Yellow fever and yellow fever vaccination

Yellow fever is a viral illness transmitted between primates by several species of mosquito. It is not transmitted directly from person to person, although there have been reports of vertical transmission and it could be transmitted via organ donation or blood transfusion from an infected person.¹The 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.

Epidemiology²³

Yellow fever is endemic in 13 countries in South America and 29 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 173,000 cases of yellow fever per year, with up to 82,000 deaths.

Yellow fever is rare in the UK; the available data (up to 2018) shows only one, or zero, cases per year. ⁴

Pathophysiology

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 factors

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

Presentation²

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:

  • Fever.

  • Myalgia, especially back pain.

  • Headache.

  • Shivering.

  • 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.

• 15% will then develop severe infection, 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.

Investigations

• 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.

Differential diagnosis

• Falciparum malaria.

• Dengue.

• 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 antiviral treatment outside of the research setting. 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.

Complications

These are varied and may include:

• Hepatorenal failure.

• Myocarditis.

• Secondary bacterial infections.

• Pulmonary oedema.

• Haemorrhage and DIC.

• Encephalitis.

Prognosis

• Infancy and age older than 50 years is associated with increased severity of illness and increased mortality.

• Severe illness 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%.

Prevention

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.²

Yellow fever vaccination

• Yellow fever vaccination is not available on the NHS and is given only by registered Yellow Fever Centres.⁵

Vaccination schedule³

• 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.³

• Expert advice should be sought for those who may require a booster dose because their initial vaccine may be less long-lasting. This includes those who were vaccinated under the age of two, when pregnant, when infected with HIV, when immunosuppressed, or before undergoing a bone marrow transplant.⁶

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

• 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.⁷

• 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.

  • A desensitisation protocol should be used for those who have egg allergy, as the vaccine is grown in embryonated chicken eggs.

  • Those who have a thymus disorder or have had a thymectomy for any reason.

  • 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.

  • Expert advice should be sought if considering vaccination in a woman who is breastfeeding an infant aged less than nine months old, as there have been case studies of encephalitis in very young babies whose breastfeeding mothers were vaccinated.⁸

  • 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 is not recommended for pregnant women except during outbreaks.²

Adverse reactions

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 neurological 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. The fatality rate is 60%. It is extremely rare (three cases per million doses of vaccine). It generally occurs in older patients (hence the MHRA warning discussed above) and in those with immunosuppression.

Dr Mary Lowth is an author or the original author of this leaflet.