 months or more in an area where there is evidence of persistent of periodic yellow fever virus transmission.
- Vaccination is generally not recommended where there is low potential for exposure to the virus (eg, no history of human cases or evidence to suggest only low levels in the past). An exception might be the subset of travellers who are at increased risk through inability to avoid mosquito bites or increased risk of exposure through travel plans.The WHO determines risk through:
- History of diagnosed cases in that area.
- Results of yellow fever sero-surveys.
- The presence of disease vectors and animal reservoirs.
- The potential for exposure to the virus.
- To prevent the spread of disease from one country to another. These requirements are established by individual countries. Those requiring proof of vaccination are those where:
- The disease occurs (although lack of requirement for vaccination does not automatically mean that the disease does not or has not occurred).
- The disease may not occur but the mosquito vector and potential non-human primate hosts are present so that propagation and establishment of the disease is theoretically possible.
- A meeting of yellow fever experts organised in 2010 stated that less than 12 hours of airport transit in an affected country conveys almost zero risk and that proof of vaccination may not be necessary; however, it still lies with individual countries to determine their entry conditions.
- A current list of countries and their requirements can be found on the WHO website.
- Yellow fever vaccine is administered as a single dose by deep subcutaneous route and provides immunity in 95-100% of travellers. Protection begins by the tenth day after vaccination in at least 95% of people. It should therefore be given at least ten days prior to travel to the endemic area, to allow sufficient immunity to develop.
- Immunity probably persists for life. Re-vaccination was formerly advised after ten years for those whose risk of contracting the disease persists. In 2013 WHO announced that they now considered that a single dose of vaccine conferred lifelong immunity. However, the International Health Regulations of 2005 still remain current and state that the vaccination certificate is valid for ten years. Some countries now consider this certificate to be valid for life[2, 7].
- The International Health Regulations are an agreement between 196 countries to work together to prevent and respond to public health crises. They were agreed in 2005 and came into force in June 2007.
- The vaccine can only be given at specialist centres.
Yellow fever vaccination requirements
- Proof of yellow fever vaccination, recorded on an International Certificate of Vaccination, is now the only vaccination certificate that should be required in international travel. Many countries require this of travellers, including those in transit, arriving from infected areas or from countries with infected areas.
- Some countries require evidence of vaccination from all entering travellers, even when they have come directly from a non-endemic country. This can be strictly enforced, particularly for people arriving in Asia from Africa or South America. Failure to comply may result in being quarantined for several days.
- The certificate is valid from the tenth day after primary vaccination and lasts for ten years. The certificate is also valid immediately after re-immunisation if the re-immunisation occurs within the ten-year period.
- If vaccination is contra-indicated, dispensation is possible and an exemption certificate of WHO standard should be issued.
- Live vaccines can be given at the same time as inactivated ones. Other live vaccines can be administered at the same time as yellow fever vaccine but must be given at different sites and in different syringes. If they are not given on the same day, they should be separated by an interval of at least three weeks. The exception is MMR vaccine, which must always be given with an interval of at least four weeks.
- It is good practice to obtain written or verbal consent, prior to vaccination.
- Patient details, together with date, time, batch number and site of vaccination should be recorded and an immunisation certificate issued, which is signed by the patient and stamped by the issuing centre.
The following groups of people should be immunised:
- Laboratory workers handling infected material
- Persons aged 9 months or older who are travelling to countries that require an International Certificate of Vaccination for entry.
- Persons aged 9 months or older who are travelling to or living in infected areas or countries in the yellow fever endemic zone, even if these countries do not require evidence of immunisation on entry.
Cautions and contra-indications to vaccine
- Age 5 months or under (infants aged 6-9 months should only be immunised if the risk of yellow fever during travel is unavoidable; expert opinion should be sought in these situations).
- Anaphylaxis or serious hypersensitivity reactions:
- It should not be given to those who have had a confirmed anaphylactic reaction or serious hypersensitivity reaction following a previous dose of the same vaccine.
- Do not give if an individual has had a confirmed anaphylactic reaction to egg.
- Those who have a thymus disorder.
- Those who are considered to be immunocompromised due to a congenital condition, disease process or treatment.
- The following are precautions:
- If an individual is acutely unwell, immunisation should be postponed until they have fully recovered. This is to avoid confusing the differential diagnosis of any acute illness by wrongly attributing any sign or symptoms to the adverse effects of the vaccine.
- Minor illnesses without fever or systemic upset are not valid reasons to postpone immunisation.
- People over 60 years of age. The risk for neurological and viscerotropic adverse events increases with age.
- Breastfeeding. There is no evidence of harm to the baby from vaccination of the breastfeeding mother. While there is a theoretical risk that yellow fever vaccine virus is excreted in breast milk, vaccination should be considered in cases where there is a real risk to the mother from yellow fever disease.
- Pregnancy. Yellow fever vaccine should not be given because of the theoretical risk of fetal infection from the live virus vaccine. Pregnant women should be advised not to travel to a high-risk area. When travel is unavoidable, the risk from the disease and the theoretical risk from the vaccine have to be assessed on an individual basis. The WHO states that the vaccine may be considered after the sixth month of pregnancy and should be administered if the destination risk is high.
The most commonly reported symptoms include:
- Headache, myalgia and low-grade fever. These are common - they can occur in 10-30% of those vaccinated.
- Injection site erythema and local soreness which can occur.
- Post-vaccine encephalitis - this is a rare event, more commonly seen in infants.
- Yellow fever vaccine-associated neurotropic disease (YEL-AND). This can occur 4-23 days after the vaccination and typically starts with a fever and headache and then progresses to include one or more of confusion, focal neurological deficits, coma and Guillain-Barré syndrome. Usually patients completely recover from this. It occurs in around four cases per million doses of the vaccine.
- Yellow fever vaccine-associated viscerotropic disease (YEL-AVD). This can occur 2-7 days after the vaccination and typically patients develop fever, malaise, headache and myalgias and then progresses to hepatitis and multi-organ failure, like wild-type yellow fever. It also has similarly high fatality rates. It is extremely rare (three cases per million doses of vaccine).
- There appear to be two distinct patterns of risk for YEL-AVD:
- The first in younger persons, particularly women, with defects in innate immunity, in whom the case fatality rate is higher.
- The second in elderly persons, particularly men with age-related immune senescence and a lower case fatality rate.
- From 1990 to 2012, the number of cases and deaths (n = 43) from YEL-AVD in travellers exceeded the reports of yellow fever (n = 6) acquired by natural infection. However, analysis of how many more cases of yellow fever would have occurred without the vaccine is difficult. Work is in progress to develop a safer inactivated yellow fever vaccine which could be useful for vaccinating people at higher risk of adverse events from the live vaccine[3, 11].
Further reading and references
Travel Health Pro; National Travel Health Network and Centre (NaTHNaC)
Thomas RE, Lorenzetti DL, Spragins W, et al; The safety of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+ Am J Trop Med Hyg. 2012 Feb86(2):359-72.
Hayes EB; Is it time for a new yellow fever vaccine? Vaccine. 2010 Nov 2928(51):8073-6. Epub 2010 Nov 3.
Gardner CL, Ryman KD; Yellow fever: a reemerging threat. Clin Lab Med. 2010 Mar30(1):237-60.
Yellow fever; World Health Organization, May 2016
Fact sheet on Yellow Fever and Yellow Fever Vaccine; National Travel Health Network and Centre (NaTHNac)
Pereira RC, Silva AN, Souza MC, et al; An inactivated yellow fever 17DD vaccine cultivated in Vero cell cultures. Vaccine. 2015 Apr 7. pii: S0264-410X(15)00396-5. doi: 10.1016/j.vaccine.2015.03.077.
MHRA updated guidance on use of yellow fever vaccine in patients with immunosuppression, with thymus dysfunction, and in those aged over 60; Medicines and Healthcare products Regulatory Agency, April 2019
Barrett AD, Teuwen DE; Yellow fever vaccine - how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol. 2009 Jun21(3):308-13. Epub 2009 Jun 10.
Yellow fever vaccination requirements and recommendations: malaria situation and other vaccination requirements; World Health Organization, 2015
Lifelong Immunity from single dose of yellow fever vaccine; World Health Organization Media Release, May 2013
Thomas RE, Lorenzetti DL, Spragins W, et al; The safety of yellow fever vaccine 17D or 17DD in children, pregnant women, HIV+ Am J Trop Med Hyg. 2012 Feb86(2):359-72.
Monath TP; Review of the risks and benefits of yellow fever vaccination including some new analyses. Expert Rev Vaccines. 2012 Apr11(4):427-48. doi: 10.1586/erv.12.6.
Jonker EF, Visser LG, Roukens AH; Advances and controversies in yellow fever vaccination. Ther Adv Vaccines. 2013 Nov1(4):144-52. doi: 10.1177/2051013613498954.