Yellow fever

Yellow fever is an acute viral haemorrhagic disease transmitted primarily by infected mosquitoes in tropical regions of Africa and South America. The illness is caused by the yellow fever virus (YFV), an RNA virus of the Flavivirus genus, and affects humans as well as other primates. Although most infections are mild, severe cases can lead to life-threatening complications, including liver failure, jaundice, internal bleeding, and shock. A safe and highly effective vaccine is available and remains the cornerstone of global prevention strategies.
Yellow fever has shaped human history since its emergence in Africa and subsequent spread to the Americas during the seventeenth century via the Atlantic slave trade. It caused numerous devastating epidemics in the eighteenth and nineteenth centuries and continues to pose public health challenges, especially in densely populated urban areas and forested regions where transmission cycles persist. Despite scientific advances, yellow fever remains a significant health burden, with outbreaks linked to environmental change, urbanisation, population movements, and declining population immunity.

Signs, Symptoms and Clinical Course

Following an incubation period of three to six days, most individuals experience a short-lived, non-specific febrile illness. Common symptoms include:

• Fever and chills
• Headache and back pain
• Fatigue and loss of appetite
• Nausea and vomiting
• Generalised muscle pain, particularly in the back

In around 85 per cent of cases, symptoms resolve within a few days, and patients make a full recovery. However, approximately 15 per cent of infected individuals enter a severe toxic phase within 24 hours of initial improvement. This phase is characterised by:

• Recurrent fever
• Jaundice, resulting from acute liver damage
• Severe abdominal pain
• Bleeding from the mouth, nose, eyes, or gastrointestinal tract (haematemesis or “black vomit”)
• Delirium, seizures, or shock
• Kidney failure

The fatality rate among those who develop jaundice ranges from 20 to 50 per cent, while severe cases generally carry a mortality rate exceeding 50 per cent. People who survive infection typically acquire lifelong immunity without long-term organ damage.

Complications

Complications of yellow fever emerge primarily during the toxic phase and may include:

• Severe hepatic injury and jaundice
• Renal failure requiring supportive management
• Cardiac rhythm disturbances
• Neurological manifestations, including seizures and delirium
• Internal bleeding affecting multiple organ systems
• Prolonged fatigue during convalescence

These complications underscore the need for early recognition, supportive care, and preventive vaccination.

Cause and Viral Biology

Yellow fever is caused by the yellow fever virus (YFV), an enveloped, single-stranded, positive-sense RNA virus approximately 40–50 nm in width. It is the type species of the family Flaviviridae and was the first human virus ever isolated (in 1927). The viral genome is approximately 10,862 nucleotides in length and encodes:

• Three structural proteins (C, prM, E)
• Seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5)

Viral replication begins when the virus binds to host cell receptors and is internalised via endocytosis. Acidification of the endosome induces a conformational change in the E protein, triggering membrane fusion and release of the viral genome into the cytosol. Replication occurs in the rough endoplasmic reticulum, where immature viral particles containing prM–E complexes assemble. These particles are processed in the Golgi apparatus by the host enzyme furin, which cleaves prM to M, thereby producing mature infectious virions.
A key feature of YFV pathogenicity is the production of subgenomic flavivirus RNA (sfRNA), generated when host exonucleases stall at pseudoknot structures within the viral untranslated region. These sfRNAs interfere with host antiviral responses and contribute to disease severity.
YFV is classified within the broader group of viral haemorrhagic fevers, reflecting its ability to damage blood vessels and disrupt coagulation.

Transmission and Epidemiological Cycles

Yellow fever virus is transmitted primarily through the bite of infected female mosquitoes, especially:

• Aedes aegypti (urban environments)
• Aedes africanus (African forest cycle)
• Haemagogus and Sabethes species (South American jungle cycle)

Transmission occurs when a mosquito ingests blood containing the virus from an infected human or primate. The virus infects and replicates in the mosquito’s midgut, disseminates to the haemocoel, and ultimately reaches the salivary glands. The mosquito can then infect a new host during subsequent blood feeding.
The virus circulates in three main epidemiological cycles:

• Urban cycle: Aedes aegypti transmits the virus between humans in densely populated areas, enabling rapid spread and large outbreaks. This remains the most significant transmission route in Africa.
• Sylvatic (jungle) cycle: The virus circulates between mosquitoes and non-human primates in forested regions of Africa and South America. Human infection occurs when individuals enter these environments.
• Intermediate (savannah) cycle in Africa: Transmission occurs between mosquitoes and both humans and monkeys in rural or semi-urban settings.

Rarely, transovarial transmission occurs, enabling mosquitoes to pass the virus to their offspring, contributing to sudden, unexplained outbreak origins.

Diagnosis and Differential Considerations

Yellow fever can be difficult to distinguish from other febrile illnesses such as malaria, dengue, viral hepatitis, leptospirosis, and other flavivirus infections, especially in its early stages. Diagnosis is confirmed using:

• Polymerase chain reaction (PCR) for viral RNA
• Serological tests detecting virus-specific antibodies
• Clinical criteria supported by epidemiological exposure

Reliable diagnosis is critical in endemic regions to initiate public health responses and control outbreaks.

Prevention and Control

Yellow fever is preventable through a safe, effective, and long-lasting vaccine, which provides immunity in more than 99 per cent of vaccinated individuals. Many countries require proof of vaccination for travellers to and from endemic areas. Additional preventive measures include:

• Mosquito control efforts, such as eliminating breeding sites and applying insecticides
• Use of personal protective measures, including repellents, protective clothing, and insecticide-treated nets
• Early case detection and population-wide immunisation campaigns during outbreaks

Immunisation of large population groups disrupts transmission cycles and significantly reduces the risk of epidemics.

Treatment and Clinical Management

There is no specific antiviral treatment for yellow fever. Management focuses on supportive care:

• Maintenance of fluid and electrolyte balance
• Monitoring and support of liver and kidney function
• Treatment of fever and pain (excluding NSAIDs due to bleeding risk)
• Prevention and control of secondary infections
• Management of haemorrhage and shock

Severe cases often require hospitalisation and, in some instances, intensive care.

Epidemiology and Global Burden

Yellow fever is endemic in tropical regions of Africa and South America. It is absent from Asia, despite the presence of competent mosquito vectors. An estimated 200,000 cases occur annually, with about 90 per cent reported in Africa. In 2013, the disease caused an estimated 130,000 severe cases and 78,000 deaths in Africa alone.
Rising incidence since the 1980s has been attributed to:

• Declining population immunity
• Increased urbanisation
• Greater human mobility
• Climate change expanding mosquito habitats

Nearly one billion people reside in areas where the virus is endemic.

Historical Impact

Yellow fever originated in Africa and arrived in the Americas during the seventeenth century through the Atlantic slave trade. From the seventeenth to nineteenth centuries, it caused numerous severe epidemics across the Americas, Africa, and Europe, particularly in major port cities. Its lethality made it one of the most feared infectious diseases of its time.
Scientific breakthroughs in the late nineteenth and early twentieth centuries, especially Walter Reed’s demonstration that mosquitoes transmit the disease, revolutionised understanding of viral transmission. The isolation of the virus in 1927 enabled the development of effective vaccines, dramatically reducing the global disease burden.