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Basic Information ⬇

AUTHOR: Glenn G. Fort, MD, MPH

Definition

Yellow fever is a mosquito-borne infection, primarily of the liver, with systemic manifestations caused by the yellow fever virus (YFV), a flavivirus that infects the liver. The clinical spectrum ranges from asymptomatic infection to life-threatening disease with severity and mortality highest in the elderly.

Synonym

Tropical hemorrhagic fever from YFV

ICD-10CM CODE
A95.9Yellow fever, unspecified
Epidemiology & Demographics
Geographic Distribution

  • South America and Africa, in countries between +15 and -15 degrees latitude (Fig. E1)
  • The World Health Organization estimates there are more than 200,000 cases/yr with 30,000 deaths/yr. >90% of cases occur in Africa
  • Outbreaks of yellow fever occurred in 2015 to 2018 in Angola and starting in 2016 in Brazil, which led that nation to recommend vaccination for the entire country instead of provinces that had traditionally had cases. In 2021, nine west African countries reported cases

Figure E1 Geographic distribution of yellow fever in Africa and the Americas.

From Cherry JD et al: Feigin and Cherry’s textbook of pediatric infectious diseases, ed 8, Philadelphia, 2019, Elsevier.

Incidence

Approximate attack rates of 3% in Africa and Amazon

Prevalence

Endemic areas: 20% of population

Predominant Sex

In Africa and the Amazon, male agricultural workers

Physical Findings & Clinical Presentation

  • Most patients with yellow fever are asymptomatic.
  • The onset of illness appears suddenly 3 to 6 days after the bite of an infected mosquito.
  • Viremic (early) phase:
    1. Fever, chills
    2. Severe headache
    3. Lumbosacral pain
    4. Myalgias, nausea, malaise
    5. Conjunctivitis
    6. Relative bradycardia (Faget sign)
  • After brief recovery, toxic phase:
    1. Jaundice
    2. Oliguria
    3. Albuminuria
    4. Hemorrhage
    5. Encephalopathy
    6. Shock
    7. Acidosis
  • Case-fatality rate: 25% to 50%.
Etiology

  • YFV (L. flavus): Small enveloped single-strand RNA virus
    1. Flavivirus infects hepatic cells
    2. Late in infection, cytopathic effects (antibody- and cell-mediated) produce pathology
  • Vector
    1. Aedes aegypti (urban)
    2. Aedes spp., Haemagogus (especially in Amazon) mosquitos (sylvan)
    3. Primary hosts: Humans and simian species
    4. Exists in two transmission cycles:
      1. Sylvatic or jungle cycle involving mosquitoes and nonhuman primates
      2. Urban cycle involving mosquitoes and humans
Pathogenesis & Pathology

  • Virus replication begins at site of mosquito bite, spreading to lymphatic channels and regional lymph nodes. Viremic spread to other organs, especially liver, spleen, and bone marrow.
  • Shock and fatal illness result from direct damage to organs and vasoactive cytokines.
  • Viral antigen found in hepatocytes, kidneys, and myocardium.
  • Midzone necrosis of liver lobules primarily affected and is highly characteristic.
  • Hemorrhages of mucosal surfaces of GI tract.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Viral hepatitis
  • Leptospirosis
  • Malaria
  • Typhoid fever
    1. Typhus
    2. Relapsing fever
  • Other hemorrhagic fevers such as dengue and Ebola (Table E1)

TABLE E1 Viral Hemorrhagic Fevers (HFs)

Mode of TransmissionDiseaseVirus
Tick-borneCrimean-Congo HF∗Congo
Kyasanur Forest diseaseKyasanur Forest disease
Omsk HFOmsk
Mosquito-borne†Dengue HFDengue (four types)
Rift Valley feverRift Valley fever
Yellow feverYellow fever
Infected animals or materials to humansArgentine HFJunin
Bolivian HFMachupo
Lassa fever∗Lassa
Marburg disease∗Marburg
Ebola HF∗Ebola
HF with renal syndromeHantaan

∗Patients may be contagious; nosocomial infections are common.

† Chikungunya virus is associated infrequently with petechiae and epistaxis. Severe hemorrhagic manifestations have been reported in some cases.

Laboratory Tests

  • CBC
    1. Mild leukopenia
    2. Thrombocytopenia
    3. Anemia
  • Liver function tests (FTs)
    1. Aspartate aminotransferase (AST) levels exceed alanine transaminase (ALT) levels
    2. Alkaline phosphatase normal or slightly elevated
    3. Elevated bilirubin levels
  • Elevated blood urea nitrogen (BUN) and creatinine
  • Proteinuria
  • Coagulation studies
    1. Demonstrate abnormal prothrombin time or
    2. Reveal disseminated intravascular coagulation
  • Terminal hypoglycemia
    1. Cerebrospinal fluid (CSF)
    2. Pleocytosis
    3. Elevated protein count
  • Specific diagnosis confirmed by:
    1. Viral isolation from blood: Labor-intensive and may take weeks
    2. Viral antigen in serum (ELISA)
    3. Viral RNA by polymerase chain reaction (PCR) in blood or tissue
    4. Immunoglobulin M-capture ELISA
      1. Preferred serologic test
      2. Appears within 5 to 7 days
      3. Rising antibody confirmed by paired sera
      4. Cross-reactivity with other flavivirus infections
    5. Immunohistochemical staining of postmortem liver biopsy specimens

Treatment ⬆ ⬇

Acute General Rx

  • Acetaminophen (for headache and fever) and H2 blockers (GI bleeding); avoid aspirin because of bleeding risk
  • Blood transfusion, volume replacement for hemorrhage and shock
  • Dialysis for renal failure
  • Avoidance of sedatives and drugs dependent on hepatic metabolism
Disposition

Follow up until hepatic, renal, central nervous system (CNS) disease resolved. Infection in humans is capable of producing hemorrhagic fever and is fatal in 20% to 50% of persons with severe disease.

Referral

To infectious diseases expert for accurate diagnosis and management

Pearls & Considerations ⬆ ⬇

Prevention

  • Yellow fever is preventable by immunization.
  • Recovery from yellow fever confers lasting immunity.
  • Live, attenuated yellow fever vaccine (YF-Vax) provides protective immunity in 95% of vaccinated patients within 10 days of vaccination. Reimmunization had been recommended at 10-yr intervals for travelers, but in June 2015 the U.S. Advisory Committee on Immunization Practices (ACIP) issued recommendations stating that a single primary dose of a yellow fever vaccine is adequate for most travelers, and in June 2016 the WHO recommended to stop requiring vaccine reimmunization, as one dose confers lifelong immunity. Vaccine certificate to verify immunization status is required before travel in many tropical countries in South America and Africa. Vaccine nonresponders are uncommon but exhibit excess antiinflammatory cytokine profiles and with high levels of T-regulatory cells; this problem is more likely to be observed in elderly individuals. Contraindications and precautions to yellow fever vaccine administration are summarized in Table E2.
  • The ACIP still recommends reimmunization for the following:
    1. Women who were pregnant at time of first vaccine
    2. Recipients of hematopoietic stem cell transplant
    3. Individuals who were HIV positive (CD4+ >200) at the time of first vaccination
    4. Individuals who plan to spend extensive time in endemic areas or travel to highly endemic areas (West Africa)
    5. Laboratory personnel who handle the yellow fever virus
  • Vaccine contraindicated in:
    1. Infants <6 mo (postvaccinal encephalitis)
    2. Immunosuppressed patients, such as those with HIV <200 CD4+ count, leukemia, and lymphoma
    3. Pregnant women and nursing mothers, as it is a live weakened virus. Vaccine can be given in pregnancy and breastfeeding if the risk of acquiring the disease from travel to areas involved with the disease is significantly higher than the vaccination risks
    4. Patients with egg hypersensitivity
  • Adverse effects of vaccine:
    1. General
      1. Mild headaches, myalgias, low-grade fevers (25% vaccinees in clinical trials)
      2. Immediate hypersensitivity reaction (history of egg allergy)
    2. Vaccine-associated neurotropic disease (postvaccine encephalitis) (1.8 cases/million)
      1. Primarily among infants
      2. Adult cases only in first-time vaccine recipients
    3. Vaccine-associated viscerotropic disease (2.2 cases/million)
      1. Disease syndrome resembling wild-type yellow fever, often fatal
      2. All cases in first-time vaccinees; age >60 yr are at particular risk
  • Yellow fever vaccine response can be significantly reduced by coadministration of the live virus combined vaccine with measles, mumps, and rubella.
  • YF-Vax became unavailable in the U.S. in mid-2017, and the shortage lasted until April 2022. An alternative but similar formulation, Stamaril (manufactured in Europe), was available under the FDA’s Expanded Access Program at high-volume yellow-fever vaccination centers.

TABLE E2 Contraindications and Precautions to Yellow Fever Vaccine Administration

Contraindications
Allergy to vaccine component
Age <6 mo
Symptomatic HIV infection or CD4+ T lymphocytes <200/mm3 (or <15% of total in children aged <6 yr)∗
Thymus disorder associated with abnormal immune function
Primary immunodeficiencies
Malignant neoplasms
Transplantation
Immunosuppressive and immunomodulatory therapies
Precautions
Age 6-8 mo
Age ≥60 yr
Asymptomatic HIV infection and CD4+ T lymphocytes 200-499/mm3 (or 15%-24% of total in children aged <6 yr)∗
Breastfeeding
Pregnancy

∗Symptoms of HIV infection are classified in Panel on Antiretroviral Guidelines for Adults and Adolescents: Guidelines for the use of antiretroviral agents in adults and adolescents with HIV, Washington, DC, 2019, U.S. Department of Health and Human Services.

From Ryan ET et al: Hunter’s tropical medicine and emerging infectious diseases, ed 10, New York, 2020, Elsevier.

Suggested Readings ⬆

  1. Reno E. : Prevention of yellow fever in travellers: an updateLancet Infect Dis. ;20:e129-e137, 2020.
  2. Staples J.E. : Yellow fever vaccine booster doses: recommendations of the Advisory Committee on Immunization PracticesMMWR (Morb Mortal Wkly Rep). ;64(23):647-650, 2015.
  3. Waggoner J.J. : Yellow fever virus: diagnostics for a persistent arboviral threatJ Clin Microbiol. ;56(10), 2018.