1. Cara Heuser, MD Intermountain Healthcare and University of Utah Park City, February 2016 Common Pregnancy Questions: Structured Fitness and Occupational Activities

4. Let’s Talk About Zika, Baby!

6. At A Glance - Zika in the U.S. (as of Feb 10, 2016) US States – Travel-associated Zika virus disease cases reported: 52 – Locally acquired vector-borne cases reported: 0 US Territories – Travel-associated cases reported: 1 – Locally acquired cases reported: 9

7. Current Concerns Associated temporally and geographically with fetal-neonatal microcephaly – +biologic plausibility Case report of Zika virus particles and RNA present in the brain of a fetus with microcephaly and abnormal CNS findings at autopsy Transmission of Zika to the fetus has been documented in all trimesters; Zika virus RNA has been detected in fetal tissue from early missed abortions, amniotic fluid, term neonates and the placenta Uncertainties include the incidence of Zika virus infection among pregnant women in areas of Zika virus transmission, the rate of vertical transmission, and the rate with which infected fetuses manifest complications such as microcephaly or demise – As yet, no case-control nor cohort studies to strengthen causative link/provide clinically useful counseling information

8. Objectives National/International Recommendations on – Testing – Prevention Symptoms/Clinical Presentation Association with Microcephaly History & Microbiology

11. Utah DOH Laboratory tests for Zika virus infection diagnosis are of limited availability, but include polymerase chain reaction (RT‐PCR) for Zika RNA and Zika virus immunoglobulin M (IgM) and neutralizing antibodies on serum specimens. Given the overlap of symptoms and endemic areas with other viral illnesses, patients should also be evaluated for other possible flavivirus infections. Testing for Zika virus has multiple limitations. – Currently, only the CDC in Fort Collins, Colorado and a few public health laboratories are able to perform testing. The Utah Public Health Laboratory (UPHL) does not currently perform this test. CDC is working with laboratories to expand availability of testing. – There is substantial serological cross‐reactivity among the flaviviruses and current IgM antibody assays cannot reliably distinguish between Zika and dengue virus infections. Therefore, an IgM positive result in a dengue or Zika ELISA test should be considered indicative of a recent flavivirus infection. – In patients who have been immunized against yellow fever or Japanese encephalitis virus or who are infected with another flavivirus (e.g., West Nile or St. Louis encephalitis virus) in the past, cross‐reactive antibodies in both the IgM and neutralizing antibody assays may make it difficult to identify which flavivirus is causing the patient’s current illness. Because antibody tests may cross‐ react with other flaviviruses (e.g., dengue, yellow fever, Chikungunya, or Japanese B encephalitis) and produce false positives, it is recommended that the patient be tested for these viruses as well. CDC will not perform these tests, and this testing should be done through a regular commercial laboratory. – Acute serum (≥ 3 mL) collected within the first 7 days following symptom onset can be tested by PCR. IgM antibodies may be detectable by day 4 of illness but are more reliably identified later on in the course of infection; convalescent specimens, collected 2‐3 weeks later, may be necessary to confirm or rule‐out infection.

14. What is the link between Zika virus in Brazil and the high numbers of infants born there with microcephaly? The time frame and geographic location of reports of infants with microcephaly coincides with the outbreak of Zika virus infections in Brazil. The baseline prevalence of congenital microcephaly is difficult to determine because of underreporting, and the inconsistency of clinical criteria used to define microcephaly. Although population-based estimates of congenital microcephaly in Brazil vary, the number of infants with microcephaly currently being reported in Brazil is greater than would be expected. What birth defects have been reported in in infants with confirmed Zika virus infection? Brain abnormalities reported in infants with microcephaly and laboratory- confirmed congenital Zika infection include microcephaly and disrupted brain growth. S Some infants with possible Zika virus infection have been found to have intracranial calcifications, ventriculomegaly, lissencephaly and abnormal eye findings. It is not known if Zika virus infection caused any of these abnormalities. How is microcephaly diagnosed after? Although a universally accepted definition of microcephaly does not exist, microcephaly is most often defined as head circumference (occipitofrontal circumference) greater than 2 standard deviations below the mean, or less than the 3rd percentile based on standard growth charts Myriad other causes of microcephaly include aneuploidy, infectious (CMV, rubella, toxo), fetal alcohol syndrome, etc

15. Prevention Travel Advisories Sexual Transmission Mosquito control and Avoidance

17. Sexual Transmission Current information about possible sexual transmission of Zika is based on reports of three cases. – The first was probable sexual transmission of Zika virus from a man to a woman, in which sexual contact occurred a few days before the man’s symptom onset. – The second is a case of sexual transmission currently under investigation (unpublished data, 2016, Dallas County Health and Human Services). – The third is a single report of replication-competent Zika virus isolated from semen at least 2 weeks and possibly up to 10 weeks after illness onset; reverse transcriptase- polymerase chain reaction testing of blood plasma specimens collected at the same time as the semen specimens did not detect Zika virus. The man had no sexual contacts. Because no further testing was conducted, the duration of persistence of Zika virus in semen remains unknown. Men who reside in or have traveled to an area of active Zika virus transmission who have a pregnant partner should abstain from sexual activity or consistently and correctly use condoms during sex (i.e., vaginal intercourse, anal intercourse, or fellatio) for the duration of the pregnancy. Men who reside in or have traveled to an area of active Zika virus transmission who are concerned about sexual transmission of Zika virus might consider abstaining from sexual activity or using condoms consistently and correctly during sex. Couples considering this personal decision should take several factors into account.

18. Geography Areas with active mosquito-borne transmission of Zika virus – Prior to 2015, Zika virus outbreaks occurred in areas of Africa, Southeast Asia, and the Pacific Islands. – In May 2015, the Pan American Health Organization (PAHO) issued an alert regarding the first confirmed Zika virus infections in Brazil. – Currently, outbreaks are occurring in many countries. – Zika virus will continue to spread and it will be difficult to determine how and where the virus will spread over time. US Territories – Local mosquito-borne transmission of Zika virus has been reported in the Commonwealth of Puerto Rico, the US Virgin Islands, and America Samoa. US States – No local mosquito-borne Zika virus disease cases have been reported in US states, but there have been travel-associated cases. – With the recent outbreaks, the number of Zika cases among travelers visiting or returning to the United States will likely increase. – 80% of cases will not be diagnosed. – These imported cases could result in local spread of the virus in some areas of the United States.

19. Barbados Bolivia Brazil Colombia Commonwealth of Puerto Rico, US territory Costa Rica Curacao Dominican Republic EcuadorEl Salvador French Guiana Guadeloupe Guatemala Guyana Haiti Honduras Jamaica Martinique Mexico Nicaragua Panama Paraguay Saint Martin Suriname U.S. Virgin Islands Venezuela

20. Worldwide Oceania/Pacific Islands – American Samoa – Samoa – Tonga Africa – Cape Verde

21. Microbiology & History

22. Microbiology “Arbovirus” (ARthropod-BOrne virus) is a descriptive term applied to hundreds of predominantly RNA viruses that are transmitted by arthropods, notably mosquitoes and ticks. – Four families of viruses: Bunyaviridae, Flaviviridae, Reoviridae, Togaviridae Flavivirus, genus of viruses in the family Flaviviridae, enveloped viruses that contain genomes which consist of nonsegmented single-stranded positive-sense RNA Often maintained in complex cycles involving vertebrates such as mammals or birds and blood-feeding vectors. Until recently, only a few had caused clinically significant human diseases, the most historically important of these is yellow fever virus (flavus means "yellow” in Latin), the first recognized viral cause of deadly epidemic hemorrhagic fever. Structure: Icosahedral-like/ Capsid: Enveloped/Genomic arrangement: Linear Effective human vaccines are in use for the prophylaxis of yellow fever (live attenuated-1937), Japanese, and tick-borne encephalitis, Vaccines in trials or development for Dengue, West Nile, Eastern Equine Encephalitis Two lineages of Zika: African and Asian with current outbreak (& French Polynesian outbreak) most similar to Asian strain Full genome sequence has not been published

23. History-Viral Family These viruses started to emerge millennia ago, when North African villagers began to store water in their dwellings Connection between arthropods and disease first postulated in 1881 by Cuban doctor Carlos Finlay who hypothesized that Yellow fever may be transmitted by mosquitos Confirmed by Major Walter Reed in 1901 Primary vector, Aedes aegypti, spread globally from 15 th -19 th centuries Four unexpected arrivals of important arthropod-borne viral diseases in the Western Hemisphere over the past 20 years – dengue, which entered this hemisphere stealthily over decades and then more aggressively in the 1990s; – West Nile virus, which emerged in 1999; and – chikungunya, which emerged in 2013

24. History-Zika Discovered incidentally in Uganda in 1947 in the course of mosquito and primate surveillance Name comes from the Zika forest in Uganda Circulated predominantly in wild primates and arboreal mosquitoes and rarely caused recognized “spillover” infections in humans Decades ago, African researchers noted that Zika tended to follow chikungunya epizootics and epidemics. An analogous pattern began in 2013, when chikungunya spread pandemically from west to east, and Zika later followed In 2014, zika spread eastward across the Pacific to French Polynesia, then Easter Island (2015), then to Americas With the exception of West Nile virus, which is predominantly spread by culex-species mosquitoes, the arboviruses that recently reached the Western Hemisphere have been transmitted by aedes mosquitoes, especially the yellow fever vector mosquito A. aegypti

25. Current global distribution of Aedes aegypti mosquitos (red=highest; blue=none)

28. What Now?

29. Future Directions Vaccine—in investigation Mosquito control with usual measures Oxitec mosquito – May reduce mosquito population by 95% – Oxford University 1999 – Inability to develop past the larval stage Establish a likely causative link between zika and microcephaly (or not) – Obtain data for clinical counseling

30. What I (we?) Learned… Follow national/international guidelines – Check back frequently! – ACOG, SMFM, CDC, WHO, PAHO – State Health Departments can help with testing Discuss with patients/providers the current uncertainty regarding the exact nature of the link between Zika and microcephaly Remember that in our patient population (US), other public-health risks likely pose a much greater maternal- fetal threat and should continue to be emphasized – Vaccines (flu, tdap) – Seatbelt use – Substance use – Many others