THE ZIKA VIRUS INFECTION

                                                      THE ZIKA VIRUS INFECTION 

HISTORY/EPIDEMIOLOGY

The Zika virus is a positive-sense, single-stranded RNA virus from the family Flaviviridae that was originally discovered in rhesus monkeys in Uganda in 1947. The virus is transmitted primarily through the bite of an infected mosquito from the genusAedes, mainly Aedes aegypti, which inhabits most tropical and subtropical regions (as well as some temperate ones) and transmits numerous other arboviral diseases such as dengue, chikungunya, and yellow fever.  Aedes mosquitoes tend to live near, and feed off of, human beings and usually bite during the daytime, peaking during the early-morning and late-afternoon or evening hours.

Although Zika has been known to exist since 1947, it was not identified in humans until 1952 in Uganda and the United Republic of Tanzania.  Between the 1960s and the 1980s, rare cases of human infection were sporadically recorded in Africa and Asia, typically characterized by mild illness.  Prior to 2007, however, no outbreaks and only 14 cases of the Zika virus disease had been documented in humans anywhere in the world.  

That changed with the first recorded major outbreak of the disease among humans in 2007, on the Pacific island of Yap in the Federated States of Micronesia.  No hospitalizations or deaths were reported during the outbreak, and the clinical features were not unlike those observed in earlier cases: mild fever, malaise, headache, joint pain (arthralgia), and rash.  After the Yap outbreak, new outbreaks took place in other groups of Pacific islands, including French Polynesia, with similar results.  

In February 2016, Zika seized the world’s attention like never before when the World Health Organization declared an international public health emergency following a 2015 outbreak in Brazil that had quickly spread throughout Central and South American and the Caribbean. Researchers found direct associations between Zika infection and clusters of microcephaly and other neurological disorders and congenital deformities that were increasing an alarming rate throughout the region.

The 2015-2016 outbreak gave rise for the first time to a scientific consensus that the Zika virus is a cause of congenital infection and associated birth defects, including microcephaly, and Guillain-Barré syndrome.  Since then, researchers and public-health authorities have expressed concern that the outbreak may foreshadow much greater threats to human beings around the world.

In the United States, isolated cases of local transmission of the Zika virus by mosquitos were reported in Texas and Florida in 2016 and 2017, but the Centers for Disease Control (CDC) reports that there are currently no cases of local Zika transmission in the continental United States.  As of April 1, 2021, the CDC reported no existing cases of the Zika virus in the continental United States and only seven cases in U.S. territories, all acquired through presumed local mosquito-borne transmission.  The mosquitos capable of spreading Zika can be found throughout the continental United States and U.S. territories.

To date, a total of 86 countries and territories have reported evidence of mosquito-transmitted Zika infection.

I.              TRANSMISSION

The Zika virus is transmitted through both horizontal and vertical transmission.  The virus is primarily maintained by horizontal transmission between Aedes aegypti mosquitos and humans, although other Aedes species are also competent vectors.  In horizontal transmission, a mosquito bites a person who is already infected with the Zika virus, causing the mosquito to become infected as well. Then, when the infected mosquito bites another person, the virus enters that person’s bloodstream and causes an infection.  The same species of mosquitos also serve as competent vectors of dengue fever, chikungunya, yellow fever, and other arboviral diseases that cause disease in humans, primarily in tropical and subtropical regions of the world.

Horizontal transmission also occurs from one person to another through sexual contact, although condoms have been found to reduce the risk of getting the Zika virus during sex.  This is an area of particular concern because of the association between the Zika virus infection and adverse pregnancy and fetal outcomes.

In addition to horizontal transmission, the Zika virus can be passed vertically from a pregnant woman to her fetus (and from infected female mosquitos to their offspring).  If a mother has been bitten by an infected mosquito and then becomes infected herself, Zika can penetrate the placenta and reach the fetus.  This could cause the child to be born with microcephaly and other congenital malformations, collectively known as congenital Zika syndrome. Child outcomes vary according to the extent of brain damage. 

Congenital Zika syndrome can include other malformations such as limb contractures, excessive muscle tone, eye abnormalities, and hearing loss.  The risk of congenital malformations occurring following an infection during pregnancy remains unknown.  An estimated 5% to 15% of infants born to women infected with the Zika virus during pregnancy have signs of Zika-related complications.  Congenital malformations occur following both symptomatic and asymptomatic infection. 

In regions with active transmission of the Zika virus, public health experts recommend that everyone with the Zika virus infection and their sexual partners (particularly pregnant women) be given information about the risks of sexual transmission of the virus.  The World Health Organization (WHO) recommends that sexually active men and women be offered counseling and a full range of contraceptive methods so that they can make informed choices about whether and when to conceive while minimizing the risk of adverse pregnancy and fetal outcomes. 

Women who have had unprotected sex and want to avoid pregnancy for fear of passing on the Zika virus should be given ready access to emergency contraceptive services and counseling.  Pregnant women should practice safe sex – including the correct and consistent use of condoms – or avoid sex altogether for the duration of the pregnancy.

In regions with no active transmission of the Zika virus, the WHO recommends that people returning from areas of active Zika virus transmission practice safe sex or abstinence for six months in the case of men, and two months in the case of women, to minimize the risk of infecting their sexual partners.

II.            RISK FACTORS

The chief factors that increase the risk of contracting the Zika virus are (i) living or traveling in countries that have had outbreaks; (ii) having unprotected sex; and (iii) living in areas where mosquitos dwell.

Living or traveling in a tropical or subtropical area increases the risk of exposure to the Zika virus.  Particularly high-risk areas include several of the Pacific Islands; several countries in Central, South and North America; and the islands near West Africa, including the island nation of Cabo Verde, site of a Zika outbreak of unprecedented magnitude in Africa in 2015-2016 – the first on the continent to be associated with microcephaly.  Because the mosquitoes that carry the Zika virus are found worldwide, it is likely that outbreaks will continue to spread to new regions.

Reported cases of the Zika virus infection in the United States have primarily afflicted travelers returning to the country from travel abroad.  As noted above, however, the mosquitos capable of spreading Zika can be found throughout the continental United States and U.S. territories.  Local transmission has been reported in Florida, Texas, the U.S. Virgin Islands, and Puerto Rico.

Another common method by which the Zika virus spreads from one person to another is through sex.  Having unprotected sex for the first three months after traveling outside the country can increase the risk of contracting the Zika virus infection.  It is therefore recommended that pregnant women who have sex with someone who has recently lived in or traveled to an area with a high incidence of Zika use a condom or abstain from sexual contact until after the baby is born.  Other people can also reduce the risk of sexual transmission by using a condom or avoiding sex for up to three months after traveling abroad.

Finally, people who live where mosquitos dwell – for example, tropical areas, unsanitary areas, near river banks, or near massive water reserves – are all at increased risk of contracting Zika virus.

III.          SIGNS AND SYMPTOMS

Most people who are infected with the Zika virus – up to 80% -- will have no symptoms, in which case they are said to have a Zika virus infection. The 20% who do develop symptoms are said to have the Zika virus disease, and their symptoms can range from the mild – e.g.,headaches, rashes, low-grade fever, joint or muscle pain, abdominal pain, conjunctivitis, itching, and fatigue or discomfort – to far more severe consequences such as brain damage, paralysis, and even death.

The mildest Zika symptoms usually don’t last longer than two days to a week after the 12-day incubation period, and very few cases require hospitalization.  Death is extremely rare. 

On the other extreme, the health consequences of the Zika virus disease can be severe, permanent, and even deadly.  As noted above, if a mother has been bitten by an infected mosquito and then becomes infected herself, Zika can penetrate the placenta, reach the fetus, and cause severe birth defects such as microcephaly and other malformations, including damage to the central nervous system and severe developmental disabilities in children.  The results can include vision and hearing loss, resulting in cognitive and speech disorders accompanied by social and motor development problems in the children. In very rare cases, Zika can cause swelling of the brain or spinal cord or a blood disorder resulting in bleeding, bruising, and/or slower blood clotting.

Congenital Zika syndrome is a distinct species of the Zika virus disease defined by a common set of defects and disabilities in fetuses and babies who have been infected with the Zika virus during pregnancy.  Many of these symptoms can result from other types of infections during pregnancy, but congenital Zika syndrome has been characterized by a unique pattern of features that often include (i) severe microcephaly involving the partial collapse of the skull; (ii) a reduction in brain tissue with a specific pattern of brain damage; (iii) scarring, changes in pigmentation, and other damage to the back of the eye; (iv) a limited range of motion in the joints, such as clubfoot; and (v) excessive muscle tension that reduces movements of the body shortly after birth.

Apart from Zika’s possible effects on the fetus during pregnancy, infections in healthy adults have been linked to Guillain-Barré syndrome,a rare disorder in which the body's immune system attacks the nerve cells, causing muscle weakness and possibly even paralysis.  Guillain-Barré syndrome has a mortality rate of between 4% and 7%, so most people recover and anywhere from 60% to 80% of them are able to walk within six months.  However, symptoms such as weakness, numbness, and fatigue can continue beyond that point.

Because the symptoms of the Zika virus disease are very similar to those of dengue fever and chikungunya, the disease is often misdiagnosed.

IV.         DIAGNOSIS

The Zika virus disease is usually diagnosed through an analysis of symptoms, prior mosquito bites, and travel history.  Diagnosing Zika often implicates a broad range of differential diagnoses, most commonly dengue fever and chikungunya.  The circulation of all three diseases, particularly in the Americas, has posed public health challenges because of their common mode of transmission and the number of cases of microcephaly related to the Zika virus, post-chikungunya chronic joint disease, and severe dengue. Researchers have emphasized the importance of clinicians familiarizing themselves with the various clinical presentations and laboratory methods associated with each disease to they can make the differential diagnosis, start appropriate treatment, and prevent complications.  

Like Zika, both dengue and chikungunya are contracted through mosquito bites.  However, dengue usually produces a high fever, while Zika’s is usually mild.  Both Zika and dengue fever are associated with muscle pain, but unlike Zika, dengue fever does not usually result in conjunctivitis.  Like dengue but unlike Zika, chikungunya produces a high fever in human beings.  Chikungunya generally causes swelling and pain around the large joints, while Zika primarily affects the small joints.  Chikungunya can be so debilitating that victims can’t even walk in a straight line.

In addition to differential diagnosis, accurately diagnosing the Zika virus disease also requires good timing.  In the first seven days after the onset of symptoms, the most reliable method for confirming a Zika virus infection is RT-PCR, or reverse transcription polymerase chain reaction testing, which looks signs of for the virus’ genetic material, RNA. This method is effective in the early stages after infection because the body has not yet developed antibodies against the virus.  There are drawbacks to RT-PCR, however: Genetic material can be detected for only a brief time after the onset of symptoms, and in people without symptoms, PCR can more difficult to interpret.

After seven days, once antibodies are present, serology is used to look for Zika IgM antibodies.  A definitive diagnosis based only on serology is made difficult by the high degree of cross-reactivity between the Zika virus and other flaviviruses and their vaccines. For example, there is significant cross-reactivity between the Zika and dengue antibodies, but a distinguishing characteristic of the Zika IgM is that it is at least four times higher than the dengue IgM.  If it is not at least four times higher, then the Zika diagnosis is questionable.

There is scientific consensus that the Zika virus infection during pregnancy can cause microcephaly.  Routine ultrasounds performed during pregnancy can usually detect microcephaly in the fetus during the second or early third trimester.  After birth, microcephaly is diagnosed by measuring the circumference of the head to determine whether it is smaller than that of other babies of the same age and gender.  The measure value for microcephaly is more than two standard deviations below average.  

V.           TREATMENT

There is no specific vaccine, cure, or even medication for the Zika virus disease. As a result, the most effective treatment for those with mild symptoms is supportive care, i.e.,symptom management, improvement of quality of life, and care for patients on treatments.  Below are some of the ingredients of a typical program of supportive care:

·     Get plenty of rest.

·     Drink fluids to prevent dehydration (and, at worse, renal failure).

·     Take medications such as acetaminophen (Tylenol®) to reduce fever and joint pain.

·     To reduce the risk of bleeding, do not take aspirin or other non-steroidal, anti-inflammatory drugs (NSAIDS) until dengue can be ruled out.

·      If taking medicine for another medical condition, talk to a healthcare provider before taking additional medication.

VI.         RESEARCH STUDY AND CASE STUDY

In 2017, the CDC led a research study into the effects of the Zika virus on the health and development of 19 children born with Zika-related microcephaly during the 2015 outbreak in Brazil.  The children were 19 to 24 months old, and all had severe neurological impairments that will require a lifetime of care, including (i) impaired language and motor skills, and (ii) enormous deficits in vision and hearing.

The study found that these deficits made learning extremely difficult for the children.  Teaching them basic concepts required the highly repetitive use of coordinated sounds, vibrations, eye-hand movements, facial expressions, and other stimuli.

A typical 6-to-9-month-old child without microcephaly is usually able to mimic sounds and words such as “mama” and “papa.” Healthy children also use their mouths and hands to explore the world around them, and you can tell from their facial expressions that they enjoy the process of discovery.  They are quite agile, able to sit up without support and roll over.    

The toddlers in the CDC study in Brazil, however, experienced their baby years very differently.  They barely made sounds and often seemed catatonic.  They rarely blinked their eyes, and because their faces were expressionless, scientists had to guess at their responses to external stimuli.  Because many of them had stiff muscles, parents in Brazil led a campaign inject Zika-infected children with Botox as a muscle relaxant.  Other recurring symptoms suffered by the children in the study included seizures, sleeping problems, pneumonia, and bronchitis, which can last a lifetime.

The CDC found that the best hope for helping these children is extensive therapy, where the key is to stimulate all their senses at once and keep repeating the process to drill the concepts into them and build on their sensory connections to the world.

Our case study involves 24-year-old Daryle Koltay, who is the oldest known person born with Zika-related microcephaly.

When he was born in Florida, Daryle’s head had a circumference of 12 inches – two inches below average.  He was his mother’s third child, but the only one with microcephaly.  His mother could not bring herself to celebrate his birth. Today, he has the mind of a 7-year-old.

Daryle’s age suggests that the Zika virus has been in the United States since well before the outbreak in Brazil.  Daryle’s mother, Lisa, did not travel during her full-term pregnancy, but once doctors told her about her Daryle’s condition, she remembered receiving several mosquito bites while pregnant.

Doctors told Lisa that Daryle’s future medical complications could include deafness, blindness, and paralysis. 

A 2018 study conducted in the United States found that slightly more than 4% of children whose mothers were infected with Zika during pregnancy were born with microcephaly, while another 2% had postnatal-onset microcephaly.

 

REFERENCES: 

Belluz, Julia. “The New, Confusing Zika Travel Advice, Explained.” Vox, Vox, 22 Mar. 2019, www.vox.com/2019/3/22/18275679/zika-travel-advice-explained.

Chiu, Chi-Fen, et al. “The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier.” Frontiers, Frontiers, 30 Jan. 2020, www.frontiersin.org/articles/10.3389/fmicb.2020.00214/full#:~:text=10.3389%2Ffmicb.2020.00214-,The%20Mechanism%20of%20the%20Zika%20Virus%20Crossing%20the,and%20the%20Blood%2DBrain%20Barrier&text=Zika%20virus%20(ZIKV)%20infection%20causes,of%20microcephaly%20and%20meningoencephalitis%20patient.

Faizan, Md Imam, et al. “Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism.” Intervirology, Karger Publishers, 13 Jan. 2017, www.karger.com/Article/FullText/452950.

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“Zika and Microcephaly: First Trimester of Pregnancy Most Critical.” Institut Pasteur, 19 Dec. 2016, www.pasteur.fr/en/zika-and-microcephaly-first-trimester-pregnancy-most-critical#:~:text=Using%20innovative%20mathematical%20modeling%20techniques,in%20the%20journal%20The%20Lancet.

“Zika Virus Infection: Epidemiology, Clinical Manifestations ... : Current Opinion in Infectious Diseases.” LWW, journals.lww.com/co-infectiousdiseases/fulltext/2016/10000/zika_virus_infection__epidemiology,_clinical.6.aspx.