Yellow Fever

• Disease Overview: Yellow fever is a mosquito-borne viral illness.
• Geographical Distribution: It occurs in tropical and subtropical areas of South America and Africa.
• Transmission: The virus is transmitted primarily through the bites of Aedes and Haemagogus species of mosquitoes.
• Symptoms and Severity: Clinical features vary widely, from a mild febrile illness to severe cases involving hemorrhage and liver disease. Jaundice, which gives the disease its name “yellow,” occurs in severe cases. Severe disease symptoms include jaundice, multi-organ failure, hemorrhagic complications, and shock.
• Diagnosis: Diagnosis is based on travel history to endemic areas, exposure to mosquitoes, vaccination status, clinical symptoms, and laboratory findings.
• Disease Course: While most cases are mild and resemble other viral infections, severe disease can have a mortality rate up to 50%.
• Human Role in Transmission: Infected humans can transmit the virus to mosquitoes during the viremic phase, which can further spread the infection.
• Treatment: No specific antiviral treatment is available.
• Prevention: Vaccination is highly recommended for travelers to endemic areas. Preventing mosquito bites remains critical in avoiding the disease.

Etiology

• Virus Classification: Yellow fever is caused by an RNA virus belonging to the genus Flavivirus, related to viruses that cause West Nile, St. Louis, and Japanese encephalitis.
• Transmission Vectors: The virus is transmitted by tree-hole breeding mosquitoes, notably Aedes aegypti and Haemagogus species.
• Transmission Cycles: There are three distinct cycles:
  • Jungle Cycle: Involves transmission between non-human primates and mosquitoes. Humans get infected via mosquito bites in jungle areas.
  • Intermediate (Savannah) Cycle: Occurs in the African savannah, affecting humans living or working at jungle borders. Transmission can occur directly between monkeys and humans or from humans to humans via mosquitoes.
  • Urban Cycle: Begins when a viremic human from a jungle or intermediate area enters an urban setting, enabling the transmission of the virus to other humans through mosquitoes.
• All three transmission cycles are present in Africa, with jungle transmission predominating in South America.
• Yellow fever is restricted to Africa and South America, despite the global presence of the Aedes aegypti mosquito.
• The peak transmission periods are January to March in South America and July to October in Africa.
• The World Health Organization estimates around 200,000 cases of YF annually, likely an underestimate due to underreporting and asymptomatic cases.
• Historically, the highest burden of YF has been in West Africa, with significant outbreaks in Angola and Brazil.
• The risk of yellow fever for travelers is based on risk estimates in indigenous populations:
  • West Africa: Estimated risk for illness and death for an unvaccinated traveler for a 2-week stay is 50 per 100,000 and 10 per 100,000, respectively.
  • South America: Estimated risk is 5 per 100,000 for illness and 1 per 100,000 for death.
• Transmission Note: Direct transmission from person to person or primate to human without mosquito involvement has not been observed.

Pathophysiology

• Incubation Period: Ranges from 3 to 6 days.
• Organ Involvement: The virus rapidly disseminates to multiple organs after entry.
  • Liver: Most significantly affected, leading to severe jaundice due to damage.
  • Kidneys: Can suffer damage similar to the liver, potentially resulting in acute renal failure.
  • Upper GI Tract: Involvement can lead to black vomit, caused by mixing of gastric acids with blood.
  • Central Nervous System: Features include cerebral edema, hemorrhage, and commonly encephalopathy.

Differential Diagnosis

The differential diagnosis of yellow fever is broad and makes a careful travel history important. It includes:

• Viral hemorrhagic fevers
• Viral hepatitis
• Malaria
• Lassa fever
• Ebola virus
• Typhoid fever
• Dengue fever
• Disseminated Intravascular Coagulation
• Louse-borne relapsing fever
• West Nile virus encephalitis
• Japanese encephalitis
• Herpes simplex encephalitis
• Eastern and Western equine encephalitis
• Venezuelan Equine encephalitis
• Enterovirus meningitis
• Mycoplasma meningitis
• Cytomegalovirus infection in immunocompromised host
• Tuberculous meningitis
• Nipah virus infection
• Rocky Mountain spotted fever
• Fungal meningitis
• Leptospirosis
• Neurocysticercosis
• Amebic meningoencephalitis 

History and Physical Examination

• Travel and Immunization History: Important to establish exposure risk.
• Symptoms: Patients may present with headache, malaise, jaundice, myalgias, severe back pain, chills, and fever.
• Remission and Recurrence: A brief remission period may be followed by a resurgence of symptoms and severe intoxication.
• Physical Findings: Key signs include Faget sign (pulse-temperature dissociation), facial flushing, conjunctival injection, jaundice, dark urine, and potential bleeding in mucous membranes and the gastrointestinal tract.

Evaluation

• Diagnostic Tests:
  • Antigen Detection: Monoclonal enzyme immunoassay in serum.
  • Genomic Detection: Polymerase chain reaction (PCR) for viral genome sequences.
  • Serological Tests: ELISA and antibody titers.
  • Imaging and Other Tests: Lumbar puncture, CT scans for CNS involvement, chest X-ray for respiratory distress, ECG for cardiac issues.
  • Blood Work: Typically shows leukopenia, elevated transaminase levels, neutropenia, and possibly abnormal coagulation profiles.

Treatment / Management

• Reportable Disease: Yellow fever is a reportable infection, and cases must be communicated to health authorities.
• Symptom Onset: Symptoms usually appear 3 to 6 days after infection.
• Supportive Care: There is no specific treatment for yellow fever. Management focuses on supportive care, especially in severe cases:
  • Hydration and monitoring in an Intensive Care Unit (ICU).
  • Monitoring for Complications: Such as disseminated intravascular coagulation (DIC), hemorrhage, and kidney and liver dysfunction.
  • Coagulopathy Management: Administering fresh frozen plasma.
  • Renal Support: Dialysis may be necessary for renal failure.
• Isolation and Precautions:
  • Isolate patients until diagnosis is confirmed to prevent mosquito transmission.
  • Follow universal precautions when treating patients, although human-to-human transmission via contact is not a concern.
  • Prevent patients from exposing themselves to mosquitoes to avoid further spread.
• Complications
  • Multiorgan failure
  • ARDS
  • Sepsis
  • Respiratory failure
  • Myocarditis
  • Encephalitis
  • Hemorrhage
  • DIC

Vaccination

• Live-attenuated Vaccine(Stamaril): A safe and effective vaccine is available and recommended for travelers and residents in endemic areas.
  • Efficacy: One dose provides lifelong immunity for 99% of recipients and becomes effective within 30 days.
  • Composition: It is a heat-stable, lyophilised live attenuated vaccine using the 17D-204 strain of YF virus, grown in chicken embryos.
  • Dosage and Administration:
    • Dose for Adults and Children: 0.5 mL administered via intramuscular (IM) or subcutaneous (SC) injection for individuals aged ≥9 months.
    • Booster Dose: A single 0.5 mL dose if required.
  • Side Effects:
    • Mild Reactions: Include mild headache, myalgia, low-grade fever, occurring in 2-5% of vaccinees, typically 5-10 days post-vaccination.
    • Immediate Hypersensitivity Reactions: Rare, occurring in less than 1:1,000,000 recipients, including rash, urticaria, and/or asthma, predominantly in those with egg allergies.
    • Severe Hypersensitivity: Anaphylaxis occurs at a rate of 1.8 per 100,000 doses.
  • Serious Adverse Events:
    • Yellow Fever Vaccine-Associated Neurotropic Disease (YEL-AND):
      • About 50 cases documented, mostly in infants under 7 months historically, but now also reported in adults.
      • Recovery usually rapid and complete; estimated incidence between 4 to 6 cases per 1,000,000 doses.
    • Yellow Fever Vaccine-Associated Viscerotropic Disease (YEL-AVD):
      • Over 100 cases since 1973; presents like yellow fever initially, can progress to severe organ failure and death.
      • Case-fatality ratio is approximately 65%.
      • Higher risk in individuals over 60 years; incidence of 1.2 per 100,000 doses, rising to much higher rates in those over 75.
      • History of thymus disease significantly increases risk.
      • YEL-AVD is almost exclusively seen in primary vaccine recipients.

International Travel Requirements for Yellow Fever

• What You Need for Travel:
  • If you’re traveling from a country with yellow fever risk, you’ll need to show one of the following:
    • Vaccination Certificate: An International Certificate of Vaccination or Prophylaxis (ICVP) showing you’ve been vaccinated against yellow fever. Proof of vaccination is not valid until 10 days after getting the vaccine, the time needed to develop immunity to yellow fever virus. A single dose of yellow fever vaccine protects most people for life, but a booster dose after 10 years may be recommended for some travelers.
    • Exemption Letter: A medical exemption letter if you can’t get vaccinated due to health reasons.
• Requirements for Transit:
  • Some countries ask for these documents even if you’re just passing through their airport, especially if your layover is longer than 12 hours.
• Validity of Vaccination Certificate:
  • Since 2016, the vaccination certificate lasts a lifetime based on WHO guidelines that show one vaccination provides decades of protection.
• Before You Travel:
  • Check the yellow fever entry requirements for any countries you plan to visit or transit through by contacting their embassies or consulates.

Australia’s Travel Requirements for Yellow Fever

• Who Needs a Vaccination:
  • Travelers over 1 year old must have a valid International Certificate of Vaccination or Prophylaxis (ICVP) if they:
    • Enter Australia within 6 days after leaving a country listed on Australia’s yellow fever–declared places.
    • Stayed overnight or longer in an at-risk area.
• Where to Get Vaccinated:
  • Only accredited Yellow Fever Vaccination Centres can administer yellow fever vaccinations and issue ICVPs. These centers are approved by relevant state or territory health authorities.
• Certificate Requirements:
  • The ICVP must include:
    • Name of the vaccinated person.
    • Date of vaccination (day, month in letters, and year).
    • Type of vaccine received.
    • Manufacturer and batch number of the vaccine.
    • Signature and professional status of the health professional administering the vaccine.
    • Official stamp from the administering center.
    • Signature of the vaccinated person or their guardian.
• Validity of ICVP:
  • As of June 16, 2016, an ICVP is valid for the lifetime of the vaccinated person.
  • The certificate becomes valid 10 days after vaccination.
• Upon Arrival Without a Valid ICVP:
  • Travelers arriving without a valid ICVP are given information about yellow fever and are advised to seek medical assessment if they develop symptoms related to yellow fever within 6 days of leaving a yellow fever–declared place.
• Additional Information:
  • A list of yellow fever–declared places is available from the Australian Government Department of Health.

Other Specific Country Requirements:

• India:
  • Strict vaccination requirements for travelers over 6 months old arriving within 6 days from areas with YFV transmission risk.
  • Countries reporting yellow fever cases are listed as ‘infected’ by the Indian government.
  • Travelers arriving by ship must show vaccination proof if they stopped at any port in a country with yellow fever risk 30 days before arrival.
  • Detention in isolation for up to 6 days is possible for travelers without a valid ICVP.
• Malaysia and Singapore:
  • Both require a valid ICVP from travelers arriving from countries with yellow fever transmission.
  • This includes travelers who transit for more than 12 hours in an airport located in a YF risk country.
  • Age exemption for vaccination proof is 1 year or older

Exemptions to Yellow Fever Vaccination

• Who Can Be Exempted:
  • People who have a medical contraindication to the yellow fever vaccine can still travel to countries where there is a risk of yellow fever transmission.
  • Specific Contraindications:
    • Anaphylaxis to Vaccine Components: Contraindicated in individuals who have experienced anaphylaxis after:
      • A previous dose of any yellow fever vaccine.
      • Any component of a yellow fever vaccine.
      • Eggs (though some children with egg allergies may be safely vaccinated under specialist supervision).
    • Infants: Generally contraindicated for those under 9 months due to severe adverse event risks. Exceptions may be made during mass outbreaks starting from 6 months of age.
    • Immunocompromised Individuals: The vaccine is usually not recommended due to the risk of severe vaccine-related adverse events and poor immunogenicity.
    • Thymus Disorders: Contraindicated for individuals with a history of thymus disorders due to the risk of yellow fever vaccine-associated viscerotropic disease.
  • Precautions
    • Adults Aged ≥60 Years: Higher risk of severe adverse events. Vaccination should only be considered if traveling to endemic areas and informed of potential risks.
    • Haematopoietic Stem Cell Transplant Recipients: Recommended to receive an additional vaccine dose if at risk, regardless of last vaccination timing.
    • People with HIV: Can be vaccinated unless severely immunocompromised or symptomatic. Reduced immune response but generally well-tolerated.
    • People with Possible IFNAR1 Deficiency: A condition affecting some of Western Polynesian heritage; associated with severe reactions to certain live vaccines. Seek immunologist advice before vaccination.
  • Special Considerations
    • Pregnant Women:
      • Generally contraindicated due to risks associated with live vaccines.
      • If travel is unavoidable and risk of yellow fever is high, vaccination might be considered.
      • No evidence of adverse outcomes from vaccination during pregnancy; reassurance can be given if vaccinated early in pregnancy.
    • Breastfeeding Women:
      • Avoid vaccination if breastfeeding infants under 9 months.
      • If exposure to yellow fever cannot be avoided, vaccination should be considered despite potential risks.
      • Rare cases of transmission through breast milk have been documented, but long-term outcomes in infants have been normal.
• Requirements for an Exemption Letter:
  • The exemption letter must be dated and signed, written on the letterhead stationery of an accredited Yellow Fever Vaccination Centre.
  • The letter should clearly state that the yellow fever vaccine is medically contraindicated.
  • It must display the official stamp of the centre, which is provided by the relevant state or territory health authority.
  • Medical exemption letters should be specific to the current trip. For subsequent trips, a new exemption letter is required.
• Incorporation into ICVP:
  • The immunization provider must complete, stamp, and sign the “Medical Contraindications to Vaccination” section of the International Certificate of Vaccination or Prophylaxis (ICVP).
• Upon Arrival in Australia with an Exemption:
  • Travelers arriving in Australia with a medical exemption letter for yellow fever are given information about the disease.
  • They are advised to seek medical assessment promptly if they develop symptoms associated with yellow fever within six days of leaving a yellow fever-declared area.
• Travel to Other Countries:
  • Travelers needing an exemption for yellow fever vaccination when traveling to other countries should contact the foreign embassy or consulate of the destination country in Australia.
  • The embassy or consulate can advise on the necessary language(s) for the exemption letter.

Mosquito Bite Prevention Strategies

• using insect repellents containing at least 30% DEET
• using mosquito nets (preferably insecticide-treated nets)
• minimising outdoor exposure at dusk and dawn – peak mosquito feeding times
• permethrin-treated clothing
• wearing long-sleeved garments
• sleeping in air-conditioned or well-screened areas.
• removing standing water to prevent mosquito breeding.

Prognosis and Complications

• Variable Outcomes: Yellow fever ranges from subclinical to life-threatening; approximately 10-25% of patients develop severe symptoms including jaundice, fever, and multi-organ failure.
• Case Fatality Rates: These vary by region; they are generally lower in West Africa compared to South America. Overall mortality rates for severe cases can range from 3% to 70%, depending on the virulence of the infecting strain and the patient’s condition.
• Critical Period: The most severe outcomes and deaths usually occur within the first 10 days of the toxic phase of the infection.
• Risk Groups: Higher mortality rates are observed in infants, the elderly, and unvaccinated individuals. Post-vaccination complications, though rare, can include neurological and viscerotropic reactions.

Considerations for Eradication

• Challenges to Eradication: Due to factors like sylvatic transmission cycles (involving nonhuman primates), deforestation, urbanization, and limited resources, eradication of yellow fever is unlikely in the near future.
• Public Health Strategy: Continuous effort is required to manage and prevent yellow fever through vaccination, public education on mosquito control, and maintaining robust surveillance systems to monitor and respond to outbreaks.