Yellow fever virus — Questions

Leptospirosis can reproduce the fever, jaundice, bleeding and renal impairment of severe yellow fever and is treatable, so it must be excluded; severe malaria, viral hepatitis and other viral haemorrhagic fevers also enter the differential.

The remaining options do not cause this jaundice-plus-haemorrhage-plus-renal picture.

Vaccine-associated viscerotropic disease resembles severe wild-type yellow fever, has a case-fatality near 50%, occurs in first-time recipients and increases markedly with age, which is why elderly travellers are vaccinated only when exposure risk is genuine.

Vaccine-associated neurotropic disease is the separate encephalitic reaction; the other options are not the recognised viscerotropic syndrome.

Since 2013 the WHO has held that a single dose of 17D gives lifelong protection, and the International Health Regulations were amended in 2016 so that a valid vaccination certificate no longer expires.

The former recommendation was a ten-year booster; the other schedules do not apply to this live-attenuated vaccine.

The coagulopathy of severe yellow fever makes liver biopsy dangerous, and it has caused fatal haemorrhage. The definitive tissue diagnosis is instead made post-mortem by immunostaining or PCR for viral antigen in the liver.

The other complications are not the reason biopsy is contraindicated in acute yellow fever.

The period of intoxication follows a brief remission and brings jaundice, acute kidney injury and a haemorrhagic diathesis, by which time viraemia has usually cleared; death, when it occurs, is around the seventh to tenth day.

The period of infection is the initial viraemic febrile phase, the period of remission is a short symptom-free interval where many recover, and the incubation period precedes symptoms.

During the early viraemic days, reverse-transcriptase PCR (and NS1 antigen detection) on blood is the test of choice; IgM-capture ELISA becomes useful from about day four.

Plaque-reduction neutralisation resolves cross-reactivity but is confirmatory rather than an early frontline test, liver biopsy is contraindicated in acute illness, and convalescent serology is too slow to guide acute management.

The sylvatic cycle circulates between non-human primates and forest canopy mosquitoes, with humans infected incidentally when they enter the forest; this is why young men clearing land are most exposed.

Pigs amplify Japanese encephalitis, wild birds amplify West Nile and Japanese encephalitis, and rodents maintain hantaviruses and arenaviruses.

The urban cycle is driven by Aedes aegypti, a domestic container-breeding mosquito, with humans as the sole amplifying host. This is the cycle responsible for explosive city epidemics.

Anopheles transmits malaria, Culex tritaeniorhynchus transmits Japanese encephalitis, Haemagogus drives the sylvatic (jungle) cycle in the Americas, and Culex quinquefasciatus is a West Nile vector.

A single dose gives lifelong protection, and since 11 July 2016 the certificate is valid for the life of the vaccinee; a booster can no longer be required for entry. The certificate itself becomes valid 10 days after vaccination.

The former 10-year validity and any booster or renewal requirement no longer apply, and the certificate is recognised internationally.

Councilman bodies are apoptotic hepatocytes, the dominant mechanism of liver injury in yellow fever, seen with midzonal coagulative necrosis and strikingly little inflammation; intranuclear Torres bodies also occur.

Negri bodies are seen in rabies, Guarnieri bodies in poxvirus infection, Cowdry type A inclusions in herpesvirus infection, and Downey cells are the atypical lymphocytes of Epstein-Barr virus.

Theiler attenuated the virulent Asibi strain by serial passage in chick embryo tissue to produce 17D, a live vaccine still in use and used as a backbone to carry other flavivirus antigens.

The remaining options describe inactivated, recombinant subunit, mRNA and virus-like particle approaches.

The urban cycle is a human-to-human loop transmitted by Aedes aegypti, distinct from the sylvatic (jungle) cycle that maintains these viruses among forest animals and forest mosquitoes. Anopheles transmits malaria, and Ixodes is a tick.

The live-attenuated 17D yellow fever vaccine is highly effective and is required under the International Health Regulations for travel to and from endemic countries.

No licensed vaccine exists for West Nile or Zika; dengue and chikungunya vaccines exist but are not International Health Regulations travel requirements.

The vaccine is produced in embryonated chicken eggs, so severe egg allergy is a contraindication. Other contraindications are significant immunosuppression, thymus disorders and infancy under six months.

Controlled hypertension, prior dengue, splenectomy and stable ischaemic heart disease are not contraindications to 17D.

Significant immunocompromise, including symptomatic HIV or a CD4 count below 200, contraindicates this live vaccine because it can replicate unchecked. Stable HIV with a CD4 count of at least 200 is acceptable.

Age over 60, breastfeeding and egg allergy are cautions weighed against the risk of travel, not absolute bars.

The yellow fever 17D vaccine is a live attenuated whole virus, derived by passaging the virulent Asibi strain in chick embryo tissue. It replicates in the recipient and gives durable immunity from a single dose.

The inactivated polio, recombinant hepatitis B, HPV virus-like particle and recombinant zoster vaccines are all non-living.

Faget’s sign is a pulse that is slow relative to the height of the fever, characteristic of the viraemic period of yellow fever (and also of typhoid).

Romaña’s sign is the periorbital oedema of acute Chagas disease, Koplik spots are pathognomonic of measles, Forchheimer spots occur in rubella and scarlet fever, and Pastia’s lines are seen in scarlet fever.

Despite abundant Aedes aegypti, yellow fever has never established endemic transmission in Asia, a puzzle attributed to dengue cross-protection, vector competence and historical trade patterns; about 90% of the burden falls on Africa.

South America carries the minority of cases, the virus is not eradicated from Africa, and it is a tropical rather than temperate disease.

Necrosis is midzonal and the reticulin framework is preserved, so survivors regenerate normal architecture and heal without cirrhosis. Transaminases can remain raised for weeks, but there is no postnecrotic scarring.

The remaining options describe fibrotic or destructive processes that do not occur in yellow fever hepatitis.

Yellow fever virus is the type species of the genus Orthoflavivirus (family Flaviviridae), a small enveloped positive-sense single-stranded RNA virus; the family name derives from flavus, Latin for yellow.

Alphavirus holds chikungunya, Orthonairovirus holds Crimean-Congo haemorrhagic fever virus, Phlebovirus holds Rift Valley fever virus, and Orthohantavirus holds the hantaviruses.

a. Severe yellow fever in the period of intoxication. The biphasic pattern (febrile illness, brief remission, then jaundice, bleeding and renal impairment) in an unvaccinated traveller from an endemic forest is characteristic.

b. By this stage viraemia is waning, so serology (IgM-capture ELISA) is the mainstay, supported by reverse-transcriptase PCR or NS1 antigen if he is still within the viraemic window; plaque-reduction neutralisation resolves flavivirus cross-reactivity. Liver biopsy is contraindicated.

c. Supportive intensive care: fluid and electrolyte management, organ support including renal replacement for acute kidney injury, correction of coagulopathy with blood products, and avoidance of salicylates. There is no licensed antiviral.

d. Notify the case as a notifiable medical condition and prevent mosquito access to the viraemic patient to block onward transmission.

• Severe egg allergy, because the vaccine is grown in embryonated chicken eggs.
• Significant immunosuppression, including symptomatic HIV with a low CD4 count, and thymus disorders.
• Infancy under six months (and caution between six and nine months), given the risk of vaccine-associated neurotropic disease.
• Advanced age, a caution rather than an absolute bar, because vaccine-associated viscerotropic disease rises steeply in first-time recipients over about 60 years.

• Sylvatic (jungle) cycle: between non-human primates and forest canopy mosquitoes, Haemagogus and Sabethes species in the Americas and Aedes africanus in Africa; humans infected incidentally.
• Intermediate (savannah) cycle: between monkeys and humans via tree-hole Aedes, for example Aedes furcifer and Aedes luteocephalus, the commonest source of African outbreaks.
• Urban cycle: human to human via Aedes aegypti, the domestic container-breeding mosquito responsible for explosive city epidemics.

A complete answer links the viscerotropic tropism of the virus to the triphasic clinical course and the mechanisms of organ failure.

Viral entry and dissemination

After a mosquito bite the virus replicates in local lymph nodes, seeds the reticuloendothelial system and produces a high-titre viraemia that carries it to the liver, kidney and other organs. Nonstructural proteins antagonise interferon induction and signalling, helping the virus reach the viraemia that precedes severe disease.

Hepatic and renal injury

The liver is the principal target. Necrosis is midzonal, sparing cells around the central vein and portal tracts, and hepatocytes die by apoptosis into eosinophilic Councilman bodies with minimal inflammation. Because the reticulin framework is preserved, survivors heal without cirrhosis. The kidney shows acute tubular necrosis, producing the heavy albuminuria that is a clinical hallmark.

Systemic mechanisms of severe disease

Direct cytopathic injury alone does not explain shock. A dysregulated innate response, a high circulating cytokine load, coagulopathy that may progress to disseminated intravascular coagulation, and increased vascular permeability combine to cause multi-organ failure.

Clinical course

After an incubation of about three to six days, illness runs a triphasic course: a viraemic period of infection (fever, myalgia, Faget’s sign), a brief remission, and in a minority a period of intoxication with jaundice, acute kidney injury and a haemorrhagic diathesis including the classic black vomit. Death is usually on the seventh to tenth day, and case-fatality among jaundiced cases is roughly 20% to 50%; management is supportive because no antiviral exists.