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Zany Over Zika Virus: An Overview of Diagnosis and Treatment Modalities

Pyzocha, Natasha J. DO; Chinchen, Stephanie E. MD; Maurer, Douglas M. DO

doi: 10.1249/JSR.0000000000000346
Environmental Conditions: Section Articles

Zika virus has been a recent international public health concern with outbreaks occurring in the Americas, Caribbean, and Pacific. The zoonotic infection is primarily spread to humans by the bite of an infected Aedes mosquito. The virus also can be transmitted via bodily fluids, sexual intercourse, and maternal-fetal vertical transmission. Asymptomatic presentation is common. If symptoms do occur, individuals display a low-grade fever, maculopapular rash, arthralgia, or conjunctivitis 2 to 7 d after infection. Infection is concerning due to its associated fetal effects in pregnant women and relationship with Guillain-Barre syndrome. Diagnosis should be suspected in individuals with the appropriate symptomatology and exposure history. Diagnostic tests for the Zika virus are available and vary based on symptom duration. Treatment is supportive, and surveillance is suggested for all pregnant women. Prior infection is thought to provide immunity toward future exposures. Prevention and education is key in decreasing the spread of disease.

1Department of Family Medicine, Evans Army Community Hospital, Fort Carson, CO; and 2Department of Family Medicine, Madigan Army Medical Center, Fort Lewis, WA

Address for correspondence: Natasha J. Pyzocha, DO, Department of Family Medicine, DiRaimondo Aviation Clinic, Bldg 1058, Fort Carson, CO 80913; E-mail: Natasha.j.pyzocha.mil@mail.mil.

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Introduction

Due to the recent surge of Zika virus cases, expanding borders of transmission, and harmful side effects on pregnant women and fetuses, debate on what should and can be done about this virus continues. This epidemic has been the focus of many global health organizations and providers should be knowledgeable on screening, diagnosis, treatment, and prevention.

The Zika virus is an arthropod-borne single-stranded ribonucleic acid (RNA) flavivirus that is transmitted primarily through the bite of a female Aedes mosquito. Though several species of the Aedes subgenus have been linked to Zika virus outbreaks, Aedes aegypti and Aedes albopictus are thought to be the primary contributing vectors (17). The virus also can be transmitted via human-to-human transmission via sexual contact, blood transfusion, organ transplantation, and maternal-fetal vertical transmission. Zika virus RNA has been isolated from blood, saliva, semen, vaginal fluid, urine, cerebrospinal fluid, amniotic fluid, and breast milk (2). Viral RNA also has been found in brain tissue and placentas from nonviable infants with microcephaly born to infected mothers (13). Nosocomial transmission via occupational exposure in health care settings has not been described, but providers should use standard precautions if evaluating a patient with suspected Zika virus (16).

Fetal outcomes associated with maternal Zika infection can be devastating and include microcephaly, ocular manifestations, such as foveal reflex loss, macular neuroretinal atrophy, lens subluxation, and iris coloboma, early pregnancy loss, and fetal demise. There also have been reports of Guillain-Barre syndrome associated with Zika virus.

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Epidemiology

Zika virus was first isolated from an Ugandan forest rhesus monkey in 1947 (9). In 1948, it was detected in mosquitoes in Africa (15). Some of the earliest human illness caused by Zika virus were recognized in Nigeria in 1953 (12). Sporadic infections were reported across Africa and Asia until widespread outbreaks occurred in Micronesia (2007) and French Polynesia (2013 to 2014), affecting 67% to 70% of the population (17). The ongoing outbreak now affecting the Western hemisphere is thought to have started in February 2014 in Chile, spreading to Brazil, and then the United States (10). Local transmission has been reported in Florida. An updated map of the current distribution of active Zika transmission can be found at the U.S. Centers for Disease Control and Prevention (CDC) web site: http://www.cdc.gov/zika/geo/index.html (19).

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Prevention

Given the potentially devastating outcomes of Zika infection and lack of an available vaccine, prevention of transmission and prompt screening of affected individuals is imperative. Avoiding mosquito bites, planning for travel, and protection from sexual transmission are the cornerstones of prevention. The CDC recommends wearing long-sleeved shirts, pants, and an Environmental Protection Agency (EPA) registered insect repellant to deter bites. Additional protection for children should include covered cribs, strollers, and carriers with mosquito netting. To secure the home, screens on windows and doors should be used and standing water in tires, buckets, planters, pools, and birdbaths eliminated. After returning from travel to an endemic area, asymptomatic travelers should prevent mosquito bites for 3 wk (21).

Pregnant patients are advised to avoid travel to regions endemic to Zika virus. The CDC maintains up to date information on its web site for travelers and providers to consult for currently affected areas (19). Both men and women trying to conceive should receive counseling on the risk of infection before travel to these endemic areas, and if travel is necessary, take steps to limit mosquito bites and transmission from their partners. After traveling to these areas, if asymptomatic, couples should wait at least 8 wk before trying to conceive to decrease the risk of birth defects associated with Zika infection during pregnancy (22).

Condoms and other barrier devices protect against infection and are recommended if infection is a concern. Studies are ongoing to determine how long Zika virus can remain in semen and vaginal fluids (24). Symptomatic men or those diagnosed with Zika should use condoms for at least 6 months. Zika virus can remain in semen for up to 188 d after onset of symptoms, even when it is no longer detected in the blood. Zika virus can be detected in female genital tract secretions for up to 11 d after onset of symptoms. Symptomatic women or those diagnosed with Zika virus should use condoms for 8 wk. Those who have traveled to a Zika endemic area, but have no symptoms, should consider using condoms for at least 8 wk. For pregnant couples that live in areas with infected mosquitoes, condoms should be used for the entire pregnancy, whether or not either partner is symptomatic (22,23).

Screening is available for those concerned about infection. Pregnant patients who live or have traveled to a Zika endemic area, shows signs or symptoms of Zika virus infection, or have had unprotected sex with a partner that has traveled to an endemic area should be tested in the first and second trimesters of pregnancy (20). All pregnant patients should be asked about symptoms of Zika and potential exposure at every prenatal visit (21).

There is not currently a vaccine available for the Zika virus, but several are under development. Vaccines for other flaviviruses have been developed including yellow fever, Japanese encephalitis, tick-borne encephalitis, and dengue. As of March 2016, 18 companies and research institutions have been working on a vaccine for Zika virus but none had reached clinical trials. Vaccination of pregnant women and women of childbearing age are the prime target for these vaccines (18).

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Diagnosis

The incubation period for Zika virus is estimated to be 2 to 14 d between mosquito bite and onset of symptoms. Mild symptoms resolve in 2 to 7 d. They are similar in both adults and children and include maculopapular pruritic rash (90%), low-grade fever (65%), arthralgia primarily affecting small joints of hands and feet (65%), and nonpurulent conjunctivitis (55%) (17). Clinical diagnosis can be made if two or more of these symptoms are present. Other common symptoms may include myalgia, headache, retro-orbital pain, edema, vomiting, abdominal pain, diarrhea, and mucous membrane ulcerations. Rarely, thrombocytopenia, palatal petechiae, and uveitis are seen (Table 1). The physical examination should consist of vital sign review, a careful skin inspection, and head, ears, eyes, nose, and throat examination.

Table 1

Table 1

The differential diagnosis for Zika virus is broad due to its nonspecific symptoms and can be easily mistaken for an acute respiratory infection. It is important to rule out or assess for concurrent dengue and chikungunya, as they have similar symptoms and are transmitted by the same mosquito vector (Table 2) (25). Other diagnoses that present similarly include parvovirus, rubella, enterovirus, adenovirus, alphaviruses, measles, leptospirosis, malaria, rickettsial infection, influenza, infectious mononucleosis, acute human immunodeficiency virus (HIV) infection, meningococcal disease, and group A Streptococcus (Table 3). To differentiate between potential causes, a detailed history and physical examination should be completed. The approach to diagnostic testing depends on local resources. Complete blood count and routine chemistries are often normal but laboratories may show mild leukopenia, thrombocytopenia, and hepatic transaminitis. All suspected cases should be reported to local health departments in the United States for coordination of testing. Options for testing include reverse transcriptase-polymerase chain reaction (RT-PCR), serum virus-specific immunoglobulin M (IgM), plaque reduction neutralization test (PRNT), and culture. The RT-PCR distinguishes Zika from other flaviviruses (such as dengue or yellow fever) and is typically performed on serum and urine samples. The sensitivity varies within 14 d after symptom onset and therefore is used in the early course of collection in testing for the disease. IgM and PRNT have a greater sensitivity at the end of the first week of illness up to 12 wk after symptoms. IgM and PRNT can cross-react with other flaviviruses, possibly making a greater number of false positives. Culture is rarely used. The CDC performs most of the Zika testing (23).

Table 2

Table 2

Table 3

Table 3

Testing should be performed in individuals with typical clinical manifestations and relevant exposure. Specific directions regarding laboratory testing is dependent on how long ago clinical symptoms started. If symptoms started less than 2 wk ago, RT-PCR of serum and urine are recommended. Serum is typically positive for viremia 3 to 7 d after infection and urine positive for up to 14 d (17).

After negative Zika virus RT-PCR, or if the patient presents 2 to 12 wk after the onset of symptoms, Zika virus serologic testing should be performed (IgM). If IgM results are positive, equivocal, or inconclusive, the PRNT should be completed to determine if the IgM reflects recent infection or a false-positive result. PRNT also can be used to differentiate antibodies of closely related viruses. This test is labor-intensive, costly, involves handling of live virus, and is not widely performed; therefore, should not be routinely ordered. After PRNT is completed, titers will determine if no infection is present, Zika is present, or if another flavivirus is present (Figure). If clinical presentation occurs greater than 12 wk, there is no role for Zika virus testing. The most up to date information on diagnostic testing recommendations for Zika can be found on the CDC web site: http://www.cdc.gov/zika/hc-providers/testing-for-zikavirus.html (23).

Figure

Figure

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Reporting Cases

The World Health Organization (WHO) developed Zika virus case definitions to provide global standardization for classification and reporting (8). A suspected case is a person presenting with a maculopapular rash and/or fever with arthralgia, arthritis, or nonpurulent/hyperemic conjunctivitis. A probable case meets suspected case criteria plus laboratory evidence of positive IgM antibody against Zika virus, and contact with a confirmed case or history/living/traveling to an area with Zika virus within the past 2 wk. A confirmed case is a person with laboratory confirmation by viral RNA, antigen in serum or other bodily fluids, or IgM antibody against Zika virus, and positive PRNT testing.

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Management

Clinical symptoms of Zika virus are normally self-limiting and last several days to a week. Symptomatic treatment is the key to management of the disease, and it is recommended that patients rest and prevent dehydration. Acetaminophen can be used for fever and pain. Aspirin and other nonsteroidal anti-inflammatories should be avoided until dengue infection is ruled out to decrease the risk of hemorrhage. Aspirin also should be avoided in children to prevent Reye syndrome.

Protective immunity for humans has been hypothesized against homologous strains of Zika virus after it is contracted. A study conducted in rhesus macaques showed that a rechallenge of the virus 10 wk after the initial challenge resulted in no detectable virus replication, indicating immunity (6). This theory has not been tested clinically in humans.

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Psychological Support

The WHO recommends psychosocial support for both patients and families diagnosed with Zika virus (7). Unless trained to assess and manage severe symptoms of distress, the WHO recommends referral to specialized care. Basic social support should be provided and strengthened by advocating adequate rest, regular eating, talking with family and friends, discussing problems with a trusting person, doing activities that help relaxation, and physical exercise. Trained psychologists also can assist in counseling modalities for parents with a child plagued by microcephaly and neurodevelopmental complications.

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Complications

The WHO, CDC, and other scientific groups have concluded that Zika virus can cause microcephaly and other fetal anomalies (6). Microcephaly is defined as a small head size for gestational age and sex, indicative of an underlying problem during brain growth. This appears to be a consequence of infection in early pregnancy. Estimates of microcephaly are uncertain due to lack of data, but retrospective analysis from the French Polynesian outbreak estimated baseline microcephaly prevalence of 2 per 10,000 neonates. The study also estimated that the risk of microcephaly associated with Zika virus was 95 cases per 10,000 women infected in the first trimester based on eight microcephaly cases with the risk of microcephaly in the first trimester during that outbreak being 1% (4). When comparing this to Brazilian data, likely estimated risk of microcephaly due to Zika virus in the first trimester range from 0.88% to 13.2% (11). Other related Zika virus fetal outcomes seen include central nervous system abnormalities, ocular abnormalities, hearing loss, club foot, neurologic abnormalities, fetal loss, or impaired growth. Histopathological changes seen on autopsy studies of fetal brain tissue include parenchymal calcification, microglial nodules, gliosis, cell degeneration, and necrosis without significant findings in other tissues or placenta (13).

Neurologic complications also have been associated with Zika virus. These include Guillain-Barre syndrome, brain ischemia, myelitis, and meningoencephalitis (17). Increased reports of Guillain-Barre syndrome also were seen in the French Polynesian outbreak and statistics revealed that out of 28,000 persons who sought medical care for that outbreak, 38 cases were diagnosed (17).

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Future Outlooks

This widespread Zika virus outbreak has stimulated many public health concerns. With theoretical immunity after infection of the virus, there is an expected decrease in the incidence over time but many individuals will be affected in the meantime. Models developed by the WHO predict that 3 to 4 million people across the Americas will contract Zika virus through early 2017 with potential spread throughout many other parts of the world.

In November 2015, the Pan American Health Organization issued an epidemiologic alert regarding Zika virus to Latin American countries urging women to avoid pregnancy due to the potential complications of microcephaly. This concerned countless women of childbearing age especially because in most Latin American countries, abortion is illegal or highly restricted (1). A nonprofit organization providing access to abortion medications through online telemedicine analyzed abortion requests from January 2010 through March 2016. In those Latin American countries that issued the warning to prevent pregnancy, requests for abortion increased significantly, showing that pregnant women are at a particular risk due to the virus, and the infection is very concerning to this population.

Biologists are researching the reason why Zika virus recently became a common infection. Exact emergence in the past decade is unknown; however, during this same time frame, there also has been a surge in dengue fever and chikungunya. With all three infections using the same vector, there is potential evidence suggesting a common underlying mechanism for emergence. A viral mutation affecting transmission, increased virulence, or globalization and urbanization could be the cause of these outbreaks. Further research is needed to prevent continued spread of Zika virus and other related RNA diseases.

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Conclusions

Zika virus continues to be a major international public health concern. Until an effective vaccine is developed, prevention is the key to further episodes of the disease. Diagnosis should be reported accurately using appropriate screening criteria and laboratory confirmation. Treatment continues to be supportive, and new research is published daily on the management for Zika virus complications. The importance of detection and surveillance of pregnant women infected with the virus is paramount given the known fetal anomalies, particularly microcephaly.

The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Department of Defense or the U.S. Government.

The authors declare no conflict of interest and do not have any financial disclosures.

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