Zika Virus Infection

Zika virus belongs to the genus Flavivirus and is primarily transmitted by Aedes aegypti mosquitoes, but can also be transmitted sexually and transplacentally. Although most infected patients are asymptomatic, some may present with low-grade fever, pruritic rash, and conjunctivitis. Congenital Zika syndrome is the most severe complication of a Zika virus infection, where transplacental fetal infection manifests with ocular defects, microcephaly, spasticity, and seizures. The diagnosis is made either by RT-PCR or serology. Since there is no definitive management for a Zika virus infection, the treatment is mostly supportive. Prevention includes controlling the mosquito population, using insect repellants, and wearing protective clothing.

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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 used as messenger RNA (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses use 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

General characteristics

  • Genus: Flavivirus
  • Also classified as an arbovirus because it is transmitted by an arthropod
  • Structure:
    • Positive sense
    • Linear ssRNA
    • Enveloped 
    • Icosahedral capsid
Transmission electron microscopic image of zika virus

Transmission electron microscopic image of Zika virus:
A member of the family Flaviviridae, grown in LLC-MK2 culture cells. Virus particles are 40 nm in diameter, and have an outer envelope and inner dense core. Also note the smooth membrane vesicles, which are recognized as the replication complex for this virus family.

Image: “22059” by CDC. License: Public Domain

Epidemiology

  • 1st identified in Uganda in 1947
  • Now widely distributed in the tropical and subtropical zones of: 
    • Asia
    • Africa
    • Micronesia
    • South and Central America 
  • Local outbreaks have recently been reported in the United States.
World map of zika virus risk (2016)

World map showing the distribution of Zika virus (2016)

Image: “CDC map of Zika virus distribution as of 15 January 2016” by CDC. License: Public Domain

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Pathogenesis

Reservoirs

  • Humans
  • Nonhuman primates

Transmission

  • Most commonly transmitted by Aedes aegypti mosquitoes
  • Transplacental transmission can occur if pregnant women are infected.
  • Sexual transmission possible
Aedes aegypti bloodfeeding

Aedes aegypti feeding on human skin

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

Host risk factors

  • Recent travel to endemic areas (tropical and subtropical areas)
  • Sexual intercourse with a currently infected or recently infected individual

Pathophysiology

  • The A. aegypti mosquito serves as a vector:
    • Zika virus replicates within the midgut of a mosquito.
    • After replication, the virus lives in the salivary glands of the mosquito.
  • Mosquito bites a human host, inoculating virus into keratinocytes.
  • The virus moves to the lymph nodes before spreading systemically.
  • In congenital Zika syndrome, the virus infects the neural progenitor cells of the fetus.

Clinical Presentation

Zika virus infection in adults

  • Incubation period: 3–14 days
  • The majority of patients remain asymptomatic after the incubation period.
  • If symptomatic, the findings are nonspecific: 
    • Headache
    • Arthralgia
    • Myalgia
    • Fever
    • Pruritic rash
    • Non-exudative conjunctivitis
  • Potential complications:
    • Guillain-Barré syndrome
    • Meningoencephalitis
    • Transverse myelitis

Congenital Zika syndrome

  • Most concerning complication of Zika virus infection
  • Zika virus infects the neural progenitor cells in the CNS.
  • Findings include:
    • Subcortical calcifications
    • Microcephaly
    • Ventriculomegaly
    • Ocular defects 
    • Spasticity
    • Seizures

Diagnosis and Management

Diagnosis

  • Specific diagnostic studies based on time since infection:
    • 0‒14 days after infection: PCR of blood or urine samples to detect Zika RNA
    • > 14 days after infection: serology (for antibodies against Zika)
  • Nonspecific laboratory abnormalities: 
    • Leukopenia
    • Thrombocytopenia
    • Elevated CRP and erythrocyte sedimentation rate (ESR)
  • Perform PCR or serologies to rule out coinfection with dengue or yellow fever viruses.

Management

  • No curative therapies are available.
  • Symptomatic management:
    • Oral or IV fluids to maintain adequate hydration
    • Acetaminophen to decrease fever and joint pain
  • Notify the CDC.

Comparison of Species

Table: Comparison of species
Zika virus West Nile virus Dengue virus
Characteristics
  • Enveloped
  • Icosahedral
  • Positive-sense ssRNA
  • Enveloped
  • Icosahedral
  • Positive-sense ssRNA
  • Enveloped
  • Icosahedral
  • Positive-sense ssRNA
  • 4 distinct serotypes
Transmission
  • Aedes mosquitoes
  • Transplacental
  • Sexual
Culex mosquitoes Aedes mosquitoes
Clinical
  • Fever
  • Headache
  • Rash
  • Myalgias
  • Conjunctivitis
  • Fever
  • Headache
  • Rash
  • Myalgias
  • Encephalitis
  • Meningitis
  • Fever
  • Headache
  • “Breakbone” pain
  • Rash
  • Hemorrhage
  • Shock
Diagnosis
  • Clinical
  • Travel history
  • Serology
  • PCR
  • Clinical
  • Travel history
  • Serology
  • PCR
  • Clinical
  • Travel history
  • Cell cultures
  • ELISA
  • RT-PCR
  • Serology
Management Symptomatic treatment
Prevention
  • Mosquito control
  • Personal protection with insect repellants and protective clothing
  • Mosquito control
  • Personal protection with insect repellants and protective clothing
  • Mosquito control
  • Vaccine

Differential Diagnosis

The following conditions are differential diagnoses for congenital Zika syndrome:

  • Congenital toxoplasmosis: a congenital TORCHES infection caused by the protozoa Toxoplasma gondii. Toxoplasmosis is most commonly transmitted by the ingestion of undercooked pork, but can also be transmitted after contact with cat feces. Congenital toxoplasmosis presents with the triad of chorioretinitis, hydrocephalus, and diffuse intracranial (rather than subcortical) calcifications. Diagnosis is made with serology. Treatment is using pyrimethamine-sulfadiazine. 
  • Congenital cytomegalovirus infection: a congenital TORCHES infection caused by cytomegalovirus, also known as human herpesvirus 5 (HHV-5). Cytomegalovirus is transmitted by urine, blood, saliva, sex, and organ transplantation. Congenital cytomegalovirus presents with hearing loss, seizures, “blueberry muffin” rash, and periventricular (rather than subcortical) calcifications. Diagnosis is made by serology or PCR. Treatment is using ganciclovir or valganciclovir. 
  • Congenital herpes infection: a congenital TORCHES infection caused by herpes simplex virus (HSV) 2. Herpes simplex virus is transmitted transvaginally from an infected mother to the fetus while the fetus is in contact with lesions in the birth canal. Congenital herpes infection presents with skin and mucous membrane vesicles similar to those seen in adults. Congenital herpes infection can also be disseminated and involve multiple organs. Diagnosis is confirmed using viral PCR, and treatment includes acyclovir.

References

  1. LaBeaud, A.D. (2021). Zika virus infection: An overview. UpToDate. https://www.uptodate.com/contents/Zika-virus-infection-an-overview
  2. Nielsen-Saines, K. (2021). Congenital Zika virus infection: Clinical features, evaluation, and management of the neonate. UpToDate. https://www.uptodate.com/contents/congenital-Zika-virus-infection-clinical-features-evaluation-and-management-of-the-neonate
  3. Navalkele, B.D. (2020). Zika virus: Background, pathophysiology, epidemiology. Medscape. https://emedicine.medscape.com/article/2500035-overview
  4. Vouga M, et al. (2018). Updated Zika virus recommendations are needed. Lancet. 392(10150), 818–819. https://pubmed.ncbi.nlm.nih.gov/30146329/
  5. Moreira-Soto, A., et al. (2018). Exhaustive TORCH pathogen diagnostics corroborate Zika virus etiology of congenital malformations in Northeastern Brazil. mSphere, 3(4) https://pubmed.ncbi.nlm.nih.gov/30089647/
  6. Shehu, N.Y., et al. (2018). Pathogenesis, diagnostic challenges and treatment of Zika virus disease in resource-limited settings. Niger Postgrad Med J. 25(2), 67–72. https://pubmed.ncbi.nlm.nih.gov/30027916/

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