MICROBIOLOGY

• Zika virus (ZIKV): Aedes spp. [Fig 1] mosquito-borne arbovirus of the genus Flavivirus (related to yellow fever and Dengue viruses)
  • Single-stranded, positive-sense RNA virus
    • In the same clade (closest relationship) as Spondweni virus.
    • The next nearest "relatives" among the flaviviruses are St. Louis encephalitis virus, Ilheus virus and Rocio virus.

• Phylogenetic analysis reveals two main lineages based on sequencing of non-structural protein gene (NS5):
  
  • African lineage[48] predominantly zoönotic cycle between non-human primates and arboreal Aedes spp and thought to likely circulate in tropical rain forests and surrounding rural areas in tropical sub-Saharan Africa.
    • Also transmitted Aedes spp - human - Aedes spp cycle in urban areas
    • The Asian lineage virus, known to circulate primarily in urban areas, has caused several documented outbreaks in SubSaharan Africa in 2017 but extent of urban circulation unknown due to poor surveillance systems.
  • Asian lineage zoonotic cycle between non-human primates and arboreal Aedes spp; also transmitted Aedes spp - human - Aedes spp cycle in urban areas.
    
    • Asia: single cases reported in returning travelers as well as endemic clusters of human cases without an obviously sustained transmission.
    • The Americas: widespread epidemic activity in urban and rural areas since 2015; additional human case clusters.
      • U.S.: local acquisition in Florida (July 2016), Puerto Rico.
    • 12 nucleotide (3 amino acid) insertion in the structural envelope gene noted in the Asian lineage virus.
• Strain-specific virulence: it remains unknown if ZIKV-associated complications identified during the pandemic in The Americas apparent enhanced viral fitness, more efficient transmissibility, or a more severe disease phenotype were due to changes in the genome of the ZIKV strains or due to a large number of cases observed and more comprehensive surveillance of outcomes.[11]
  • In vitro studies and experimental animal studies suggest that ZIKV mutations may have increased the infectiousness of the ZIKV at least one of the mosquito vectors, Aedes aegypti and thereby, the risk of fetal infection with associated microcephaly.
  • HOWEVER, these birth defects have been observed without these mutations, including adverse fetal outcomes during a 2018 Asian stain outbreak in India.
  • The virus demonstrates neurotropism both in vivo and in in vitro systems.[24][20][50]
• Viral culture systems demonstrated as permissive for Zika virus growth in vitro (using isolate from French Polynesia)[32]:
  • Immature dendritic cells
  • Human dermal fibroblasts: demonstrated enhanced viral replication
  • Epidermal fibroblasts
• Zika virus infection activates an antiviral innate immune response with the production of type 1 interferons in infected cells.
• ZIKV and dengue viruses share antigenic similarities and occur in similar locations globally.
  • Prospective studies amongst humans with evidence of prior dengue virus infection (anti-dengue virus antibodies) suggest a decreased risk of ZIKV infection or associated disease[13].
  • However, more data are needed.
• Autochthonous transmission of ZIKV has been reported in 87 countries and territories in tropical and subtropical areas (such as Texas and Florida) of the world.
• ZIKV appears to be inactivated by:
  • KMNO₄
  • Ether
  • Temperature >60^oC
  • No effect from 10% ethanol.

CLINICAL

Modes of transmission:

• Mosquito bite: Aedes spp mosquitoes, most commonly Ae. aegypti (Asia and the Americas) and Ae. africanus (sub-Saharan Africa)
  • Ae. aegypti: Usually bites from dawn to dust but may bite at any time, both indoors and outdoors.
  • Efficiency of Ae. albopictus as a transmission vector is currently unclear but appears to be less than Ae. aegypti
• Vertical transmission: a causal link between ZKV in mother and microcephaly or other adverse effects in the fetus or newborn has increasing evidence of linkage (see Clinical Spectrum).
  • There is no risk to the fetus if ZKV has cleared from the mother’s body prior to conception.
  • Risk appears greatest if acquired during the first trimester but abnormalities including CNS have been reported also in second > third trimesters.
• Breast milk: no documented transmission but the virus has been isolated from breast milk.[38]
• Sexual transmission: Estimates are that 1% of all infections are due to sexual transmission.[15]
  • Male-to-female (M2F) vaginal-penile intercourse[39][52].
  • M2F sexual transmission may occur for several months after the onset of symptoms in the male.[39][25]
  • Male-to-male (M2M) via insertive anal intercourse[30].
  • Female-to-male (F2M) is suspect based upon a single report of RT-PCR positive secretions in cervical mucus and on an endocervical swab collected from a symptomatic patient[31] and a single suspected case in New York City[26].
• Blood transfusion: possible.
  • During an outbreak in French Polynesia in 2014, 2.8% of blood donors tested positive for Zika.[46]
  • See recommendations below re: blood donation deferral.
• Endemic transmission locations
  
  • Sub-Saharan Africa: initial identification in the Zika Forest in Uganda in 1947 in primates; Uganda and other African location infections in humans.
  • Asia
  • Oceania
  • The Americas: 48 countries and territories (including Florida and Texas in the continental U.S.).
• Animal reservoir:
  • Brazilian monkeys living close to humans have had proven infection. It is unknown if non-human primates will be a inter-epidemic reservoir in the future
  • NO evidence of a nonprimate reservoir for the virus

Clinical Spectrum:

• Lifelong immunity is presumed after infection with any strain of the virus.
• Asymptomatic: most infections (50-80%)
  • This means that ZIKV transmission may be continuing in an area without an identifiable outbreak
  • There was a large, unreported Zika virus outbreak in Cuba in 2017 with cases continuing to be identified in 2018.

• Symptomatic:
  • The incubation period for symptomatic infection: 3-14 days after the bite of an infected mosquito
  • Mild illness: accounts for > 95% symptomatic infections and is clinically indistinguishable from mild dengue or chikungunya infections
    
    • Common symptoms (based upon outbreaks in Yap Island and French Polynesia):
      • Low-grade fever (65-73%)
      • Arthralgia (65-75%)
      • Non-purulent conjunctivitis (55-63%)
      • Diffuse, erythematous maculopapular skin rash, often pruritic, which usually begins on the trunk and spreads to the arms and legs, palms and soles are spared (90-95%)
      • Less common
        • Myalgia
        • Headache
        • Retro-orbital pain
        • Peripheral edema[52][35]
    • Similar clinical manifestations in all age groups, genders, and in pregnancy
    • Duration of symptoms: several days to 1 week
    • Hospitalization or death: rare
  • Severe illness or death: little data available, but potential risk factors may include:
    • Immunocompromised status: persons requiring chronic steroids (rheumatologic conditions, others); unknown if HIV is a risk factor for poor outcome
      • Confirmed Zika virus infection reported in an HIV-infected person (mild case, pt w/ suppressed viral load x 10 years, CD4 >700 cells/mm^3[27]).
    • Alcoholism
  • Neurological syndromes, temporally related to ZKV infection:
    • Congenital defects: can occur following maternal infection during any trimester. Infection during the first trimester appears to have the greatest risk of adverse outcomes to the fetus.[17]
      • Congenital Zika syndrome -- The prominent features (not pathognomonic, but very common) include:
        • Fetal brain disruption sequence (arises from partial brain disruption during gestation; this results in the collapse of the fetal skull because of decreased intracranial hydrostatic pressure
        • Subcortical calcifications
        • Pyramidal and extrapyramidal signs
        • Ocular lesions
          • Retina: focal pigmented mottling
          • Chorioretinal atrophy
        • Congenital contractures
        • Risk of outcome if ZIKV infection during pregnancy: 5-14%
        • Neonatal mortality in first week of life: 4-7%
      • Fetal microcephaly and other neurological syndromes following maternal infection during pregnancy: Risk of outcome if ZIKV infection during pregnancy: 4-6%.
        
        • Some data suggest that adverse outcomes other than microcephaly may occur even with infection as late as the third trimester of pregnancy[28].
        • Spontaneous abortion and full-term infants with microcephaly and other neurological deformities have been reported in areas where epidemic ZKV is circulating.
      • Other outcomes: US children born to mothers infected during pregnancy but with no identified birth defects --- 9% had 1 or more neuro-developmental abnormalities at 2 years.
    • Guillain-Barré syndrome (GBS): the result of a post-infectious immune response or direct viral neurotropism
      • Occurrence: 2-3/10,000 infections (similar to what is observed following Campylobacter spp infection)
      • Autoimmune, acute, ascending polyradiculoneuropathy
        • Only reported to be associated with the Zika outbreaks since 2007
        • Bilateral, lower, symmetrical sensorimotor deficit with associated generalized areflexia
        • Antecedent clinical syndrome consistent with ZKV infection 7 to 15 days before the onset of GBS
        • Case fatality from complications occurring during the acute phase: 3.5% to 12.0%; average 5% even with optimal care
        • Recovery may take weeks to months
      • Miller-Fisher variant of GBS
        • Clinical triad: ophthalmoplegia, areflexia, and ataxia
        • May be due to inflammation of nerves post-infection.

• Strain-specific virulence: it remains unknown if ZIKV-associated complications identified during the pandemic in The Americas apparent enhanced viral fitness, more efficient transmissibility, or a more severe disease phenotype were due to a changes in the genome of the ZIKV strains or due to the large number of cases observed and more comprehensive surveillance of outcomes.
  • In vitro studies and experimental animal studies suggest that ZIKV mutations may have increased the infectiousness of the ZIKV at least one of the mosquito vectors, Aedes aegypti and thereby, the risk of fetal infection with associated microcephaly
  • HOWEVER, these birth defects have been observed without these mutations, including adverse fetal outcomes during a 2018 Asian stain outbreak in India.
• DIFFERENTIAL DIAGNOSIS
  
  • Mild illness (consider the person’s exposure and travel history)
    
    • Dengue
    • Chikungunya
    • Acute HIV infection
    • Rubella
    • Cytomegalovirus infection
    • Epstein-Barr virus infection
    • West Nile virus
    • Atypical measles
    • Secondary syphilis
    • Early Rocky Mountain spotted fever
    • Ehrlichia chaffeensis (human monocytic ehrlichiosis, HME)
    • Salmonella typhi (enteric fever)
    • Rickettsia prowazekii (louse-borne typhus)
    • Leptospirosis
    • Psittacosis
    • Rat bite fever
  • Fetal/newborn microcephaly
    
    • Chromosomal disorders
      • Down’s syndrome
      • Cri du Chat syndrome
      • Trisomy 13
      • Trisomy 19
    • Other maternal infections
      • Rubella
      • Toxoplasmosis
      • Cytomegalovirus
      • Note: Dengue and chikungunya viruses are NOT associated with microcephaly
    • Maternal alcohol or drug abuse
    • Maternal diabetes
    • Mercury poisoning
    • Maternal, uncontrolled phenylketonuria (PKU)
  • Antecedent infections associated with GBS compared with controls[57]
    • Campylobacter jejuni
    • Cytomegalovirus
    • Epstein-Barr virus
    • Mycoplasma pneumoniae

• Diagnostic tests: ZKV nationally notifiable disease in the U.S. as of 2016.
  • General Concepts
    • CDC and several state and local health departments are testing for Zika virus infection.
      • Instructions for submitting diagnostic specimens through a state health department to the Division of Vector Borne Diseases, Arbovirus Diagnostic Laboratory at CDC can be found at www.cdc.gov/zika/hc-providers/diagnostic.html
        • Zika IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA): for the qualitative detection of IgM antibodies in serum or CSF (see below)
    • Testing of samples in the U.S. is limited to those collected from patients meeting CDC criteria. The CDC Testing Algorithm can be found at http://www.cdc.gov/zika/pdfs/laboratory-guidance-zika.pdf
  • Testing modalities
    • Culture: not available outside of research laboratories.
    • Molecular Tests = definitive diagnosis.
    • Use in diagnosis
      
      • All symptomatic persons: Zika RNA can sometimes be detected early in the course of illness. rRT-PCR should be performed on serum collected < 14 days after symptom onset (urine may be positive longer).
        • Urine should ALWAYS be collected with a patient-matched serum sample.
        • A positive rRT-PCR on any sample confirms infection and NO additional test is needed. However, a negative rRT-PCR does NOT exclude Zika infection.
        • Serum should be analyzed for IgM serological testing
      • Asymptomatic PREGNANT women who have traveled to an area of known active Zika transmission but WITHOUT ongoing possible exposure to Zika virus: NOT recommended for routine Zika testing.[1]
      • Asymptomatic PREGNANT women with possible ONGOING Zika virus exposure: IgM serological testing is NOT recommended. Should be offered Zika virus NAT testing 3 times during pregnancy (the first at the initiation of prenatal care. If the infection is confirmed, no further testing of the mother is needed in pregnancy. If no infection, test twice more during pregnancy)[1]
      • Duration of rRT-PCR positivity in pregnant women: appears that women with affected fetuses may have prolonged detection of Zika virus in RNA in serum[3]
    • Serological (Antibody) Tests= presumptive, but inconclusive, for diagnosis
      • General concepts: Zika virus-specific IgM and neutralizing antibodies develop by about the end of the first week of illness
        • IgM levels are quite variable but generally may be detectable as early as the fourth day of illness and usually remain elevated for 15 to 19 months[14] with one report until 25 months after infection.[10] IgM testing of serum is indicated for 2 to 12 weeks post illness onset.
        • If serum rRT-PCR is negative on serum and urine, it does NOT rule out infection. IgM antibody testing for Zika, Dengue and chikungunya viruses should be done
        • If no previous testing done and illness commenced 14 or more days ago, then serum should be tested for Zika, dengue and chikungunya IgM
        • Cross reacting antibodies from other flaviviruses may cause false positives, including persons who have received yellow fever, Japanese encephalitis, and tick-borne encephalitis virus vaccines.
        • Past natural infections with Dengue, West Nile virus, St Louis encephalitis viruses and other less common flavivirus infections may also cross-react with the serological test
        • See Section: "Other Information" for CDC guidance on test result interpretation
      • FDA-cleared diagnostic tests: ALL for the detection of IgM antibodies in human serum. If POSITIVE, confirmation by plaque reduction neutralization test (PRNT) is indicated
        • ZIKV Detect 2.0 IgM Capture ELISA (cleared on 23 May 2019): for the detection of ZIKV immunoglobulin M (IgM) antibodies in human blood. Had been previously available for use under an Emergency Use Authorization (EUA)
        • ADVIA Centaur Zika Test (cleared on 17 Jul 2019): for the detection of IgM antibodies in human blood. Had been previously available for use under an EUA.
        • LIAISON XL Zika Capture IgM Assay II (cleared on 28 Oct 2019): for the detection of IgM antibodies in human blood. Had been previously available for use under an EUA.
      • Plaque reduction neutralization test (PRNT): this complex test provides more substantive evidence of infection, particularly to distinguish cross-reacting antibodies in initial serological testing. Discuss the use of this test with your state or local health department should you think it is indicated. See Section: "Other Information" for CDC guidance on test result interpretation
  • Testing Algorithm---RECOMMENDED TESTING APPROACHES ARE CONTINUING TO CHANGE AND BE UPDATED:
    • Depends upon
      • Patient population: General population vs pregnant woman vs newborn
      • Scenario-based testing schedule

Table adapted from CDC -- Zika virus testing guidance: (https://www.cdc.gov/zika/laboratories/lab-guidance.html. opens in new tab), CDC Dengue and Zika virus diagnostic testing for patients with clinically compatible illness and risk for infection with both viruses (https://www.cdc.gov/zika/hc-providers/testing-guidance.html) and Interim Guidance for diagnosis, evaluation, and management of infants with possible congenital Zika virus infection --- United States (https://www.cdc.gov/mmwr/volumes/66/wr/mm6641a1.htm), and Musso, D et al. N Engl J Med 2019; 381:1454 DOI: 10.1056/NEJMra1808246.

• Tissue Specimen Testing: Testing of fixed or frozen tissue for Zika, Dengue and chikungunya viruses is available at CDC. Request should be coordinated through the provider’s state or local health department. Collection and submission guidance can be found at: https://www.cdc.gov/zika/laboratories/test-specimens-tissues.html.

SITES OF INFECTION

• Virus injected by mosquito into dermis.
  • Virus replication begins in dendritic cells near the inoculation site; then is carried to lymph nodes and into the bloodstream.
• Viremia occurs in symptomatic persons and is assumed to be lower-grade in asymptomatic infection.
  • Viral nucleic acid has been identified up to 11 days after illness onset.
  • Viral nucleic acid has been identified in asymptomatic pregnant women
• Infection of neural tissue has been confirmed in spontaneously aborted fetuses born to mothers in the epidemic area of Brazil and in neonatal deaths as well as elective termination of pregnancy among women with affected fetuses.[24][21]

TREATMENT

FOLLOW UP

• Non-pregnant patient (at the time of infection and for 8 weeks thereafter) with uncomplicated ZKV infection: none

• Pregnant women: See table above with testing algorithm.
• An infant born to at-risk mother testing positive for Zika virus during pregnancy: see table above for testing and follow up algorithm.

• Guillain-Bare syndrome patients: as outlined under "Treatment"

OTHER INFORMATION

Basis for recommendation

1. Oduyebo T, Polen KD, Walke HT, et al. Update: Interim Guidance for Health Care Providers Caring for Pregnant Women with Possible Zika Virus Exposure - United States (Including U.S. Territories), July 2017. MMWR Morb Mortal Wkly Rep. 2017;66(29):781-793.  [PMID:28749921]

   Comment: This is the most up-to-date recommendations from the CDC issued in late July 2017.
   

2. Rabe IB, Staples JE, Villanueva J, et al. Interim Guidance for Interpretation of Zika Virus Antibody Test Results. MMWR Morb Mortal Wkly Rep. 2016;65(21):543-6.  [PMID:27254248]

   Comment: Provides guidance for interpretation of antibody testing for suspected Zika virus infection when the test used initially was the IgM ELISA are done to detect Zika and Dengue viruses and then a Zika virus and Dengue virus PRNT are done to sort out the diagnosis. This is critically important for the interpretation of the PRESUMPTIVE diagnostic IgM test results.
   

3. Meaney-Delman D, Oduyebo T, Polen KN, et al. Prolonged Detection of Zika Virus RNA in Pregnant Women. Obstet Gynecol. 2016.  [PMID:27479770]

   Comment: Report of 5 pregnant women reported to the US Zika Pregnancy Registry with detectable Zika virus PCR products up to 46 days after symptom onset. This finding provides the rationale for the testing recommendation for women even 14 days or more after last exposure to an endemic area and who test positive by Zika IgM ELISA.
   

4. Brooks JT, Friedman A, Kachur RE, et al. Update: Interim Guidance for Prevention of Sexual Transmission of Zika Virus - United States, July 2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):745-7.  [PMID:27466758]

   Comment: The interim guidance is distilled in the Box for couples in which one or both partners have traveled to or reside in an area with active Zika transmission. If the woman is pregnant. Barrier methods should be used against infection for the duration of pregnancy. For couples who are not pregnant and are not planning pregnancy then recommendations are based on the presence of symptomatic vs asymptomatic infection and gender as well as residence vs non-residence in the endemic area.
   

5. Olson CK, Iwamoto M, Perkins KM, et al. Preventing Transmission of Zika Virus in Labor and Delivery Settings Through Implementation of Standard Precautions - United States, 2016. MMWR Morb Mortal Wkly Rep. 2016;65(11):290-2.  [PMID:27010422]

   Comment: Emphasized the importance of standard precautions in health care settings to prevent inadvertent transmission from infected secretions to providers.
   

6. Staples JE et al. Interim guidelines for the evalution and testing of infants with possible congenital Zika virus infection--United States, 2016. Morb Mortal Wkly Rprt. 2016; 65(3):63-67

   Comment: This document along with the companion CDC guidance related to evaluation and testing of pregnant women for Zika virus infection provide providers with a sucinct and clear guidance for use in evaluation and managment of patients.
   

7. Hennessey M et al. Zika virus spreads to new areas---Region of the Americas, May 2015-January 2016. Morb Mortal Wkly Rprt. 2016; 65(3):55-58.

   Comment: This is a short update of the distribution of ZIKV in the American region. By 20 Jan 2016, locally transmitted cases had been reported to the Pan American Health Organization from Puerto Rico and 19 other countries or territories in the Americas. NO local transmission has been documented in the continental US, but multiple cases of ZIKV infection have been diagnosed in returning travelers from endemic areas. Therefore, in certain areas of the US, especially those with Aedes aegypti mosquitos, the local transmission could occur in the future. Ae. albopictus could also become a vector, but its competency to become a major and sustaining virus vectors are unknown. The report notes that although there has been a 20-fold increase in microcephalic births in Brazil since the outbreak began compared to the pre-epidemic period, it is not known how many of these cases are associated with ZIKV. Specific recommendation: " until more is known, and out of an abundance of caution, pregnant women should consider postponing travel to any area where Zika virus transmission is ongoing"
   

8. Oster AM, Brooks JT, Stryker JE, et al. Interim Guidelines for Prevention of Sexual Transmission of Zika Virus — United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65:120–121. DOI: http://dx.doi.org/10.15585/mmwr.mm6505e1

   Comment: The CDC’s interim recommendation re preventing sexual transmission of ZIKV
   

9. Food and Drug Administration. Recommendations for Donor Screening, Deferral, and Product Management to Reduce the Risk of Transfusion Transmission of Zika Virus. Guidance for Industry. 16 Feb 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm486359.htm (accessed 1/28/2020)

   Comment: FDA Press Release RE this Guidance: As a safety measure against the emerging Zika virus outbreak, today the U.S. Food and Drug Administration issued a new guidance recommending the deferral of individuals from donating blood if they have been to areas with active Zika virus transmission, potentially have been exposed to the virus, or have had a confirmed Zika virus infection.
   “The FDA has critical responsibilities in outbreak situations and has been working rapidly to take important steps to respond to the emerging Zika virus outbreak,” said Luciana Borio, M.D., the FDA’s acting chief scientist. “We are issuing this guidance for immediate implementation in order to better protect the U.S. blood supply.”
   While there have been no reports to date of Zika virus entering the U.S. blood supply, the risk of blood transmission is considered likely based on the most current scientific evidence of how Zika virus and similar viruses (flaviviruses) are spread and recent reports of transfusion-associated infection outside of the U.S. Furthermore, about 4 out of 5 of those infected with Zika virus do not become symptomatic. For these reasons, the FDA is recommending that blood establishments defer blood donations from individuals in accordance with the new guidance.
   In areas without active Zika virus transmission, the FDA recommends that donors at risk for Zika virus infection be deferred for four weeks. Individuals considered to be at risk include those who have had symptoms suggestive of Zika virus infection during the past four weeks, those who have had sexual contact with a person who has traveled to, or resided in, an area with active Zika virus transmission during the prior three months, and those who have traveled to areas with active transmission of Zika virus during the past four weeks.
   In areas with active Zika virus transmission, the FDA recommends that Whole Blood and blood components for transfusion be obtained from areas of the U.S. without active transmission. Blood establishments may continue collecting and preparing platelets and plasma if an FDA-approved, pathogen-reduction device is used. The guidance also recommends blood establishments update donor education materials with information about Zika virus signs and symptoms and ask potentially affected donors to refrain from giving blood.
   “Based on the best available evidence, we believe the new recommendations will help reduce the risk of collecting blood and blood components from donors who may be infected with the Zika virus,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.
   Following the issuance of these recommendations, the FDA also intends to issue guidance that will address appropriate donor deferral measures for human cells, tissues, and cellular and tissue-based products (HCT/Ps), given recent reports of sexual transmission of the virus.
   In addition to protecting the nation’s blood supply, the FDA is also prioritizing the development of blood screening and diagnostic tests that may be useful for identifying the presence of the virus, preparing to evaluate the safety and efficacy of investigational vaccines and therapeutics that might be developed, and reviewing technology that may help suppress populations of the mosquitoes that can spread the virus.
   The FDA, an agency within the U.S. Department of Health and Human Services, promotes and protects the public health by, among other things, assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
   

References

10. Griffin I, Martin SW, Fischer M, et al. Zika Virus IgM 25 Months after Symptom Onset, Miami-Dade County, Florida, USA. Emerg Infect Dis. 2019;25(12):2264-2265.  [PMID:31742511]

    Comment: Analysis of ZIKV-infected patients in Florida. 7% (26/30) had IgM 6 months later. In a survival analysis, ≈76% had IgM at 25 months. Zika virus IgM persists for years, complicating serologic diagnosis.
    

11. Musso D, Ko AI, Baud D. Zika Virus Infection - After the Pandemic. N Engl J Med. 2019;381(15):1444-1457.  [PMID:31597021]

    Comment: This is a comprehensive review of the Zika virus to date but given the changing landscape of Zika virus testing recommendations, this section is already outdated. Nonetheless, it is an outstanding synopsis of the virus, pathogenesis, epidemiology, clinical aspects and control & control.
    Rating: Important
    

12. Kama M, Aubry M, Naivalu T, et al. Sustained Low-Level Transmission of Zika and Chikungunya Viruses after Emergence in the Fiji Islands. Emerg Infect Dis. 2019;25(8):1535-1538.  [PMID:31310218]

    Comment: Since the outbreak in 2013, sustained cases described.
    

13. Rodriguez-Barraquer I, Costa F, Nascimento EJM, et al. Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region. Science. 2019;363(6427):607-610.  [PMID:30733412]

    Comment: It looks at the important question of whether or not pre-existing dengue antibody may increase or decrease one’s risk of Zika virus infection.
    Rating: Important
    

14. Griffin I, Martin SW, Fischer M, et al. Zika Virus IgM Detection and Neutralizing Antibody Profiles 12-19 Months after Illness Onset. Emerg Infect Dis. 2019;25(2):299-303.  [PMID:30666931]

    Comment: Confusion may arise long after initial infection due to cross-reactivity with other flaviviruses such as dengue. Also, IgM appears to persist which may unintentionally imply recent infection.
    

15. Mead PS, Duggal NK, Hook SA, et al. Zika Virus Shedding in Semen of Symptomatic Infected Men. N Engl J Med. 2018;378(15):1377-1385.  [PMID:29641964]

    Comment: This prospective study among 184 men with symptomatic ZIKV infection provides important insights into the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. A total of 1327 semen samples from 184 men (1038 urine samples from 183 men were obtained 14 to 304 days after illness onset). ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. Shedding in semen decreased continuously during the 3 months after illness onset. Nonetheless, shedding continued for 281 days in 1 man (1%). Independent factors for prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness.
    ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. But, the infectious virus was shed for a much shorter period of time (just a few weeks after illness onset).
    Rating: Important
    

16. Ikejezie J, Shapiro CN, Kim J, et al. Zika Virus Transmission - Region of the Americas, May 15, 2015-December 15, 2016. MMWR Morb Mortal Wkly Rep. 2017;66(12):329-334.  [PMID:28358795]

    Comment: This is an important surveillance document demonstrating the march of Zika virus transmission in the Americas and the parallel of increase in Guillain Barre reported cases. The color maps are instructive as are the histograms graphs of GBS with respect to Zika.
    

17. Shapiro-Mendoza CK, Rice ME, Galang RR, et al. Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy - U.S. Territories, January 1, 2016-April 25, 2017. MMWR Morb Mortal Wkly Rep. 2017;66(23):615-621.  [PMID:28617773]

    Comment: This article from CDC examines the outcomes of 2,459 (1 Jan 2016 to 25 Apr 2017) completed pregnancies among women with laboratory evidence of recent maternal Zika virus infection in U.S. territories (including the Commonwealth of Puerto Rico and the U.S. Virgin Islands) with local transmission of Zika virus. Approximately 5% of the fetuses and infants had evidence of possible Zika-associated birth defects. This percentage was similar to that reported from the 50 U.S states. Birth defects were seen following estimated maternal infection in any trimester: First (8%); Second (5%) and Third (4%). These data support the recommendations to pregnant women living in affected areas and also reinforces the recommendation against travel to the endemic area during pregnancy.
    Rating: Important
    

18. D'Angelo DV, Salvesen von Essen B, Lamias MJ, et al. Measures Taken to Prevent Zika Virus Infection During Pregnancy - Puerto Rico, 2016. MMWR Morb Mortal Wkly Rep. 2017;66(22):574-578.  [PMID:28594787]

    Comment: This important article on the application of Zika virus acquisition prevention strategies among pregnant women in Puerto Rico during a 15 month period ending in March 2017. It highlights that even with education and voiced understanding the consistent application of prevention strategies throughout pregnancy is difficult. For example, only 46% of women reported wearing mosquito repellent daily and only 11.5% wore pants and long sleeves daily. Additionally sobering was that < 80% were tested for Zika virus infection during pregnancy.
    Rating: Important
    

19. Reagan-Steiner S, Simeone R, Simon E, et al. Evaluation of Placental and Fetal Tissue Specimens for Zika Virus Infection - 50 States and District of Columbia, January-December, 2016. MMWR Morb Mortal Wkly Rep. 2017;66(24):636-643.  [PMID:28640798]

    Comment: Detection of Zika virus RNA in clinical and tissue specimens can provide definitive laboratory evidence of recent Zika virus infection. Although viremia is typical of short duration, Zika virus RNA may be detected for long periods in placental, fetal, and neonatal brain tissue. The newest CDC guidance (See Oduyebo T et al. above) notes that the CDC may provide Zika virus testing of placental and fetal tissues in clinical situations where this information could add diagnostic value.
    In this report, 546 submitted placental tissues from live births were tested from women with possible Zika virus exposure during pregnancy; 60 (11%) were positive by the Zika virus reverse transcription-polymerase chain reaction (RT-PCR). There were placental or fetal tissues tested from 81 pregnancy losses/ 18 (22%) were positive by Zika virus RT-PCR.
    When the mother has a recent, but unspecific flavivirus infection, 10% of 363 live birth placentas tested positive for Zika virus RT-PCR and from 10% of 86 live birth placentas with negative maternal Zika virus immunoglobulin M (IgM) where possible maternal exposure occurred >12 weeks before serum collection.
    Rating: Important
    

20. Garcez PP, Loiola EC, Madeiro da Costa R, et al. Zika virus impairs growth in human neurospheres and brain organoids. Science. 2016;352(6287):816-8.  [PMID:27064148]

    Comment: This in vitro study compared the effects of Zika virus with dengue virus infection on human neural stem cells grown as organoids (Organoids are three-dimensional organ-bud grown in vitro that shows realistic micro-anatomy. Brain organoids are derived from stem cells that mimic the developing human brain’s cellular organization). The Zika virus human brain cells reduced their size and viability in vitro and caused programmed cell death
    compared with dengue virus infection.
    Rating: Important
    

21. Meaney-Delman D, Hills SL, Williams C, et al. Zika Virus Infection Among U.S. Pregnant Travelers - August 2015-February 2016. MMWR Morb Mortal Wkly Rep. 2016;65(8):211-4.  [PMID:26938703]

    Comment: This is a report of 4 cases of Zika virus infection in pregnant women (Patients A-D). One of the 4 had an apparently normal infant delivered at 40 weeks gestation with exposure at 15 weeks; 1 spontaneous abortion occurred; 1 elective abortion with a highly affected fetus with absent corpus callosum and brain atrophy. One patient, who had resided in Brazil until 12 weeks gestation delivered a child with chorioretinitis and hypertonia, difficulty swallowing and hypotonia.
    Rating: Important
    

22. Dupont-Rouzeyrol M, Biron A, O'Connor O, et al. Infectious Zika viral particles in breastmilk. Lancet. 2016;387(10023):1051.  [PMID:26944028]

    Comment: This article provides evidence of the cultivable virus in breast milk collected from a symptomatic mother. Transmission to the infant was not proven
    Rating: Important
    

23. D'Ortenzio E, Matheron S, Yazdanpanah Y, et al. Evidence of Sexual Transmission of Zika Virus. N Engl J Med. 2016;374(22):2195-8.  [PMID:27074370]

    Comment: This correspondence provides a case of sexual transmission from male travelers returned from an endemic area to sexual partners. Case 1 was a female sexual partner of a man who had traveled to Brazil and had engaged in both vaginal sexual intercourse (without ejaculation) and oral sex (with ejaculation). The male partner has been ill but symptoms had resolved 1 day prior to sexual contact.
    

24. Driggers RW, Ho CY, Korhonen EM, et al. Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities. N Engl J Med. 2016;374(22):2142-51.  [PMID:27028667]

    Comment: A case report of an affected fetus following maternal infection in the 11th week of pregnancy. The electively aborted fetus had a high viral load in amniotic fluid and virus particles identified in brain tissue with substantial brain abnormalities.
    Rating: Important
    

25. Turmel JM, Abgueguen P, Hubert B, et al. Late sexual transmission of Zika virus related to persistence in the semen. Lancet. 2016;387(10037):2501.  [PMID:27287833]

    Comment: Sexual transmission from male to female with symptom onset 44 days after onset of symptoms in her partners corresponding to sexual transmission between 34 and 41 days after the male index case. The exposure location was Martinique, located in the Caribbean. The male had had a febrile illness with maculopapular rash, arthralgia, and conjunctival injection but no hematospermia or dysuria.
    Rating: Important
    

26. Davidson A, Slavinski S, Komoto K, et al. Suspected Female-to-Male Sexual Transmission of Zika Virus - New York City, 2016. MMWR Morb Mortal Wkly Rep. 2016;65(28):716-7.  [PMID:27442327]

    Comment: A non-pregnant female who had traveled to a Zika endemic area and who developed symptoms on the day after return to the USA along with a heavier than usual menses and had documented infection with positive real-time reverse transcriptase PCR in both urine and semen on day 3 of illness. Seven days after a single episode of condomless sexual intercourse with her male partner who had not traveled to a Zika endemic area, he developed symptoms of illness consistent with Zika infection and the infection was confirmed by rRT-PCR of urine but not semen.
    Rating: Important
    

27. Calvet GA, Filippis AM, Mendonça MC, et al. First detection of autochthonous Zika virus transmission in a HIV-infected patient in Rio de Janeiro, Brazil. J Clin Virol. 2016;74:1-3.  [PMID:26615388]

    Comment: A single report in the literature of ZIKV infection in an HIV infected person. However, the patient had a suppressed viral load and a high CD4 count on antiretroviral therapy for many years. Await more data on this infection who are more immunocompromised.
    

28. França GV, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet. 2016;388(10047):891-7.  [PMID:27372398]

    Comment: This is a retrospective review of congenital Zika virus infections in Brazil. These data suggest that maternal infection through the third trimester may have adverse outcomes, other than microcephaly. However, more data are needed to support this retrospective observations/investigations
    Rating: Important
    

29. Boulet SL, D'Angelo DV, Morrow B, et al. Contraceptive Use Among Nonpregnant and Postpartum Women at Risk for Unintended Pregnancy, and Female High School Students, in the Context of Zika Preparedness - United States, 2011-2013 and 2015. MMWR Morb Mortal Wkly Rep. 2016;65(30):780-7.  [PMID:27490117]

    Comment: Important pro-active approach to the prevention of mother-to-fetus Zika virus transmission through the prevention of unwanted pregnancy, which in the USA are now approximately 50% of all pregnancy. Effective contraceptive use is felt to be a key prevention strategy.
    Rating: Important
    

30. Deckard DT, Chung WM, Brooks JT, et al. Male-to-Male Sexual Transmission of Zika Virus--Texas, January 2016. MMWR Morb Mortal Wkly Rep. 2016;65(14):372-4.  [PMID:27078057]

    Comment: A man who developed symptomatic Zika virus infection 2 days after returning from Venezuela had condomless insertive anal sex with a male partner the day before and the day after illness onset. The male partner became symptomatic. Both had laboratory-confirmed Zika virus infection.
    Rating: Important
    

31. Prisant N, Bujan L, Benichou H, et al. Zika virus in the female genital tract. Lancet Infect Dis. 2016;16(9):1000-1001.  [PMID:27427201]

    Comment: Demonstration of rRT-PCR positive cervical mucus and a collected endocervical swab of a 27-year-old woman with symptomatic Zika virus infection.
    

32. Hamel R, Dejarnac O, Wichit S, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol. 2015;89(17):8880-96.  [PMID:26085147]

    Comment: This study highlights the importance of identifying cellular tropisms in ZIKV infection which may help to guide interventions for prevention and control. Using skin biopsy specimens collected from healthy volunteers, the authors infected cells with 10^6 plaque-forming units of ZIKV-containing supernatants and then studied for growth and response. Human skin cells including dermal fibroblasts, epidermal keratinocytes and immature dendritic cells were found to be permissive for virus growth, localized in the dermis and epidermis. Fibroblasts appeared to form autophagosomes associated with enhanced viral replication, which is seen in some other arboviruses.
    

33. Zika virus outbreaks in the Americas. Wkly Epidemiol Rec. 2015;90(45):609-10.  [PMID:26552108]

    Comment: Brief, activity report as of November 2015, of ZIKV activity in the Americas from the first detection on Easter Island, Chile (located in the south-eastern Pacific Ocean) in February 2014. Thereafter, it was not until May 2015 that reports from the mainland in the Americas emerged with the first documented outbreak in northeast Brazil where 14 states were affected including Alagoas, Bahia, Ceara, Maranhao, Mato Grosso, Para, Paraiba, Parna, Pernambuco, Piaui, Rio de Janeiro, Rio Grande do Norte, and Sao Paulo. In October 2015, Columbia reported its first endemic case. Subsequent to this report, the virus has been identified in >14 countries in Latin America and the Carribean.
    Rating: Important
    

34. Tappe D, Nachtigall S, Kapaun A, et al. Acute Zika virus infection after travel to Malaysian Borneo, September 2014. Emerg Infect Dis. 2015;21(5):911-3.  [PMID:25898277]

    Comment: Ths letter to the editor provides an interesting case report in which a case of classic acute clinical ZIKV infection is reported in a 45-year-old German female traveler to Borneo with onset of illness 6 days after return from a 3-week vacation in Malaysia who then went on to develop hearing problems (dull metallic sound followed by decreased in hearing) which lasted about 10 days before full resolution. This is the first report of hearing loss associated with ZIKV infection.
    

35. Zammarchi L, Tappe D, Fortuna C, et al. Zika virus infection in a traveller returning to Europe from Brazil, March 2015. Euro Surveill. 2015;20(23).  [PMID:26084316]

    Comment: This is a single case report of a presumptive case (serologically confirmed) of Zika virus infection in a male traveler in his early 60s who traveled from Italy to Salvador de Bahia, Brazil for 12 days and presented with illness 4 days after his return. What is notable in this case was that in addition to the slightly pruritic erythematous rash, conjunctivitis and fever he was noted to have painful edema of the hands and feet. This is a feature that has been reported in severe dengue infections where it is believed to represent capillary leak due to the effect of released cytokines on the tight junction of capillary epithelial cells. Laboratory testing in this patient revealed a negative NS-1 for dengue as well as low antibody levels on paired sera to dengue, chikungunya, Japanese encephalitis, West Nile virus, and yellow fever virus.
    Rating: Important
    

36. Musso D, Cao-Lormeau VM, Gubler DJ. Zika virus: following the path of dengue and chikungunya? Lancet. 2015;386(9990):243-4.  [PMID:26194519]

    Comment: This brief letter, appearing in response to the Pan American Health Organization’s alert issued on 7 May 2015 re Zika virus transmission in northern Brazil provides informative maps that highlight the similarities in the spread of the chikungunya virus and Zika virus outside of its usual Africa-Asia confined distribution before 2005.
    

37. Gourinat AC, O'Connor O, Calvez E, et al. Detection of Zika virus in urine. Emerg Infect Dis. 2015;21(1):84-6.  [PMID:25530324]

    Comment: This brief report provides evidence of ongoing detection of ZIKV amplicons in urine testing by RT-PCR >10 days after illness onset compared with detectable RT-PCR products in serum for < 5 days. As cultures were not obtained concomitantly, it is not known if replicating virus was present. However, this finding has potential implication for infection control practitioners and others designing prevention strategies.
    Rating: Important
    

38. Dupont-Rouzeyrol M, O'Connor O, Calvez E, et al. Co-infection with Zika and dengue viruses in 2 patients, New Caledonia, 2014. Emerg Infect Dis. 2015;21(2):381-2.  [PMID:25625687]

    Comment: Although submitted as a letter to the journal, it importantly reminds providers that Aedes spp carry dengue, chikungunya and Zika viruses. The viruses may co-circulate and therefore, co-infection can occur. Here co-infection with both ZIKV and DEN occurred and highlights the importance of considering co-infection when transaminases are elevated and leukopenia and thrombocytopenia are seen.
    

39. Musso D, Roche C, Robin E, et al. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21(2):359-61.  [PMID:25625872]

    Comment: Isolation of the virus or a positive RT PCR of semen could indicate the potential for sexual transmission. This may be more likely if hematospermia is present but this has not yet been determined. This has implications for advising patients re safer sex or abstinence until completely recovered from illness. Note, a number of flaviviruses also have this characteristic, e.g., West Nile virus.
    

40. Buathong R, Hermann L, Thaisomboonsuk B, et al. Detection of Zika Virus Infection in Thailand, 2012-2014. Am J Trop Med Hyg. 2015;93(2):380-383.  [PMID:26101272]

    Comment: Report of 7 laboratory-confirmed cases of Zika virus (ZIKV), 3 by sequential serological testing (IgM ELISA followed by plaque reduction neutralization test at CDC) and 4 by ZIKV RT-PCR developed at the US Army Research Institute of Medical Sciences (AFRIMS) among Thai nationals from various locations in Thailand over from March 2012 to July 2014. The retrospective laboratory investigation of clinical illness cluster samples (rash, conjunctivitis or arthralgias, and serum negative for dengue or chikungunya and negative IgM for measles and rubella) was prompted by the identification of the virus in a Canadian tourist who had only visited Thailand. These 7 ZIKV infections were identified among 38 subjects (18.4%). Genomic sequencing of the non-structural 5 genes indicated the isolated virus RNA was of Asian ZIKV lineage. None to the case-patients were reported to be pregnant. None had a serious illness.
    

41. Oehler E, Watrin L, Larre P, et al. Zika virus infection complicated by Guillain-Barre syndrome--case report, French Polynesia, December 2013. Euro Surveill. 2014;19(9).  [PMID:24626205]

    Comment: This case report provides an excellent case summary and brief discussion of this neurological adverse outcome following ZIKV infection. This case is notable for only antecedent arthralgia the day before the onset of initial neurological symptoms. This same outbreak in French Polynesia was ultimately associated with 74 adverse neurological outcomes, the majority of which were due to GBS.
    

42. Cao-Lormeau VM, Roche C, Teissier A, et al. Zika virus, French polynesia, South pacific, 2013. Emerg Infect Dis. 2014;20(6):1085-6.  [PMID:24856001]

    Comment: Phylogenetic analyses and discussion of outbreak in Oceania.
    

43. Ioos S, Mallet HP, Leparc Goffart I, et al. Current Zika virus epidemiology and recent epidemics. Med Mal Infect. 2014;44(7):302-7.  [PMID:25001879]

    Comment: This is an excellent summary of both sporadic case reports, disease clusters and epidemics from the first reported human case in 1964 through the epidemic in the French Polynesia islands from 2013-2014. The article provides the general epidemiology and clinical features including a summary and graphic display of the 73 neurological complications (Guillain-Barre syndrome, immune thrombocytopenic purpura, meningoencephalitis seen during the epidemic in French Polynesia). GBS appeared to be the predominant neurological complication. Vectors thought to be associated with transmission in each geographic location is discussed, when known
    Rating: Important
    

44. Tappe D, Rissland J, Gabriel M, et al. First case of laboratory-confirmed Zika virus infection imported into Europe, November 2013. Euro Surveill. 2014;19(4).  [PMID:24507467]

    Comment: Despite the previous 2007 outbreak in Yap Island and the known circulation of ZIKV in Asia before this outbreak in Micronesia, the 1st case of infection in a returning traveler was not diagnosed until 2013. The German traveler, in his 50s, returned from a 3-week beach vacation in Thailand and reported onset of illness after less than 2 weeks into his vacation with arthralgia, peripheral edema, rash, fever, chills, and malaise in the setting of reported mosquito bites. Although dengue IgM was identified on indirect IFA, IgG was negative as was NS-1 testing. Because of the elevated Dengue IgM with negative IgG further investigations were undertaken for other flaviviruses. Zika-specific RT PCR was positive as was ZIKV IgM and IgG. Testing for Japanese encephalitis, yellow fever, West Nile, and chikungunya viruses was all negative.
    

45. Grard G, Caron M, Mombo IM, et al. Zika virus in Gabon (Central Africa)--2007: a new threat from Aedes albopictus? PLoS Negl Trop Dis. 2014;8(2):e2681.  [PMID:24516683]

    Comment: This is more of an ecological study than one that definitively proves that Ae. albopictus is an important vector for the Zika virus infection. This vector which can competently transmit dengue viruses and some lineages of the chikungunya virus was shown to competently replicate Zika virus. And, as this vector has become increasingly important as an arboviral disease vector in Gabon in Central Africa, it is likely to play some role there in virus transmission. However, this does not answer whether it would also be an important vector for the Asian lineage virus currently circulating in the Americas and the Caribbean. As its distribution includes temperate as well as tropical/semitropical areas in the Western Hemisphere, a distribution similar to the West Nile Virus could occur should Ae. albopictus become the predominant competent vector.
    

46. Musso D, Nhan T, Robin E, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19(14).  [PMID:24739982]

    Comment: Virus isolation from blood has been noted for up to at least 11 days after the onset of symptoms. Therefore, the potential for transfusion-associated ZiKV must be considered. However, our knowledge of the natural history of asymptomatic infection will need a closer study to determine if viremia is present and for how long after exposure. This would have important implications for blood donation deferral policies in person who have traveled to endemic areas.
    

47. Besnard M, Lastere S, Teissier A, et al. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. 2014;19(13).  [PMID:24721538]

    Comment: This describes the perinatal transmission of Zika virus infection in mothers who were likely viremic at parturition. Although the newborns did develop a mild illness, there appeared to be no other adverse effect. This finding is similar to the reported perinatal transmission of dengue infection outcomes.
    Rating: Important
    

48. Faye O, Freire CC, Iamarino A, et al. Molecular evolution of Zika virus during its emergence in the 20(th) century. PLoS Negl Trop Dis. 2014;8(1):e2636.  [PMID:24421913]

    Comment: The authors report their analysis of the envelope and NS5 genes of 47 Sub-Saharan African Zika virus genes collected from mosquitoes, humans and other mammals isolated in Burkina Faso, Central African Republic, Cote d’Ivoire, and Senegal in West Africa. over a period of time from the 1960s through 2001. These data and those from early Ugandan isolates were use to examine the lineage over time. A model of geographic spread of the virus was created to estimate introductory pathways and sites. Additionally, recombination events, uncommon in flavivirus were noted with recurrent loss and gain the N-linked glycosylation site in the envelope protein which was postulated to be related to mosquito cell infectivity. The authors postulate that the changes could be related to changes in the enzootic cycle of the virus. Similar analyses of isolates from Oceania and the Americas may help in understading the explosive epidemics and adverse outcomes of human infections noted, if a putative virulence factor can be found.
    Rating: Important
    

49. Diallo D, Sall AA, Diagne CT, et al. Zika virus emergence in mosquitoes in southeastern Senegal, 2011. PLoS One. 2014;9(10):e109442.  [PMID:25310102]

    Comment: ZIKV was first isolated from Ae. luteocephalus collected in 1968 in the Saboya Forest in Senegal (western part of the country) and then was isolated in a human in 1969. The ZIKV IgM seroprevalence in the western region among humans in 1988 and 1990 was 10.1% and 2.8% respectively suggesting possible outbreak activity in 1988. Subsequently, the virus has been isolated in mosquitos in the region but there has not been ongoing human serosurveillance.
    

50. Balm MN, Lee CK, Lee HK, et al. A diagnostic polymerase chain reaction assay for Zika virus. J Med Virol. 2012;84(9):1501-5.  [PMID:22825831]

    Comment: Describes an RT-PCR method developed and utilized during the Yap Island epidemic. This is one of the tests used by CDC for definitive confirmation of infection
    

51. Haddow AD, Schuh AJ, Yasuda CY, et al. Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage. PLoS Negl Trop Dis. 2012;6(2):e1477.  [PMID:22389730]

    Comment: Prior to the publication of this paper in 2012, only 2 ZIKV strains had been genetically characterized in detail. This reported analysis added 5 new strains and thereby led to the identification of 2 distinct lineages: African and Asian. The latter also includes strains isolated from Yap in Oceania are in this lineage which supported epidemiological data that the Yap strain had originated in Asia, not surprising given the geographic proximity of Malaysia and Cambodia, the origin of 2 of the other collected strains. Importantly, several of the strains showed deletions in a potential glycosylation site of the envelope gene (a 4 codon/12 amino acid deletion). The question of the meaning of these differences remains given that prior phylogenetic analysis of envelope/NS5 sequences of several African lineage strains suggested that such changes may be related to virus activity in the vector. This highlights the need for additional combined epidemiological and phylogenetic research of newly identified epidemic strains in the Western Hemisphere.
    Rating: Important
    

52. Foy BD, Kobylinski KC, Chilson Foy JL, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17(5):880-2.  [PMID:21529401]

    Comment: This is a case report supporting likely sexual transmission of Zika virus (ZIKV) from a man to his wife after he departed Senegal and returned to the US. His wife had not traveled with him. Sexual intercourse occurred before the onset of symptoms in the traveler. His wife develops symptoms including rash, within a week of sexual contact. Both the traveler and his wife were diagnosed with presumptive ZIKV infection based upon independent testing of paired sera at different laboratories. Notably, after the traveler’s fever and the rash had resolved, he developed fatigue, arthralgia, symptoms of prostatitis and hematospermia. This highlights the need to advise patients regarding possible sexual transmission and to consider the use of condoms or abstinence until all symptoms of illness have resolved.
    Rating: Important
    

53. Fokam EB, Levai LD, Guzman H, et al. Silent circulation of arboviruses in Cameroon. East Afr Med J. 2010;87(6):262-8.  [PMID:23057269]

    Comment: Although the title is misleading in that infections were not "silent" per se, the report does provide important information regarding the circulation of ZIKV in this West African country. This study reports the results of arbovirus serological testing of sera from 102 febrile patients without malaria or typhoid fever seen at clinics in the Fako Division in southwest Cameroon after the identification of both dengue and chikungunya circulating in the country. Although 67% of sera reacted to more than one of the 18 arboviral antigens tested; 11.2% had a monotypic response to the Zika virus without cross reaction with other flaviviruses tested.
    Rating: Important
    

54. Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009;15(9):1347-50.  [PMID:19788800]

    Comment: This is an outstanding review if Zika virus infections and outbreaks occurring after the virus was identified outside of Sub-Saharan Africa up through the time of the outbreak on Yap Island. In addition, it provides an excellent discussion of the virus epidemiology, known pathogenesis until that time, clinical findings and diagnosis.
    Rating: Important
    

55. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360(24):2536-43.  [PMID:19516034]

    Comment: This is the first documented widespread transmission of ZIKV outside of Africa and Asia with transmission by the Aedes hesilli species. Much of what we know of the clinical manifestations of the infection come for the few outbreaks that have been identified and investigated. During this outbreak there were 49 laboratory-confirmed and 59 probable cases of ZIKV infection on this island in Micronesia. The outbreak affected and estimated 73% of the population 3 years of age and older. No microcephaly was reported associated with this outbreak although the numbers may have been too small to detect its occurrence should this be a causal factor in this birth defect.
    Rating: Important
    

56. Lanciotti RS, Kosoy OL, Laven JJ, et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis. 2008;14(8):1232-9.  [PMID:18680646]

    Comment: This is the first very large outbreak of ZIKV reported with well-characterized serological and phylogenetic data. Serological testing for evidence of immunity and/or cross-reactivity to ZIKV and 9 other flaviviruses is reported (dengue 1, 2, 3 and 4; Japanese encephalitis, yellow fever virus, West Nile virus, Murray Valley encephalitis virus and St Louis encephalitis virus). Importantly the paper demonstrates the ease with which a primary flavivirus infection which is ZIKV can be diagnosed serologically but the problem with cross-reactivity when previous flavivirus immunity is present at the time of a ZIKV infection, even when the plaque reduction neutralization test (PRNT) is used after the IgM and IgG ELISA. A real-time RT PCR test was developed for use using newly derived sequence data from several ZIKV infected patients from the outbreak; 17 of 157 samples tests were positive, 10 equivocal and 130 negative using this diagnostic modality. These 178 samples were then used to sequence the aminoacid sequences adjacent to the envelope’s 154-glycosylation site and compare it with other ZIKV strains in this area reported in GenBank. Notably, a 12 nucleotide (4 amino acid) insertion in the envelope gene glycosylation site. Changes at this site have been noted in other strains and other flaviviruses. It is unclear if this is a marker for evolutionary diversity, virulence or both.
    Rating: Important
    

57. Jacobs BC, Rothbarth PH, van der Meché FG, et al. The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study. Neurology. 1998;51(4):1110-5.  [PMID:9781538]

    Comment: This case-control study from 1998 highlights the importance of multivariate analyses when seeking associations. Here, several pathogens found, on univariate analysis, to be associated with GBS were no longer significant when more rigorous multivariate techniques were applied. Hence, Campylobacter, CMV, EBV and M. pneumoniae are statistically associated with GBS in this study of 16 infectious agents and 154 age and sex-matched controls. Studies looking more closely at the reported association of ZiKV with GBS are needed.
    

58. Olson JG, Ksiazek TG, Suhandiman , et al. Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg. 1981;75(3):389-93.  [PMID:6275577]

    Comment: This report of a clinical investigation of in-patients at a hospital in Indonesia between 1977 and 1978 for presence of alphaviruses and flaviviruses. A total of 219 patients with paired sera demonstrated evidence of flavivirus infection and alphavirus infection. Testing was performed at the US Naval Medical Research Unit No 2 (NAMRU-2) in Jakarta. Seven patients demonstrated diagnostic rises to ZIKV only; 10 others had a 4-fold rise in antibody titer in pair sera but also showed diagnostic rises in dengue-2 virus or other flavivirus. This provides evidence of the likely evidence of ZIKV in Indonesia almost 40 years ago.
    

59. Fagbami AH. Zika virus infections in Nigeria: virological and seroepidemiological investigations in Oyo State. J Hyg (Lond). 1979;83(2):213-9.  [PMID:489960]

    Comment: This article provides that reader with insight into the range of endemic infections in Sub-Saharan Africa as early as the 1960s and 1970s. Notably, ZIKV infection in non-human primates is thought to decrease the severity of yellow fever virus infection in the primates although it does not prevent disease.
    

60. SIMPSON DI. ZIKA VIRUS INFECTION IN MAN. Trans R Soc Trop Med Hyg. 1964;58:335-8.  [PMID:14175744]

    Comment: This is the first reported human case of Zika virus infection.
    Rating: Important
    

61. DICK GW. Zika virus. II. Pathogenicity and physical properties. Trans R Soc Trop Med Hyg. 1952;46(5):521-34.  [PMID:12995441]

    Comment: This is the 2nd of two landmark papers by this author re: Zika virus and provides important information not only on the pathogenesis but on the physical properties of the virus and its response to physical agents that may be of interest/importance to infection control practitioners
    Rating: Important
    

62. DICK GW, KITCHEN SF, HADDOW AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509-20.  [PMID:12995440]

    Comment: This is one of 2 landmark papers that discuss the isolation of the virus in non-human primates and its identification in Uganda.
    Rating: Important
    

63. Enfissi A, et al. Zika virus genome from the Americas. Lancet, 2016; 387: 227-228.

    Comment: This correspondence from Suriname provides genomic data collected from 4 of the first 5 patients diagnosed with locally-acquired ZIKV infection. Complete coding the viral genome was obtained for 1 patient and the viral envelope sequence for 3 others. A phylogenetic analysis was conducted for the non-structural-5 protein, the envelope protein and compared against existing databases for these virus sequences from other geographic locations. The Suriname strains belong to the Asian genotype and are most closely related to the French Polynesia outbreak strains from 2013 with >99.7% and 99.9% nucleotide and amino acid identity, respectively.
    Rating: Important
    

Media

Aedes

Typical female Aedes albopictus mosquito that may transmit Zika virus. Ae. aegypti may also transmit.

Source: CDC