Yellow Fever Virus

Yellow fever is a disease caused by the yellow fever virus, a single-stranded, positive-sense RNA virus of the genus Flavivirus. Humans and primates serve as reservoirs, and transmission occurs from the bite of an infected female mosquito. Most patients present with fever and flu-like symptoms. Severe disease can cause multiorgan dysfunction resulting in jaundice, renal dysfunction, hemorrhage, shock, and potential death. The diagnosis can be confirmed with serology and PCR. There is no antiviral treatment, so management is supportive. Prevention includes mosquito avoidance and vaccination.

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Classification

RNA Viruses Flowchart Classification

RNA virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA or RNA. RNA genome viruses can be further characterized by either a single- or double-stranded RNA. “Enveloped” viruses are covered by a thin coat of cell membrane (usually taken from the host cell). If the coat is absent, the viruses are called “naked” viruses. Viruses with single-stranded genomes are “positive-sense” viruses if the genome is directly employed as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses employ RNA dependent RNA polymerase, a viral enzyme, to transcribe their genome into messenger RNA.

Image by Lecturio. License: CC BY-NC-SA 4.0

General Characteristics and Epidemiology

Basic features of yellow fever virus

  • Taxonomy:
    • Family: Flaviviridae
    • Genus: Flavivirus
  • RNA virus:
    • Single-stranded
    • Positive-sense
    • Linear
  • Spherical
  • Icosahedral symmetry
  • Enveloped
  • Size: 40–60 nm
Yellow fever virus particles

Transmission electron microscopic image of yellow fever virus particles.
Virions are spheroidal, uniform in shape, and 40‒60 nm in diameter.

Image: “2176” by Erskine Palmer. License: Public Domain

Clinically relevant species

Yellow fever virus has only 1 serotype, which causes the disease (yellow fever).

Epidemiology

  • Approximately 200,000 infections per year worldwide
  • Approximately 30,000 deaths per year
  • Distribution:
    • South America
    • Sub-Saharan Africa (approximately 90% of cases)

Pathogenesis

Reservoirs

  • Humans
  • Primates

Transmission

Vectors:

  • Aedes mosquitoes
  • Haemagogus mosquitoes

Transmission cycles:

  • Jungle (sylvatic):
    • Cycle occurs between nonhuman primates and mosquitoes.
    • Humans become infected while working in or visiting the jungle.
  • Intermediate (savannah):
    • Cycle occurs between primates, humans, and mosquitoes.
    • Occurs in the African savannah in those who live in jungle border regions
  • Urban:
    • Cycle occurs between humans and mosquitoes.
    • The virus is brought to the urban setting by a human who was infected in the jungle or savannah.
Aedes aegypti bloodfeeding

Aedes aegypti feeding on human skin

Image: “Aedes aegypti bloodfeeding CDC Gathany” by James Gathany. License: Public Domain

Viral replication cycle

  • Virus binds to target cells via receptors → endocytosis
  • ↓ pH in the endosome → fusion of the endosomal membrane with the virus envelope → injection of nucleocapsid into the cytoplasm
  • Nucleocapsid disintegration → replication of the viral genome in the rough endoplasmic reticulum
  • Immature particles are processed in the Golgi apparatus → mature → released as an infectious virion

Pathophysiology

  • Mosquito feeds → inoculates virus into the host
  • Replication occurs at the inoculation site (dendritic cells).
  • Spreads through lymphatics → regional lymph nodes
  • Replication occurs in macrophages/monocytes.
  • Spreads through lymphatics → bloodstream → organs (particularly liver) and tissues
  • Viral replication in organ tissues results in:
    • Eosinophilic degeneration
    • Apoptosis
    • Fatty change
  • Effects:
    • Liver damage
    • Renal failure
    • Cerebral edema
    • Systemic inflammatory response → shock

Clinical Presentation

The incubation period is 3–6 days. Clinical features range from a self-limited, mild febrile illness (majority of cases) to severe, life-threatening disease.

Period of infection

The following early symptoms are nonspecific: 

  • Fever and chills
  • Headache
  • Photophobia
  • Malaise
  • Myalgias
  • Lower back pain
  • Nausea
  • Anorexia
  • Dizziness

Period of intoxication

After a 48-hour period of remission, a minority of patients will develop symptoms of severe yellow fever. This period presents with high fever and multiorgan dysfunction.

  • Hepatic dysfunction: jaundice
  • Renal dysfunction: oliguria
  • Hemorrhage (from hepatic dysfunction and DIC):
    • Epistaxis
    • Melena
    • Hematemesis (black vomit)
    • Hematuria
  • Pancreatitis:
    • Nausea and vomiting
    • Epigastric pain
  • Myocarditis
  • CNS dysfunction (from metabolic encephalopathy, cerebral edema, and/or hemorrhage):
    • Delirium
    • Seizures
    • Coma

Physical exam

Findings will depend on the severity of the disease and phase of infection, but they may include:

  • Vital signs:
    • Fever
    • Bradycardia during fever (Faget sign)
    • Hypotension
  • Ocular:
    • Conjunctival injection
    • Scleral icterus
  • Cutaneous:
    • Facial flushing
    • Jaundice
    • Petechiae
    • Ecchymosis
  • Abdominal:
    • Epigastric tenderness
    • Hepatomegaly
  • Renal:
    • Dark urine
    • Hematuria

Diagnosis and Management

Diagnosis

Specific testing:

  • Serology (ELISA) for IgM antibodies
  • PCR for viral RNA
  • Viral culture
  • Note: Liver biopsy should never be performed owing to the risk of fatal hemorrhage.

Supporting evaluation:

  • CBC:
    • ↓ WBCs with neutropenia
    • ↓ Platelets
  • Liver function tests:
    • ↑ AST and ALT
    • ↑ Bilirubin
  • Coagulation studies:
    • ↑ PT and PTT
    • ↓ Fibrinogen
    • ↑ D-dimer
  • Renal studies:
    • ↑ BUN and creatinine
    • ↑ Urine albumin and protein

Management

There is no antiviral therapy available to treat yellow fever. Management is supportive.

  • Hospitalization and ICU care is advisable because rapid deterioration can occur.
  • IV fluid hydration
  • Vasopressor support for shock
  • Monitor for:
    • Hypoglycemia
    • DIC
    • Liver dysfunction
    • Kidney dysfunction

Prevention

  • Mosquito avoidance:
    • Insect repellent
    • Protective clothing
    • Mosquito netting
    • Drain and prevent standing water
  • Vaccination is recommended for:
    • Travel to endemic areas
    • Residents of endemic regions

Comparison of Flavivirus Species

Table: Comparison of Flavivirus species
OrganismYellow fever virusHepatitis C virusDengue virus
Characteristics
  • 1 serotype
  • 40–60 nm
  • 2 serotypes
  • 55–65 nm
  • 4 serotypes
  • 40–60 nm
TransmissionMosquitoBlood-borneMosquito
Clinical presentation
  • Fever
  • Flu-like symptoms
  • Jaundice
  • Multiorgan dysfunction
  • Hemorrhage
  • Shock
  • Asymptomatic
  • Hepatitis
  • Cirrhosis
  • Hepatocellular carcinoma
  • Fever
  • Flu-like symptoms
  • Skin flushing/rash
  • Severe pain
  • Multiorgan dysfunction
  • Hemorrhage
  • Shock
Diagnosis
  • Serology
  • PCR
  • Viral culture
  • Serology
  • PCR
  • Serology
  • PCR
  • Antigen testing
ManagementSupportiveDirect-acting antiviralsSupportive
Prevention
  • Mosquito avoidance measures
  • Vaccine
  • Avoid sharing needles
  • Proper sharps and waste disposal
  • Testing donated blood
  • Mosquito avoidance measures
  • Vaccine

Differential Diagnosis

  • Malaria: mosquito-borne infectious disease caused by Plasmodium species. Malaria often presents with fever, rigors, diaphoresis, jaundice, abdominal pain, hemolytic anemia, hepatosplenomegaly, and renal impairment. A blood smear shows a single pleomorphic ring. Rapid testing for Plasmodium antigens can also be performed. Management requires a prolonged course of multiple antimalarial drugs.
  • Lassa fever: hemorrhagic fever caused by Lassa virus. Most Lassa fever infections infections are mild and flu-like. Some patients experience severe manifestations of pulmonary edema, hepatitis, bleeding, facial swelling, seizures, coma, and shock. The diagnosis is confirmed with serology and PCR. Ribavirin has been used successfully to treat Lassa fever. 
  • Ebola: highly contagious and potentially lethal hemorrhagic fever caused by Ebolavirus. Patients present with symptoms of fever, malaise, nausea, vomiting, and abdominal pain. These symptoms can progress to hemorrhage, multiorgan failure, and shock. The diagnosis is confirmed PCR, serology, and electron microscopy of tissue or blood. Management is supportive.    
  • Leptospirosis: disease caused by Leptospira interrogans. The majority of patients present with a mild flu-like illness, and the manifestations are biphasic. In about 10% of infections, icterohemorrhagic leptospirosis develops, manifesting as hemorrhage, renal failure, and jaundice. Bacterial culture takes weeks, so other diagnostic tests, such as serology and dark-field microscopy, are used. Treatment is primarily with penicillin.
  • Relapsing fever: vector-borne disease caused by multiple species of the spirochete Borrelia. Patients go through recurrent stages of fever, crisis, and afebrile periods. Meningitis, jaundice, DIC, and myocarditis may occur. The diagnosis is based on the clinical history and visualization of spirochetes on thick and thin blood smears. Management is with antibiotics, such as doxycycline, penicillin, or ceftriaxone.
  • Q fever: bacterial zoonotic infection caused by Coxiella burnetii. The clinical presentation of Q fever can vary, but it is often mild with flu-like symptoms. Other manifestations include pneumonia, hepatitis, endocarditis, and aseptic meningitis. A high degree of suspicion is required to make the diagnosis, and it is aided by serology and PCR.  Antibiotics are the mainstay of management. 

References

  1. World Health Organization. Yellow fever Fact sheet no. 100. May 2013. Archived from the original on 19 February 2014. Retrieved February 23, 2014.
  2. Tolle, M.A. (2009). Mosquito-borne diseases. Curr Probl Pediatr Adolesc Health Care 39:97–140. https://pubmed.ncbi.nlm.nih.gov/19327647/
  3. Chen, L.H., Kozarsky, P.E., Visser, L.G. (2019). What’s old is new again: the re-emergence of yellow fever in Brazil and vaccine shortages. Clin Infect Dis 68:1761–1762. https://www.ncbi.nlm.nih.gov/pubmed/30204852
  4. Lindenbach, B.D., et al. (2007). Flaviviridae: the viruses and their replication. In Knipe, D.M., Howley, P.M. (Eds.). Fields Virology, 5th ed. Philadelphia: Lippincott Williams & Wilkins, p. 1101. ISBN 978-0-7817-6060-7.
  5. Sanna, A, et al. (2018). Yellow fever cases in French Guiana, evidence of an active circulation in the Guiana Shield, 2017 and 2018. Euro Surveill 23(36):1800471. https://www.ncbi.nlm.nih.gov/pubmed/30205871
  6. Leong, W.Y. (2018). New diagnostic tools for yellow fever. J Travel Med 25(1). https://www.ncbi.nlm.nih.gov/pubmed/30184173
  7. Barrett, A.D., Higgs, S. (2007). Yellow fever: a disease that has yet to be conquered. Annu Rev Entomol 52:209–229. https://pubmed.ncbi.nlm.nih.gov/16913829/
  8. Javelle, E., Gautret, P., Raoult, D. (2019). Towards the risk of yellow fever transmission in Europe. Clin Microbiol Infect 25:10–12. https://www.ncbi.nlm.nih.gov/pubmed/30170135
  9. Wilder-Smith, A. (2019). Yellow fever: epidemiology, clinical manifestations, and diagnosis. In Baron, E.L. (Ed.), UpToDate. Retrieved April 29, 2021, from https://www.uptodate.com/contents/yellow-fever-epidemiology-clinical-manifestations-and-diagnosis
  10. Wilder-Smith, A. (2021). Yellow fever: treatment and prevention. In Baron, E.L. (Ed.), UpToDate. Retrieved April 29, 2021, from https://www.uptodate.com/contents/yellow-fever-treatment-and-prevention
  11. Yuill, T.M. (2020). Yellow fever. MSD Manual Professional Version. Retrieved April 29, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/arboviruses-arenaviridae-and-filoviridae/yellow-fever
  12. Simon, L.V., Hashimi, M.F., Torp, K.D. (2021). Yellow fever. StatPearls. Retrieved April 29, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK470425/
  13. Blyth, D.M. (2019). Yellow fever. In Brusch, J.L. (Ed.), Medscape. Retrieved April 29, 2021, from https://emedicine.medscape.com/article/232244-overview
  14. Centers for Disease Control and Prevention (2019). Yellow fever. Retrieved April 29, 2021, from https://www.cdc.gov/yellowfever/index.html

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