Causative Agent (Virus)

• Yellow Fever Virus (YFV)

• Genus: Flavivirus

• Family: Flaviviridae (same family as Dengue virus, West Nile virus, Zika virus, Japanese encephalitis virus)

• It is an RNA virus.

Reservoirs

• Humans: In urban cycles, humans are the primary reservoir, with mosquitoes transmitting the virus from person to person.

• Monkeys (Non-human primates): In jungle (sylvatic) cycles, monkeys are the primary reservoir, and mosquitoes transmit the virus among monkeys and occasionally to humans who enter the jungle.

Vector (How it Spreads)
The virus is transmitted to people primarily through the bite of infected female mosquitoes.

• Primary Mosquito Vectors:

  • Aedes aegypti: The main vector in urban areas. This mosquito also transmits dengue, chikungunya, and Zika. It breeds in domestic water containers.

  • Haemagogus species and Sabethes species: Main vectors in jungle (sylvatic) environments in South America.

  • Aedes africanus and other Aedes species: Main vectors in sylvatic and intermediate (savannah) environments in Africa.

• Mosquitoes acquire the virus by feeding on an infected human or monkey. After an extrinsic incubation period (time for the virus to replicate within the mosquito, usually 9-12 days), the mosquito becomes infectious and can transmit the virus to other hosts through its saliva when it bites.

Geographical Distribution
Yellow fever is endemic in tropical and subtropical areas of:

• Africa: Primarily sub-Saharan Africa.

• South America: Primarily the Amazon basin and surrounding areas.
  It is notably absent from Asia, despite the presence of Aedes aegypti mosquitoes, possibly due to cross-immunity from other flaviviruses or genetic factors.

Transmission Cycles

1. Jungle (Sylvatic) Cycle:

   • Involves transmission of the virus between non-human primates (monkeys) and mosquito species found in the forest canopy (e.g., Haemagogus, Sabethes in South America; Aedes africanus in Africa).

   • Humans working or living in or near jungle areas can be incidentally infected by these mosquitoes.

2. Intermediate (Savannah) Cycle (Africa only):

   • Occurs in humid and semi-humid savannahs of Africa.

   • Mosquitoes (e.g., various Aedes species) infect both monkeys and humans. Increased contact between people and infected mosquitoes leads to transmission. This is the most common type of outbreak in Africa.

3. Urban Cycle:

   • Involves transmission of the virus between humans and urban mosquitoes, primarily Aedes aegypti.

   • An infected person introduces the virus into a densely populated area with a high number of Aedes aegypti mosquitoes. This can lead to large epidemics.

Incubation Period
Typically 3 to 6 days after the bite of an infected mosquito.

Clinical Manifestations (Signs and Symptoms)
Yellow fever has a wide spectrum of illness, from asymptomatic or mild infection to severe, life-threatening disease. The illness classically occurs in two phases for those who develop severe disease, though many have only the first phase or a mild illness.

• Phase 1: Acute Phase (Period of Infection)

  • Onset is usually abrupt.

  • Symptoms:

    • Fever

    • Chills

    • Severe headache

    • Back pain

    • Generalized myalgia (muscle pain)

    • Nausea and vomiting

    • Fatigue and weakness

    • Dizziness

    • Facial flushing, conjunctival injection (red eyes)

  • Faget’s sign: A characteristic finding (though not always present) where the pulse rate is slow relative to the high fever (bradycardia with fever).

  • This phase usually lasts 3-4 days. Many people recover after this stage.

• Phase 2: Toxic Phase (Period of Intoxication)

  • About 15-25% of symptomatic patients enter this more severe phase after a brief period of remission (improvement for hours to a day).

  • Fever reappears, and more severe systemic illness develops.

  • Symptoms:

    • Jaundice: Yellowing of the skin and sclera (eyes) due to liver damage.

    • Hemorrhagic manifestations:

      • Epistaxis (nosebleeds)

      • Gingival bleeding (bleeding gums)

      • Hematemesis (“black vomit” due to bleeding into the stomach)

      • Melena (black, tarry stools)

      • Petechiae, purpura, ecchymoses (skin hemorrhages)

      • Bleeding from injection sites

    • Hepatic dysfunction: Liver damage leads to jaundice and impaired production of clotting factors.

    • Renal dysfunction: Kidney failure (oliguria, anuria, albuminuria).

    • Myocardial injury: Can lead to arrhythmias or heart failure.

    • Abdominal pain.

    • Delirium, seizures, coma (due to multi-organ failure or encephalitis).

    • Shock.

  • The toxic phase is associated with high mortality (20-50% or higher for those who enter this phase). Death usually occurs 7-10 days after onset.

Diagnosis
Diagnosis can be difficult, especially in the early stages, as symptoms can be confused with other febrile illnesses like malaria, dengue, leptospirosis, or viral hepatitis.

• 1. Virological Tests (Early phase of illness, first few days):

  • Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR): Detects viral RNA in blood or tissue samples. Most sensitive in the first 5 days of illness.

  • Virus Isolation: Culturing the virus from blood or tissue. Technically demanding and requires specialized labs.

• 2. Serological Tests (Later phase of illness, after about 5-7 days):

  • Detection of IgM antibodies: IgM antibodies usually appear by the end of the first week of illness and indicate recent infection.

    • Yellow fever-specific IgM capture ELISA.

  • Detection of IgG antibodies: IgG antibodies appear shortly after IgM and persist for life, indicating past infection or vaccination. A fourfold rise in IgG titer between acute and convalescent phase sera can also confirm infection.

  • Cross-reactivity with other flaviviruses (e.g., dengue, Zika) can complicate serological diagnosis, so Plaque Reduction Neutralization Test (PRNT) may be needed for confirmation, as it is more specific.

• 3. Other Laboratory Findings (Suggestive, not diagnostic):

  • Leukopenia (low white blood cell count) with relative neutropenia in the early phase.

  • Elevated liver enzymes (AST and ALT dramatically increased, often AST > ALT).

  • Elevated bilirubin (correlates with jaundice).

  • Prolonged prothrombin time (PT) and partial thromboplastin time (PTT) (due to impaired clotting factor synthesis by the liver).

  • Thrombocytopenia (low platelet count).

  • Albuminuria (protein in urine).

  • Post-mortem liver biopsy shows characteristic mid-zonal necrosis (Councilman bodies), but this is rarely done for diagnosis in living patients due to bleeding risk.

Treatment

• There is no specific antiviral treatment for yellow fever.

• Treatment is supportive and symptomatic, aimed at managing complications.

• This includes:

  • Rest.

  • Fluid replacement and electrolyte balance (oral or intravenous) to manage dehydration.

  • Analgesics and antipyretics for fever and pain (e.g., paracetamol). Avoid aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen as they can increase the risk of bleeding.

  • Management of nausea and vomiting.

  • Close monitoring of vital signs, fluid balance, and organ function.

• Hospitalization is recommended, especially for moderate to severe cases, to manage potential complications such as:

  • Bleeding (may require blood transfusions or clotting factors).

  • Kidney failure (may require dialysis).

  • Liver failure.

  • Shock.

  • Secondary bacterial infections (may require antibiotics).

Prevention
Prevention is key and relies on vaccination and mosquito control.

• 1. Vaccination:

  • A highly effective, safe, and affordable live-attenuated viral vaccine (17D strain) provides lifelong immunity against yellow fever for most people after a single dose.

  • Recommended for people aged 9 months or older living in or traveling to areas at risk of yellow fever transmission.

  • An International Certificate of Vaccination or Prophylaxis (ICVP or “yellow card”) is often required for entry into certain countries, particularly for travelers coming from or transiting through yellow fever risk areas.

  • Contraindications/Precautions:

    • Infants under 6 months of age (higher risk of vaccine-associated neurotropic disease).

    • Individuals with severe immunodeficiency (e.g., symptomatic HIV/AIDS, primary immunodeficiencies, recent chemotherapy or radiation, high-dose corticosteroids).

    • Individuals with a thymus disorder associated with abnormal immune function (e.g., myasthenia gravis, thymoma).

    • Severe allergy to a vaccine component (e.g., eggs, gelatin, chicken protein).

    • Caution in pregnant women (vaccinate only if risk of exposure is high and unavoidable), breastfeeding women, and individuals ≥60 years of age (higher risk of severe adverse events).

• 2. Mosquito Control (Vector Control):

  • Reducing mosquito breeding sites: Eliminating standing water where Aedes aegypti mosquitoes breed (e.g., in tires, flower pots, water storage containers).

  • Larviciding: Using insecticides to kill mosquito larvae in breeding sites.

  • Adulticiding (Fogging/Spraying): Using insecticides to kill adult mosquitoes, especially during outbreaks.

  • Personal protective measures:

    • Using insect repellent containing DEET, picaridin, or IR3535 on exposed skin.

    • Wearing long-sleeved shirts and long pants, especially during peak mosquito biting times.

    • Using mosquito nets (preferably insecticide-treated) when sleeping in areas without screens.

    • Staying in well-screened or air-conditioned accommodations.

• 3. Surveillance and Outbreak Response:

  • Early detection of cases and outbreaks through robust surveillance systems (human and animal).

  • Rapid vaccination campaigns for at-risk populations during outbreaks.

  • Intensified vector control measures.

Prognosis

• Many yellow fever infections are mild or asymptomatic.

• For those who develop severe disease (toxic phase), the case fatality rate can be 20-50% or higher.

• Recovery from severe yellow fever can be prolonged, with fatigue and weakness lasting for weeks or months.

• Those who recover generally have lifelong immunity.

Yellow fever remains a significant public health threat in endemic regions, highlighting the importance of vaccination and sustained vector control efforts.