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 Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, pruritic rash, and conjunctivitis Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure virus identification:
Viruses can be classified in many ways. Most viruses, however, will have a genome formed by either DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure or RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure. RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure genome viruses can be further characterized by either a single- or double-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure. “Enveloped” viruses are covered by a thin coat of cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: 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 RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure (mRNA), which is translated into proteins. “Negative-sense,” single-stranded viruses use RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure-dependent RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure polymerase, a viral enzyme, to transcribe their genome into messenger RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure.

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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 Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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 Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. 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 Conjunctivitis Conjunctivitis is a common inflammation of the bulbar and/or palpebral conjunctiva. It can be classified into infectious (mostly viral) and noninfectious conjunctivitis, which includes allergic causes. Patients commonly present with red eyes, increased tearing, burning, foreign body sensation, and photophobia. Conjunctivitis
  • Potential complications:
    • Guillain-Barré syndrome Guillain-Barré syndrome Guillain-Barré syndrome (GBS), once thought to be a single disease process, is a family of immune-mediated polyneuropathies that occur after infections (e.g., with Campylobacter jejuni). 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 RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
    • > 14 days after infection: serology (for antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins against Zika)
  • Nonspecific laboratory abnormalities: 
    • Leukopenia
    • Thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia
    • Elevated CRP and erythrocyte sedimentation rate (ESR)
  • Perform PCR or serologies to rule out coinfection with dengue Dengue Dengue is an infection caused by the Dengue virus (DENV), a small, positive-sense, single-stranded RNA virus of the genus Flavivirus. The majority of infections are asymptomatic. Symptomatic individuals may progress through 3 stages of the disease, with severe manifestations occurring in those with previous infections. Dengue Virus or yellow fever Yellow Fever 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. Yellow Fever Virus viruses.

Management

  • No curative therapies are available.
  • Symptomatic management:
    • Oral or IV fluids to maintain adequate hydration
    • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen to decrease fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Notify the CDC.

Comparison of Species

Table: Comparison of species
Zika virus West Nile virus West Nile Virus West Nile virus is an enveloped, positive-sense, single-stranded RNA virus of the genus Flavivirus. Birds are the primary hosts and the disease is most often transmitted by Culex mosquitoes. Most people infected with West Nile virus are asymptomatic. Some patients develop West Nile fever (a self-limited, febrile illness) and a very small proportion of patients develop West Nile neuroinvasive disease. West Nile Virus Dengue virus Dengue Virus Dengue virus (DENV) is a small, positive-sense, single-stranded RNA virus of the genus Flavivirus. The infection can be transmitted to humans by the bite of female Aedes mosquitoes. The majority of infections are asymptomatic. Symptomatic individuals may progress through 3 stages of the disease, with severe manifestations occurring in those with previous infections. 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 Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
  • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
  • Fever
  • Headache
  • “Breakbone” pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Rash
  • Hemorrhage
  • Shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of 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 Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination

Differential Diagnosis

The following conditions are differential diagnoses for congenital Zika syndrome:

  • Congenital toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis: a congenital TORCHES infection caused by the protozoa Toxoplasma Toxoplasma Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis gondii. Toxoplasmosis is most commonly transmitted by the ingestion of undercooked pork, but can also be transmitted after contact with cat feces. Congenital toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host's immune status. Toxoplasma/Toxoplasmosis presents with the triad of chorioretinitis Chorioretinitis Chorioretinitis is the inflammation of the posterior segment of the eye, including the choroid and the retina. The condition is usually caused by infections, the most common of which is toxoplasmosis. Some of these infections can affect the fetus in utero and present as congenital abnormalities. Chorioretinitis, hydrocephalus, and diffuse intracranial (rather than subcortical) calcifications. Diagnosis is made with serology. Treatment is using pyrimethamine-sulfadiazine. 
  • Congenital cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus infection: a congenital TORCHES infection caused by cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus, also known as human herpesvirus 5 (HHV-5). Cytomegalovirus is transmitted by urine, blood, saliva, sex, and organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation. Congenital cytomegalovirus Cytomegalovirus CMV is a ubiquitous double-stranded DNA virus belonging to the Herpesviridae family. CMV infections can be transmitted in bodily fluids, such as blood, saliva, urine, semen, and breast milk. The initial infection is usually asymptomatic in the immunocompetent host, or it can present with symptoms of mononucleosis. Cytomegalovirus presents with hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2) 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 Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the 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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