Yellow fever is a viral disease caused by the yellow fever virus (YFV), which belongs to the Flavivirus family. It spreads to humans mainly through the bite of infected Aedes aegypti mosquitoes, though other species such as Haemagogus and Sabethes can also transmit it in forested areas. The disease is most common in tropical and subtropical regions of Africa and South America, where warm, humid conditions allow mosquitoes to thrive.
Symptoms of yellow fever can range from none at all, or only mild illness, to severe and life-threatening disease. Early signs include fever, chills, headache, muscle aches, and nausea. In serious cases, the virus can damage the liver, leading to jaundice (a yellowing of the skin and eyes), as well as kidney failure, internal bleeding, and shock. When the disease reaches this severe stage, the death rate can be as high as 20–50%.
Yellow fever can be prevented with a highly effective vaccine known as the 17D vaccine. A single dose provides long-lasting, often lifelong, protection. Vaccination is strongly recommended for people living in or traveling to affected areas. In some countries, proof of vaccination is required for entry under international health rules.
Even though the vaccine is effective, outbreaks still occur, especially in places with low vaccination coverage, growing cities where mosquitoes spread easily, or weak healthcare systems. In recent years, there have been concerns about the return of yellow fever to densely populated urban areas, which could trigger large epidemics.
There is currently no specific medicine that cures yellow fever. Treatment focuses on supportive care, such as giving fluids to prevent dehydration, controlling pain and fever, and closely monitoring liver and kidney function. Prevention through vaccination and mosquito control remains the most effective way to reduce the impact of yellow fever.
Historical Background
Yellow fever has a long history of epidemics dating back to the 17th century, when it was first recognized in the Caribbean and the Americas. The disease spread along trade routes, particularly through ships traveling between Africa, Europe, and the Americas, and became a major threat to port cities. Severe outbreaks were recorded in Havana, Rio de Janeiro, New Orleans, and Philadelphia, where a devastating epidemic in 1793 killed nearly 10% of the city’s population and forced thousands to flee.
Throughout the 18th and 19th centuries, yellow fever was a leading cause of death in the Americas, shaping migration patterns, disrupting commerce, and influencing urban development. It also had a major impact on military campaigns, such as those of the Napoleonic Wars and the construction of the Panama Canal, where outbreaks caused high mortality among workers and soldiers.
Scientific understanding of the disease advanced in the late 19th and early 20th centuries. In 1900, the U.S. Army Yellow Fever Commission led by Walter Reed confirmed that mosquitoes, particularly Aedes aegypti, were the main vectors transmitting the virus to humans. This discovery marked a turning point in prevention and control, enabling targeted mosquito control campaigns that dramatically reduced cases in many regions.
The development of the live-attenuated 17D vaccine in the 1930s by Max Theiler, who later received the Nobel Prize in Physiology or Medicine for his work, provided an effective tool for prevention. Large-scale vaccination campaigns and vector control efforts in the mid-20th century significantly reduced yellow fever incidence, although the disease persisted in parts of Africa and South America.
Types of Yellow Fever
Yellow fever transmission occurs in three distinct cycles: sylvatic (jungle), intermediate (savannah), and urban. These cycles describe how the virus is maintained in nature and how it spreads to humans.
- Sylvatic (jungle) yellow fever: In this cycle, the virus circulates between non-human primates (such as monkeys) and forest-dwelling mosquitoes, including species like Haemagogus in South America and Aedes africanus in Africa. Humans become infected when they enter or work in forested areas and are bitten by infected mosquitoes. This type is most common among farmers, hunters, and others who spend extended periods in jungle environments.
- Intermediate (savannah) yellow fever: This cycle is more common in Africa, where it occurs in humid or semi-humid regions. Transmission takes place when mosquitoes that normally bite both monkeys and humans become infected and spread the virus within rural communities. Unlike the jungle cycle, the intermediate cycle can affect entire villages, leading to localized outbreaks.
- Urban yellow fever: In this cycle, the virus is spread directly from human to human by the Aedes aegypti mosquito, a species well adapted to urban environments. Once an infected person introduces the virus into a city with a high density of mosquitoes and low vaccination coverage, the disease can spread rapidly, leading to large-scale epidemics. Historic outbreaks in major cities such as Rio de Janeiro and New Orleans followed this pattern.
Each cycle requires different control strategies targeting mosquito habitats and human exposure.
Transmission and Causes
Yellow fever is caused by a virus transmitted primarily through mosquito bites. The infection cycle involves specific mosquito species and occurs in defined geographic regions.
How Yellow Fever Spreads
When a mosquito bites a person or a non-human primate already infected with the virus, it ingests blood containing the pathogen. The virus then undergoes an incubation period inside the mosquito, lasting about 9 to 12 days, during which it multiplies and reaches the insect’s salivary glands. Once this period is complete, the mosquito remains infectious for the rest of its life and can transmit the virus to new hosts with each bite.
In humans, after being introduced through a mosquito bite, the virus circulates in the bloodstream (viremia). Other mosquitoes feeding on this infected person can then acquire the virus, continuing the transmission cycle. Direct person-to-person spread does not occur. Rare cases of transmission have been reported through blood transfusion, organ transplantation, laboratory accidents, or from mother to child during pregnancy or childbirth, but these are uncommon compared to mosquito-borne spread.
Mosquito Vectors
The primary vector of yellow fever in urban settings is Aedes aegypti, a mosquito species well adapted to human environments. It breeds in small collections of stagnant water near homes, such as containers, discarded tires, or cisterns, and is a daytime biter. Its close association with humans makes it responsible for most large-scale urban outbreaks.
In forested regions, Haemagogus and Sabethes mosquitoes in South America, and Aedes africanus in Africa, play a crucial role in maintaining the virus in a sylvatic (jungle) cycle involving non-human primates such as monkeys.
These mosquitoes transmit the virus from primates to humans who enter forested areas, often leading to sporadic cases that can spark wider outbreaks if introduced into urban environments.
Geographic Distribution
Yellow fever is endemic in parts of tropical Africa and South America. These regions provide the suitable climate and mosquito habitats necessary for virus survival.
In Africa, the virus is found across West, Central, and East Africa. In South America, cases are mainly reported in the Amazon Basin.
The distribution is limited by environmental factors influencing mosquito populations and the presence of susceptible primate hosts.
Signs and Symptoms
Yellow fever presents distinct phases, each with specific clinical features. Early identification relies on recognizing initial symptoms, while advanced stages indicate more severe complications and higher risks.
Incubation Period
The incubation period for yellow fever typically lasts 3 to 6 days after exposure to the virus via a mosquito bite.
During this time, the infected individual usually shows no symptoms.
This phase is crucial because the virus is multiplying and spreading within the body, particularly targeting the liver, kidneys, and heart.
The person is not contagious during this period.
Early Symptoms
Initial symptoms of yellow fever include:
- Sudden onset of high fever (up to 40°C or 104°F)
- Chills and severe headache
- Muscle pain, commonly in the back and knees
- Nausea, vomiting, and fatigue
- Loss of appetite
These symptoms usually last 3 to 4 days.
Physical signs may include red eyes, flushed face, and jaundice in some cases.
Early symptoms are often mistaken for other febrile illnesses, which can delay diagnosis and treatment.
Advanced Stages
If yellow fever progresses, it enters a toxic phase characterized by the return of fever after a brief remission period.
Symptoms include:
- Severe jaundice causing yellowing of the skin and eyes
- Abdominal pain with vomiting, sometimes bloody
- Bleeding from the nose, mouth, eyes, or stomach
- Kidney failure and decreased urine output
- Delirium, seizures, or coma in severe cases
This stage can lead to multi-organ failure and death if untreated.
The fatality rate during the advanced phase can be as high as 50%.
Diagnosis of Yellow Fever
Yellow fever diagnosis relies on clinical signs, patient history, and specific laboratory testing. Identifying the disease early is crucial due to its rapid progression and potential severity.
Clinical Evaluation
Physicians begin by evaluating characteristic signs and symptoms. The illness typically starts with sudden fever, chills, headache, back pain, muscle aches, and fatigue. Gastrointestinal symptoms such as nausea, vomiting, and abdominal pain may also appear. In severe cases, patients may develop jaundice (yellowing of the skin and eyes) within 3 to 6 days of onset, indicating liver damage. Additional findings in advanced disease include bleeding from the gums or nose, blood in vomit or stool, low blood pressure, and signs of organ failure.
A detailed travel and exposure history is crucial. Patients who have recently visited or lived in endemic regions of Africa or South America, particularly areas with reported outbreaks, are at higher risk. A history of mosquito exposure further supports clinical suspicion. Physical examination may reveal jaundice, liver tenderness, signs of dehydration, and hemorrhagic manifestations.
Laboratory Tests
Definitive diagnosis requires laboratory testing to confirm infection. Common methods include:
- Serology: Detection of virus-specific IgM antibodies using enzyme-linked immunosorbent assay (ELISA). IgM typically appears within a few days after symptom onset. However, cross-reactivity with other flaviviruses (such as dengue and Zika) can complicate interpretation.
- Molecular methods: Reverse transcriptase polymerase chain reaction (RT-PCR) can detect viral RNA during the early, viremic phase of illness, usually within the first 3 to 4 days. PCR is highly specific and useful for distinguishing yellow fever from other flavivirus infections.
- Liver function tests: Elevated liver enzymes (transaminases such as AST and ALT) reflect hepatic damage. AST levels are often disproportionately higher than ALT.
- Hematological tests: Complete blood count may reveal leukopenia (low white blood cells) and thrombocytopenia (low platelets), which are consistent with viral hemorrhagic fevers.
- Virus isolation: Though rarely used in routine diagnosis due to technical complexity and biosafety concerns, isolating the virus in specialized laboratories remains a gold standard.
Differential Diagnosis
Yellow fever can resemble several other infectious diseases, making differential diagnosis essential:
- Dengue fever: Both cause fever, headache, and hemorrhage, but jaundice is more characteristic of yellow fever. Dengue often presents with a “rash” and more pronounced muscle and joint pain.
- Malaria: Common in the same regions and causes fever and anemia, but it typically lacks severe liver involvement or significant jaundice.
- Leptospirosis: May present with jaundice, renal impairment, and hemorrhagic symptoms. Serological testing helps distinguish it from yellow fever.
- Viral hepatitis (A, B, E): Causes jaundice and liver dysfunction but generally lacks hemorrhagic features and the acute hemorrhagic shock seen in severe yellow fever.
- Other viral hemorrhagic fevers (Ebola, Lassa, Marburg): These may mimic severe yellow fever but differ in epidemiological setting and often have higher transmission risks.
Complications
Yellow fever can lead to severe issues affecting multiple body systems. The complications often arise during the toxic phase and can include critical organ damage and bleeding problems.
Organ Failure
The liver is the most severely affected organ in yellow fever. Viral injury to liver cells leads to jaundice, impaired detoxification, and reduced production of clotting factors. In severe cases, this progresses to fulminant hepatic failure, characterized by encephalopathy (confusion, altered consciousness) and coagulopathy (impaired blood clotting).
Kidney failure frequently accompanies liver dysfunction. Causes include direct viral injury, acute tubular necrosis (death of kidney tissue), or reduced blood flow due to shock and dehydration. Severe renal impairment often requires renal replacement therapy, such as dialysis, to support patient survival.
Other organs can also be compromised. The heart may develop myocarditis, an inflammation of the heart muscle that can result in arrhythmias or heart failure. The lungs may suffer from acute respiratory distress syndrome (ARDS), leading to severe breathing difficulties. Multi-organ failure significantly increases the mortality rate in yellow fever, with case-fatality rates for severe cases ranging from 20% to 50%.
Hemorrhagic Manifestations
Bleeding tendencies are a hallmark of advanced yellow fever and arise from multiple mechanisms, including impaired liver function (leading to reduced clotting factor production), direct viral damage to blood vessel walls, and low platelet counts (thrombocytopenia).
Hemorrhagic signs range from mild to severe. Common presentations include bleeding from the nose (epistaxis) and gums, gastrointestinal hemorrhage such as hematemesis (“black vomit” caused by digested blood) and melena (black, tarry stools), as well as blood in urine (hematuria). Bruising (ecchymoses) and pinpoint skin hemorrhages (petechiae) may also appear.
Severe hemorrhage is strongly associated with poor outcomes. Patients with uncontrolled bleeding require intensive supportive care, which may involve blood transfusions, plasma to replace clotting factors, and careful monitoring of coagulation status.
Neurological and Systemic Complications
In addition to organ and bleeding complications, some patients develop neurological symptoms, such as seizures, delirium, or coma, largely due to liver failure and its effects on the brain (hepatic encephalopathy). Systemic shock, electrolyte imbalances, and metabolic acidosis further complicate the clinical course.
Treatment Options
Treatment for yellow fever centers on managing symptoms and preventing complications. Medical care is primarily supportive, as no specific antiviral therapy exists. Close monitoring in a healthcare setting is often necessary.
Supportive Care
Supportive care for yellow fever is primarily aimed at relieving symptoms, maintaining vital organ functions, and preventing complications. One of the main priorities is preventing dehydration, which is achieved by administering fluids and electrolytes to stabilize blood pressure and ensure proper circulation. Oxygen therapy may also be required for patients experiencing respiratory distress or low oxygen levels, helping to maintain adequate oxygen supply to vital organs.
Fever and muscle pain are managed with antipyretics such as acetaminophen (paracetamol). However, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are strictly avoided, as they significantly increase the risk of bleeding—a serious complication of yellow fever. Close monitoring of liver and kidney function through regular laboratory tests is essential, since both organs are highly vulnerable to damage during the course of the illness.
In patients with severe bleeding or coagulation disorders, blood transfusions and clotting factor support may be necessary to control hemorrhage. Nutritional support also plays an important role, with easily digestible foods and vitamin supplementation recommended to aid recovery during prolonged illness. Furthermore, disturbances in electrolyte balance, particularly in sodium and potassium levels, are common in severe cases and must be corrected promptly to avoid complications. In patients who develop acute kidney failure, dialysis may be required to maintain renal function and improve survival outcomes.
Hospitalization Guidelines
Hospital admission is recommended for patients with moderate to severe illness, especially if they present with high fever, jaundice, bleeding signs, persistent vomiting, or neurological symptoms. Intensive care is often required for those with multi-organ dysfunction, shock, or severe hemorrhage.
Isolation is not typically required to prevent person-to-person spread, since yellow fever is not contagious through direct contact. However, mosquito control measures should be implemented within healthcare facilities to prevent local transmission, including the use of bed nets, insect repellents, and eliminating breeding sites around hospitals.
Yellow Fever Vaccination
The yellow fever vaccine is a live attenuated virus vaccine that provides strong protection against the disease. It is recommended for individuals traveling to or living in areas where yellow fever is endemic.
Vaccine Efficacy
The yellow fever vaccine induces immunity within 10 days for most recipients and provides protection for at least 10 years. Studies show that a single dose is about 99% effective at preventing yellow fever infection.
Booster doses were once recommended every 10 years, but current guidelines state one dose usually suffices for lifelong protection. Some travelers or certain populations may still require boosters based on risk assessment.
The vaccine stimulates an immune response that prevents virus replication, protecting against severe illness and death caused by yellow fever virus.
Who Should Be Vaccinated
Vaccination is recommended for people aged 9 months and older living in or traveling to yellow fever endemic areas in Africa and South America. Travelers must often show proof of vaccination before entry to some countries.
People working in laboratories with yellow fever virus exposure should also be vaccinated. Infants under 6 months should not receive the vaccine due to safety concerns.
Those with a fever or moderate to severe illness should delay vaccination until recovery. Travelers should consult healthcare providers to evaluate vaccination needs based on itinerary.
Side Effects and Contraindications
Common side effects include mild headaches, muscle pain, and low-grade fever. These symptoms typically resolve within a few days.
Severe allergic reactions are rare but possible. People with a history of severe allergy to vaccine components should avoid vaccination.
The vaccine is contraindicated in infants under 6 months, pregnant women, and individuals with compromised immune systems. Caution is required for those with thymus disorders or certain autoimmune diseases.
Healthcare providers assess risks and benefits individually to ensure safe vaccination administration.
Prevention Strategies
Effective prevention of yellow fever relies on reducing mosquito populations, advising travelers on vaccination and risk areas, and encouraging individuals to protect themselves from mosquito bites.
Mosquito Control Methods
Controlling Aedes aegypti and Haemagogus mosquitoes is crucial since they are the primary vectors in urban and sylvatic cycles, respectively. Methods include eliminating standing water where mosquitoes breed, such as containers, gutters, and discarded tires. Urban control programs often emphasize regular inspections of water storage systems and waste management to reduce breeding habitats.
Chemical controls like larvicides (applied to water surfaces to kill mosquito larvae) and adulticides (such as space spraying or fogging during outbreaks) can be applied in high-risk zones. These measures are most effective when combined with environmental management.
Biological controls, such as introducing fish that consume larvae or using Bacillus thuringiensis israelensis (Bti), a bacterium toxic to mosquito larvae but safe for humans, may also help. Newer approaches include sterile insect techniques (releasing sterilized male mosquitoes) and genetically modified mosquitoes that suppress vector populations.
Travel Recommendations
Vaccination before traveling to yellow fever endemic areas is the primary preventive measure. A single dose of the live-attenuated yellow fever vaccine confers long-lasting often lifelong protection. The World Health Organization (WHO) recommends vaccination at least 10 days prior to travel to ensure immunity.
Travelers should consult health authorities for updated risk maps and ensure they carry a valid International Certificate of Vaccination or Prophylaxis (ICVP), which is required for entry into many countries to prevent cross-border spread. Some countries also impose restrictions on unvaccinated travelers during outbreaks to limit importation risks.
Health professionals advise avoiding travel during outbreak periods if possible, especially for individuals who cannot be vaccinated due to medical contraindications (e.g., infants under 9 months, people with severe egg allergies, or those with weakened immune systems).
Personal Protective Measures
Individuals play a key role in prevention by adopting personal protective strategies. Wearing long-sleeved shirts and long pants, preferably in light colors, helps reduce mosquito bites. Using insect repellents containing DEET, picaridin, oil of lemon eucalyptus, or IR3535 on exposed skin is highly effective and widely recommended by WHO and CDC.
Sleeping under insecticide-treated bed nets remains important in rural and sylvatic transmission areas with high mosquito activity, especially at night, even though Aedes aegypti bites mainly during the day. Households should install window and door screens to limit mosquito entry indoors, and indoor residual spraying may be considered in outbreak-prone areas.
Reducing outdoor activity at dawn and dusk when many mosquito species are most active further lowers exposure risk. Education campaigns emphasizing consistent use of repellents, protective clothing, and bed nets have been shown to reduce infection rates.
Personal protective measures, when combined with vaccination and mosquito control, provide a multi-layered defense that significantly lowers the risk of yellow fever transmission and outbreaks.
Epidemiology and Outbreaks
Yellow fever is endemic in 34 countries across Africa and in 13 countries in Central and South America. Globally, between 900 million and one billion people live in areas considered at risk of transmission.
The clinical course of yellow fever progresses through several stages. After an incubation period of three to six days, patients may enter the initial phase, which is marked by fever, muscle pain, headache, and nausea. In most cases, symptoms resolve at this stage. However, about 15% of patients progress to a more severe “toxic phase,” characterized by recurring fever, jaundice, bleeding, and multi-organ failure. Mortality during this stage can approach 50% within seven to ten days.
The global burden of yellow fever is significant, with an estimated 200,000 cases and 30,000 deaths annually. Earlier modeling suggested that in 2013 alone, Africa experienced between 84,000 and 170,000 severe cases and between 29,000 and 60,000 deaths. Encouragingly, between 1990 and 2021, the number of annual cases declined from approximately 342,000 to about 86,500, and the incidence rate dropped from 6.08 to 1.15 cases per 100,000 population.
In the Americas, recent years have seen concerning surges. In 2024, there were 61 confirmed cases and 30 deaths reported across Bolivia, Brazil, Colombia, and Peru. By 2025, the situation escalated dramatically, with 221 confirmed cases and 89 deaths—an increase of more than eightfold compared to the previous year. Of these, Brazil reported 110 cases with 44 deaths, Colombia recorded 64 cases with 26 deaths, Peru registered 38 cases with 13 deaths, and Bolivia confirmed 3 cases with 1 death. During the first 15 epidemiological weeks of 2025, 189 confirmed cases and 74 deaths were reported across these four countries, with case fatality rates often ranging from 40% to 50%.
In Africa, trends between 2024 and 2025 also show a resurgence after years of decline. In 2024, 124 confirmed cases were reported across 12 countries. Uganda launched a national vaccination campaign targeting 14 million people, of which 12.2 million were vaccinated free of charge by April. This campaign was linked to mandatory vaccination proof for travelers and aligned with the World Health Organization’s Eliminate Yellow Fever Epidemics (EYE) Strategy, which aims to protect up to one billion people by 2026. Elsewhere in the region, yellow fever activity persisted; in 2023, 104 cases and 39 deaths were reported across nine African countries, including Cameroon, Nigeria, the Central African Republic, and Senegal.
Vaccine supply remains a major limitation in global yellow fever prevention. The current 17D vaccine, which is egg-based, cannot be rapidly scaled up to meet surging demand. Research into mRNA-based vaccines offers potential improvements in production agility, though development faces regulatory and political hurdles.