Zika Virus — What Clinicians Need to Know

Coordinator:

Welcome, and thank you for standing by. At this time, all participants are in a listen-only mode. After the presentation, we will conduct a question-and-answer session. To ask a question, please press the Star 1 and please record your name.

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Loretta Jackson Brown:

Thank you, (Kathy). Good afternoon. I'm Loretta Jackson Brown and I'm representing the Clinician Outreach and Communication Activity -- COCA -- with the Emergency Risk Communication Branch at the Centers for Disease Control and Prevention. I'm delighted to welcome you to today's COCA call, Zika Virus - What Clinicians Need to Know.

You may participate in today's presentation by audio only via webinar or you may download the slides if you're unable to access the webinar. The PowerPoint slides and the webinar link can be found on our COCA webpage at emergency.cdc.gov/coca, click on January 26 COCA Call, the slides are located under call materials.

Free continuing education is offered for this COCA Call. Instructions on how to earn continuing education will be provided at the end of the call.

CDC, our planners and presenters and their spouses/partners wish to disclose they have no financial interest or other relationship with the manufacturers of commercial products, suppliers of commercial services or commercial supporters. Planners have reviewed content to ensure there is no bias. This presentation will not include any discussion of the unlabeled use of a product/products under investigational use.

At the end of the presentation, you will have the opportunity to ask the presenters questions. On the phone, dialing Star 1 will put you in the queue for questions. You may submit questions through the webinar system at any time during the presentation by selecting the Q & A tab at the top of the webinar screen, typing in your question.

Questions are limited to clinicians who would like information related to Zika virus disease.

For those who have media question, please contact CDC Media Relations at 404-639-3286 or send an e-mail to media@cdc.gov. If you are a patient, please refer your questions to your healthcare provider.

At the conclusion of this session, the participant will be able to; 1) describe the epidemiology, clinical manifestation, management and prevention of Zika virus disease, 2) discuss diagnostic testing for Zika virus infection and interpretation of test results, 3) articulate the importance of early recognition and reporting of cases, 4) state the recommendations for pregnant women and possible Zika virus exposure, and 5) discuss evaluation of infants with microcephaly and relationship of Zika in microcephaly.

Today's first presenter is Dr. Ingrid Rabe. Dr. Rabe is a medical epidemiologist in the Division of Vector-Borne Disease at CDC. She has 5 years of subject matter expertise in applied epidemiology in arboviral disease surveillance.

Our second presenter is Dr. Dana Meaney-Delman. Dr. Dana Meaney-Delman is a senior medical advisor in the National Center for Emerging and Zoonotic Infectious Diseases at the Centers for Disease Control and Prevention. Dr. Meaney-Delman is an obstetrician and gynecologist with over 15 years of clinical experience. In her career at CDC, she has focused on the development of evidence-based clinical guidelines for infectious diseases. Her contributions have included the development of clinical guidelines for anthrax, smallpox, Ebola and botulism.

Our final presenter today is Dr. Cynthia Moore. Dr. Cynthia Moore is a director of the Division of Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention. Dr. Moore is a pediatrician and clinical geneticist and has a Ph.D. in medical genetics. Her 24-year career at CDC has primarily focused on birth defects epidemiology.

At this time, please welcome Dr. Rabe.

Dr. Ingrid Rabe:

Thank you, Loretta. Zika virus is a single-stranded RNA virus in the genus flavivirus, family flaviviridae that is closely related to dengue, yellow fever, Japanese encephalitis and West Nile viruses. Zika virus is transmitted to humans primarily by Aedes species mosquitoes.

Among Aedes species mosquitoes, Aedes aegypti is a more efficient vector for humans. However Aedes albopictus is a possible vector. These mosquitoes also transmit dengue and chikungunya viruses. They lay eggs in peridomestic water containers and live and around households. They are aggressive biters and their peak feeding occurs during daytime - which means that the typical prevention messages for West Nile virus to reduce evening and nighttime mosquito exposures are less effective.

This map depicts the approximate distribution of Aedes aegypti and Aedes albopictus mosquitoes in the United States. As you can see, the Aedes aegypti mosquitoes have been identified across the southern half of the U.S. from California to Florida, and Aedes albopictus have been identified throughout much of the southern and eastern U.S.

Zika virus is maintained in two distinct cycles similar to yellow fever virus. In Africa there is jungle cycle where Zika virus is transmitted between nonhuman primates by mosquitoes. However, infected mosquitoes may incidentally transmit virus to human hosts. This may initiate an epidemic or urban cycle in which people infected with Zika virus develop sufficiently high levels of the virus in their blood and are capable of infecting mosquitoes that feed on them while they're viremic.

These mosquitoes can then transmit the virus to other people leading to person to mosquito to person transmission of the virus.

Other modes of transmission are possible. Maternal-fetal infections have occurred intrauterine and perinatally. Other routes include sexual transmission, blood transfusions and laboratory exposure. There is a theoretical concern of transmission to organ or tissue transplantation and Zika virus RNA has been detected in breast milk that has not been documented to cause infection in a nursing infant.

This map depicts the 21 countries or territories currently reporting active Zika virus transmission.

Zika virus was first isolated from a monkey in Uganda in 1947. Before 2007, only sporadic human disease cases were reported from Africa and Southeast Asia. In 2007, the first outbreak of Zika virus disease was reported on Yap Island in the Federated States of Micronesia. In 2013 to 2014, more than 28,000 suspected cases were reported from French Polynesia with subsequent outbreak reports from other Pacific islands.

In May 2015, Brazil reported the first locally-acquired cases in the Americas. Currently outbreaks are occurring in many countries or territories in the Americas, including the Commonwealth of Puerto Rico -- a U.S. territory -- and the U.S. Virgin Islands. Further spread to other countries in the region is likely.

Thus far local transmission of Zika virus has not been reported in the continental United States. Since 2011, there have been laboratory-confirmed Zika virus disease cases identified in travelers returning to the U.S. from areas with local transmission. With current outbreaks in the Americas, cases among U.S. travelers will most likely increase. Imported cases may result in virus introduction and local spread in some areas of the U.S. with appropriate link to the ecology.

This slide shows data on Zika virus incidence and attack rates based on a serosurvey conducted during the Yap Island outbreak in 2007. The infection rate was estimated to be 73% and the symptomatic attack rates among those infected 18%. All age groups were noted to be infected; however, adults were more likely to present for medical care. Among patients with Zika virus disease on Yap, there were no reports of severe disease, hospitalizations or deaths.

Among 31 confirmed cases, more than half reported maculopapular or papular rash, subjective fever, arthralgia and conjunctivitis. Other clinical signs and symptoms reported included myalgia, headache, retro-orbital pain, edema and vomiting.

Zika virus clinical disease is usually mild. Symptoms typically last several days to a week. In prior outbreaks, severe disease requiring hospitalization has been uncommon and fatalities were rare. More recent reports have described Guillain-Barrè syndrome in patients following suspected Zika virus infection; however, the relationship to Zika virus is not known.

In 2015 the Brazil Ministry of Health reported a substantial increase in the number of babies born with microcephaly. However, the true baseline of microcephaly incidence is unknown. Zika virus infection was identified in several infants born with microcephaly -- including deaths -- and early fetal losses. Some of the infants of microcephaly have tested negative for Zika virus infection or been attributed to other causes. The incidence of microcephaly among fetuses with congenital Zika virus infection is unknown.

To give you a sense of what the increased rates of microcephaly look like, these two maps compare the rates in the Americas and Caribbean from 2010 to 2014 with 2015. The smallest purple dots represent rates of up to 1 per 1000 live births, and the largest purple dots represent rates from 45 to 88 per live births.

It may be challenging to distinguish infections with Zika virus from those with dengue and chikungunya viruses. They're transmitted by the same mosquitoes with similar ecologies and they can circulate in the same area and they may rarely cause co-infections. Diseases due to all three viruses have similar clinical features; however, it is important to rule out dengue virus infection as proper clinical management can improve clinical outcome.

This table shows the clinical features of Zika virus disease compared with dengue and chikungunya. The number of plus signs indicates the frequency at which symptoms were reported. In comparison to dengue and chikungunya, Zika is more likely to cause a rash and fever is common but not invariably present. Cases also are more likely to present with conjunctivitis. Arthralgia although common is not as prominent as in chikungunya. Zika virus disease is not characterized by hemorrhage or shock.

There are a number of diagnostic tests for Zika virus infection, including RT-PCR to detect viral RNA in serum collected within 7 days of illness onset, serology to detect IgM and confirmatory neutralizing antibodies in serum collected at least 4 days after onset, as well as plaque reduction neutralization tests -- or PRNTs -- that can be used to detect a four-fold greater rise in virus-specific quantitative antibodies in paired sera. And immunohistochemical staining for viral antigens or PCR on fixed tissues.

The complexity of testing and interpretation of results is Zika virus serology can be positive due to antibodies against related flaviviruses such as dengue and yellow fever viruses. Neutralizing antibody testing may discriminate between cross-reacting antibodies in primary flavivirus infections, but it can be difficult to distinguish the infecting virus in people who have been previously infected or vaccinated against a related flavivirus.

There are currently no commercially-available diagnostic tests for Zika virus infection. Testing is being performing at CDC and a few state health departments. CDC is working to expand the laboratory testing in states, and healthcare providers are advised to contact their state health department to facilitate diagnostic testing.

There's no specific antiviral therapy for Zika virus disease. Treatment is supportive and entails rest, administration of fluids, analgesics and antipyretics as indicated. As alluded to earlier, suspected Zika virus infection should be evaluated and managed for possible dengue or chikungunya virus infection. Notably aspirin and other non-steroidals should be avoided until dengue can be ruled out to reduce the risk of hemorrhage.

The differential diagnosis for Zika virus disease includes other arboviruses viruses including dengue and chikungunya; bacterial infections including leptospirosis, rickettesia and Group A streptococcal infections, malaria and non-arthropod borne viruses such as parvo, rubella, measles, adeno and enteroviruses.

Zika virus disease surveillance is important to inform clinical and public health response. From a clinical perspective, clinicians should consider weekend travelers with acute onset of fever, maculopapular rash, arthralgia or conjunctivitis within 2 weeks after return from an area with Zika virus activity. Infants or fetuses of women infected during pregnancy should be evaluated for possible congenital infection and microcephaly. Upon receiving reports from clinicians, health departments should be aware of possible local transmission in areas where Aedes species are active.

As an arboviral disease, Zika virus is nationally notifiable. Healthcare providers are encouraged to report suspect cases to their health department. State health departments in turn are requested to report laboratory-confirmed cases to CDC. Timely reporting should allow health departments to assess and reduce the risk of local transmission or mitigate further spread.

Unfortunately, there are no vaccines or medications to prevent infection or disease. The primary prevention measure is to reduce mosquito exposure. CDC issued Level 2 travel notices advising pregnant women to consider postponing travel to areas with ongoing Zika virus outbreaks. If patients are infected, they should be advised to prevent mosquito exposure during the first week of illness to prevent further mosquito-borne transmission to others.

Looking forward, it is expected that Zika virus will continue to spread in areas with competent vectors. Transmission is increasing in Central America and Mexico and the Caribbean. We anticipate further spread in Puerto Rico and the U.S. Virgin Islands. In turn, travel-associated cases may introduce virus into U.S. states. Imported cases may result in some local transmission and outbreaks; however, air conditioning may limit the size and scope of outbreaks and colder temperatures during the winter months should interrupt and possibly stop further spread. Experience from dengue might be predictive. From 2010 to 2014, an average of 1.5 million dengue cases were reported to PAHO annually, with 558 travel related and 25 locally transmitted cases in the U.S. annually.

At this point, I would like hand over to my colleague Dr. Dana Meaney-Delman.

Dr. Dana Meaney-Delman:

Thank you. On behalf of the 2016 CDC Zika response team, I would like to thank you for participation in this call. In this section of the call, I will describe what is known about Zika virus during pregnancy and review the interim CDC recommendations for the evaluation of pregnant women.

Data on pregnant women infected with Zika virus are limited. The limited data available did not suggest that pregnant women are more susceptible to Zika virus disease. Pregnant women can be infected with Zika virus in any trimester; however, the incidence of Zika virus disease among pregnant women is not known. There is no evidence to suggest that pregnant women experience more severe disease during pregnancy than non-pregnant individuals.

There is evidence of transmission of Zika virus from mother to fetus during pregnancy. Zika virus infections have been confirmed in infants with microcephaly both those in Brazil and in infants of mothers who traveled to Brazil but subsequently delivered in the U.S. Additionally, Zika virus RNA has been detected in specimens of first and second trimester fetal losses, although it is not known if Zika virus disease caused the fetal losses. Zika virus RNA has been detected prenatally in amniotic fluid. In a published case report of two women at approximately 30 weeks gestation, prenatal ultrasound findings of microcephaly and intracranial calcifications prompted further fetal evaluation. Amniocentesis was performed and Zika virus RNA was detected in amniotic fluid. These women had experienced symptoms consistent with Zika virus disease during the second trimester of pregnancy.

Zika virus may also be transmitted during the time of delivery. In French Polynesia two pregnant women with signs and symptoms of Zika virus disease around the time of delivery were tested and found to be positive for Zika virus. Their neonates were subsequently diagnosed with Zika virus infection within 3 days of delivery. It is unlikely that these neonates were exposed to mosquitoes and is presumed that maternal-to-fetal transmission occurred around the time of delivery.

Because there is neither a vaccine nor prophylactic medication available to prevent Zika virus disease, CDC recommends that pregnant women in any trimester should consider postponing travel to areas where Zika virus transmission is ongoing. If a pregnant woman travels to an area with Zika virus transmission, she should talk to her healthcare provider and strictly follow steps to avoid mosquito exposures during the trip.

Strategies to avoid mosquito exposures are multifaceted. First, CDC recommends use of EPA- registered insect repellants. These repellants include DEET, Picaridin and IR3535. These insect repellants are considered for use in pregnant and lactating women when used in accordance with the package label. Insect repellants should be reapplied per the product label. Other strategies recommended to prevent mosquito exposures, include wearing long-sleeved shirts and pants to cover exposed skin, wearing permethrin-treated clothing and staying and sleeping in screened-in or air-conditioned rooms. Because Aedes mosquitoes bite mostly during the daytime, it is recommended that pregnant women practice these strategies throughout the entire day.

Healthcare providers should ask all pregnant women about recent travel. Women who have traveled to an area with ongoing Zika virus transmission during pregnancy should be evaluated for symptoms of Zika virus disease. And its symptoms as described earlier are present during or within 2 weeks of travel, testing is recommended in accordance with the CDC interim guidelines. Because of a similar geographic distribution and clinical presentation of Zika, dengue and chikungunya virus as described earlier, patients with symptoms consistent with Zika virus disease should also be evaluated for dengue and chikungunya in accordance with existing guidelines.

We will now review highlights of the CDC interim guidelines for pregnant women during Zika virus outbreak which were published on January 19, 2016. These recommendations are for healthcare providers caring for U.S. women who have traveled to areas with Zika virus transmission. These recommendations do not apply to women residing in areas of ongoing Zika virus transmission. CDC is developing guidelines specific to healthcare providers caring for women residing in areas with local transmission of Zika virus.

Women who have traveled to an area with ongoing Zika virus transmission during pregnancy should be evaluated for Zika virus disease. At this time testing is recommended for pregnant women who have a history of travel during their pregnancy to an area Zika virus transmission and who have symptoms during or within 2 weeks of travel, or those who have had fetal microcephaly or intracranial calcifications detected on fetal ultrasound.

If a maternal Zika virus test in a pregnant woman is positive or is inconclusive, a fetal ultrasound should be considered to detect microcephaly or intracranial calcifications. Amniocentesis for Zika virus testing should also be offered if a pregnant woman has a positive or inconclusive test and the pregnancy is greater than or equal to 15 weeks of gestation. Decisions about amniocentesis should be made with a healthcare provider and should consider the risks and benefits of testing. The timing of when to perform an amniocentesis to detect fetal infection is not known and should be individualized.

If a pregnant woman traveled to an area of Zika virus transmission and experience symptoms during or within 2 weeks of travel, and she's has had negative Zika virus testing, fetal ultrasound should be considered. Healthcare providers should evaluate fetal head size and intracranial anatomy. If microcephaly or intracranial calcifications are present, amniocentesis should be considered for Zika virus RT-PCR testing.

If a pregnant woman traveled to an area of Zika virus transmission, and who had experienced symptoms during or within 2 weeks of travel, had negative Zika virus testing and a normal ultrasound, healthcare providers should continue routine prenatal follow-up.

In a pregnant woman with a history of travel to an area with Zika virus transmission who did not report symptoms consistent with Zika virus disease during or within 2 weeks of travel, a fetal ultrasound should be considered to detect microcephaly or intracranial calcifications.

If either microcephaly or intracranial calcifications are detected on fetal ultrasound, then the pregnant woman should be tested for Zika virus infection. Testing should be coordinated through state, local or territorial health departments. Healthcare providers can consider offering amniocentesis and testing for Zika virus in amniotic fluid by RT-PCR.

If an ultrasound is performed and no findings are present on an initial ultrasound, serial ultrasounds can be considered to detect the development of microcephaly or intracranial calcifications at the discretion of the healthcare provider. Serial growth can be assessed sonographically every 3 to 4 weeks. If microcephaly or intracranial calcifications are detected on serial ultrasound, pregnant women should be tested for Zika virus infection. And again, testing should be coordinated through state, local or territorial health departments.

In this situation, healthcare providers can consider offering amniocentesis and testing for Zika virus in amniotic fluid by RT-PCR.

For pregnant women with laboratory evidence of Zika virus in serum or in amniotic fluid, serial ultrasounds should be considered to monitor fetal anatomy and growth every 3 to 4 weeks. Referral to a maternal-fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended. In addition, if there is evidence or maternal or fetal Zika virus infection, the following tests are recommended after delivery: Histopathologic examination of the placenta and umbilical cord, testing of frozen placenta tissue and cord tissue for Zika virus RNA, and testing of cord serum for Zika and dengue virus IgM and neutralizing antibodies.

Thank you for your attention. I'd like to turn it over to Dr. Cynthia Moore.

Dr. Cynthia Moore:

Good afternoon. I'm going to talk this afternoon about Zika virus and microcephaly. Microcephaly is a clinical finding, not a diagnosis. Infants with microcephaly have a head size that is smaller than infants as the same age and sex. Typically in the United States, below the third percentile on a standard growth chart identifies infants with microcephaly; however, standards can vary.

Head circumference is a reliable assessment of the intracranial brain volume, so microcephaly is often associated with cognitive and possibly neurologic issues. There are two known mechanisms that lead to microcephaly. Microcephaly can be primary due to abnormal development from the beginning cells that form the brain -- this is also related to a genetic etiology -- or it can be secondary due to an arrest in development or destruction of normally-forming brain tissue which can be due to infections or interruption of blood flow. Microcephaly that is present at birth is called congenital microcephaly.

Microcephaly is a difficult birth defect to monitor in populations because of inconsistent standards of definition and inconsistent use of terminology.

There have been numerous photographs in the media of infants in Brazil with microcephaly such as these two that you see on the left of your screen. Infants with congenital infections often have microcephaly as well as additional brain anomalies including scattered intracranial calcifications -- which we can see in the bottom middle picture -- enlarged ventricles and brain volume loss as seen in the bottom right picture. These abnormal CT scans can be compared to a typical newborn CT scan seen in the upper right.

This baby has severe microcephaly, but there is a range in severity. In this graphic a baby with a typical head size is depicted on the far left. The middle illustration is a baby with microcephaly. And on the far right, a baby with severe microcephaly is depicted. With the severe phenotype, you can see the loose scalp that forms folds or rugae in this case, and in this case it indicates that there has been some volume loss.

One mechanism for the development of microcephaly has been termed fetal brain disruption sequence. This mechanism was first described in 1984 but it had been noted in earlier literature. Fetal brain disruption sequence is a pattern of brain tissue destruction resulting in some collapse of the fetal skull, microcephaly, scalp rugae and neurologic impairment. You can see these features in the image at the bottom of the screen which are from a 1990 publication. This phenotype appears to be present in some of the infants with microcephaly in Brazil.

What we do know about Zika virus infection and microcephaly. Of the reported infants with microcephaly in Brazil, only a small number have been tested and were positive for Zika virus infection. But there does appear to be a pattern of microcephaly that is consistent with the fetal brain disruption sequence. However, again, this is based on photos and CT scans for a small number of affected infants in Brazil. It has also been reported though in the retrospect to the investigation of the Zika outbreak occurring in French Polynesia from 2013 to 14 which you heard about earlier, and again that was among a small group of infants, and it has been seen in infants with other intrauterine infections such as cytomegalovirus, or CMV.

On the other hand, we don't know if Zika virus infection during pregnancy causes microcephaly or other adverse pregnancy outcomes. We also don't know the full spectrum of microcephaly phenotypes that might be related to Zika infection. We don't know when in pregnancy Zika virus infection might be more likely to be transmitted from mother to the infant or is most harmful to the fetus, or how the severity of a mother's infection might impact the fetus. And finally, we also don't know the magnitude of possible risks of microcephaly and other adverse outcomes from the Zika virus infection.

I'd like to turn now to the interim guidelines for the evaluation and testing of infants with possible congenital Zika virus infection that was released in CDC's Morbidity and Mortality Weekly Report this morning. Zika virus laboratory testing in infants is recommended for infants with microcephaly or intracranial calcifications or to women who travel to or resided in an area with Zika virus transmission while pregnant and for infants born to mothers with positive or inconclusive test results for Zika virus infection.

The diagnosis of Zika virus infection is made through molecular and serological testing similar to what you've heard earlier. For infants, recommended laboratory testing includes RT-PCR for Zika virus RNA as well as IgM and plaque reduction neutralization tests for Zika virus antibodies. Additionally, IgM and neutralizing antibodies are tested for dengue virus.

Zika virus RT-PCR testing can be performed on serum specimens that can come from the umbilical cord at birth or directly from the baby, but hopefully it will be collected within 2 days of birth to -- I'm sorry, I'm having a little lapse here -- to prevent postnatal infection and if a cerebral spinal fluid -- CSF -- is obtained for other studies, we recommend that that also be tested. Histopathologic evaluation via immunohistochemical staining to detect Zika virus antigen on fixed placenta and umbilical cord can be considered. Additionally, if not already performed, a mother's serum should be tested for both Zika virus and dengue virus, IgM and neutralizing antibodies.

Now, I'm going to walk you through the algorithms that you find in today's interim guidelines. I'll start with the infant with microcephaly or intracranial calcifications that have been detected prenatally or at birth. This baby - this infant should be tested for Zika virus and further clinical evaluation and laboratory testing also is recommended for the infants. For infants with any positive or inconclusive test findings for Zika virus infection, healthcare providers should notify the state, territorial or local health department and assess the infant for possible long-term sequelae.

For infants who have negative results on all Zika virus testing that is performed, healthcare providers should evaluate for other possible etiologies as these babies do have microcephaly and intracranial calcifications and should treat as indicated.

For an infant without microcephaly or intracranial calcifications born to a mother who was potentially infected with Zika virus during pregnancy, subsequent evaluation is dependent on the results from maternal Zika virus testing. I'll go through these evaluation pathways in more detail.

If no microcephaly or intracranial calcification have been detected prenatally or at birth and a positive or inconclusive test for Zika virus infection in the mother prior to delivery, then the baby should have a thorough physical examination and Zika virus testing should be performed in this infant. If the Zika virus test samples are positive or inconclusive for Zika virus infection in the infant, then there are additional clinical evaluations and assessment for long-term sequelae. If the test is actually negative for the infant, then we would recommend, of course, routine care, appropriate follow-up on any clinical findings.

So if the mother has not undergone testing, - any previous testing for Zika virus prior to her delivery, CDC recommends she receive testing only if she had symptoms that were consistent with Zika virus disease during or within 2 weeks and any time spent in an area with ongoing Zika virus transmission.

If the mother is positive or has positive or inconclusive findings from the tests for Zika virus infection, then the infant should undergo testing for evidence of a congenital infection as described in the previous slide. If the mother's tests are negative, then no further Zika virus testing or evaluation is recommended and the infant should again receive routine care. If the mother has not received any previous testing for Zika virus but did not report any clinical illness consistent with the disease during pregnancy, no further testing of the mother or the infant is recommended. Finally, if the test results in the mother were negative for Zika virus infection, the infant should receive again routine care.

So in summary, all infants with possible congenital Zika virus infection should have the following evaluation. A thorough physical exam including careful measurements and assessment of gestational age - and this is actually just the usual standard of care. The infant should have a cranial ultrasound unless prenatal ultrasound results from the third trimester demonstrate no abnormalities of the brain, and that is of course to look for calcifications that may be not be evident otherwise. Further evaluation and potential consultation with appropriate specialists for neurologic abnormalities, any dysmorphic features, hepato/splenomegaly, and rash or other skin lesions. Of course the baby should have a hearing screen at birth before discharge from the hospital or within one month of birth. And again, this testing is part of newborn screening in every state.

And finally, an eye exam to include visualization of the retina, optic nerve and macula either before discharge or within one month of birth. And then other evaluations which are specific to the infant's clinical presentation and the physician's judgment should be considered. If any abnormalities are noted in the evaluations, the consultation with the appropriate specialist is recommended.

For infants with microcephaly, consultations are recommended with a clinical geneticist or dysmorphologist, a pediatric neurology to help determine appropriate brain imaging, additional evaluation and potential treatment. Pediatric disease specialist should be considered after testing for other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus, lymphocytic choriomeningitis virus and herpes simplex viruses.

Further testing includes complete blood count, platelet count and liver function enzyme tests. Consideration of genetic and other teratogenic causes may be based on additional congenital anomalies that are identified through the clinical exam or imaging studies.

Regarding long-term follow-up, healthcare providers should report the case to the health department and monitor for additional guidance as it's released or the guidelines are updated. He or she should conduct additional hearing screen at 6 months plus any appropriate follow-up or hearing abnormalities detected during newborn screening. Careful evaluation of the head circumference and developmental characteristics and milestones through the first year of life are important. And again, obtaining appropriate consultation with medical specialists.

Let's go for it, I think we got the slides just slightly out of order. Summary is the next one. Yes, thank you.

So to summarize, Zika virus continues to circulate and cause locally transmitted disease in the Americas. Healthcare providers should consider the possibility of Zika virus infection in travelers with acute fever, rash, arthralgias or conjunctivitis within 2 weeks after return from an area where Zika virus transmission is ongoing or had residence in an area with reported Zika virus transmission.

Reports from Brazil indicate a substantial increase in the rate of congenital microcephaly and studies are underway to help characterize this relationship.

Pregnant women should consider postponing travel to areas of Zika virus' transmission.

Go back to remaining questions. At this point many questions remain and you've heard several of them as we've done our presentation. We're working rapidly to answer them. For example, we don't know the incidence of maternal/fetal transmission by trimester and whether any factors like severity of the Zika infection or the mother's immune response might influence transition. We also don't know the magnitude of risk of microcephaly and other fetal and neonatal outcomes or the risk of Guillain-Barre Syndrome from Zika virus infection.

And I think we have another one to go back to. One more. Maybe I did them all. Go forward, activities and plans. Yes.

CDC's activities and plans. So we are coordinating a response with the Pan American Health Organization, other regional partners and international partners. We are assisting with investigation of microcephaly and Guillain-Barré Syndrome. We are continuing to evaluate and revise our guidance as new data emerge. And we will distribute this guidance through our health advisories, MMWR publications and our CDC Website. We will communicate regularly with clinicians through these COCA calls, professional organizations and state and local partners.

One more. One more. One more. Okay, that's great.

So here are some additional resources that you may want to take time to look at after the call and we've also included a slide with selected references.

We want to thank our many collaborators and partners for this important work and I finished - I think we finished our presentation and are ready for any questions.

Loretta Jackson Brown:

So thank you presenters for providing our COCA audience with a wealth of information. We will now open up the line for the question-and-answer session. Questions are limited to clinicians who would like information related to Zika virus disease. For those who have media questions, please contact CDC media relations at 404-639-3286 or send an e-mail to media@cdc.gov. And if you are a patient, please refer your questions to your healthcare provider.

When asking a question, please state your organization and also remember you can submit questions through the webinar system as well. Operator?

Coordinator:

Thank you. If you do have a question, please press the Star1 and please record your name. To withdraw your question press Star 2. Once again, to ask a question, please press Star 1 and please record your name. One moment.

Loretta Jackson Brown:

And as we're waiting for the first question on the phone, we do have several questions through the webinar system so I will move through a couple of those.

The first one is: Are Zika rashes notably pruritic or macular? If one of our presenters would like to take that one.

Dr. Ingrid Rabe:

This is Ingrid. And so macular and pruritic.

Loretta Jackson Brown:

Either or. Okay, so we'll move on to the next one on the webinar system. And this one has to do with sexual transmission. So is there any information on sexual transmission based time limits? And this participant is relating this to the Ebola outbreak, related that they found much later the virus was still in the semen.

Dr. Ingrid Rabe:

This is Ingrid speaking again. So there has been a number of media reports of recent incidence, so a lot of interest in this and the reason for that is there were two reports that are pertinent to this topic. One was a report of possible sexual transmission that occurred potentially from a researcher to their partner upon return from presumably acquiring Zika virus infection while working in Senegal. The evidence of sexual transmission was based on serologic testing in both the returning researchers and the partner and was suggested from that point of view; however, there were no positive PCR findings from that and it was in the context of hematospermia.

The second report was also a report of hematospermia with detection of viral RNA at two weeks after acute illness; however, there was no transmission implicated in that particular report. It was merely documentation of viral RNA.

So at this point in time, we are limited in the amount of information we have available as far as Zika is concerned. We do not know if and how long there might be viral excretion in the semen and they are certainly questions looking into that. At this point, however, there are no specific recommendations based on that given the limited available data.

Loretta Jackson Brown:

Thank you. Operator, do we have anyone on the phone?

Coordinator:

All right. Our first question comes from Warner Hudson. Please state your organization.

Warner Hudson:

Hi, UCLA. I have two questions. So it sounds like someone previously vaccinated against yellow fever might test positive. Which test would be positive and also if there's time, if a pregnant woman gets a blood-borne pathogen exposure and she's working in a Zika area, can she get a blood-borne transmission of Zika if she's exposed? Thank you.

Dr. Ingrid Rabe:

Sorry, I'll address both of those questions. It's Ingrid speaking again.

In terms of the prior yellow fever vaccine, we do see a cross-reactivity with any of the related flaviviruses which could of course affect yellow fever vaccine as well. And for years after vaccination with yellow fever vaccine, we do see positivity on IgM assays as well as neutralizing antibody assays. So that may complicate interpretation because neutralizing antibodies may be raised to yellow fever and another infecting flavivirus and it may be difficult to differentiate the particular infecting strain.

As far as the - I'm not sure if the question pertained particularly to the risk of transfusion transmission or pertaining that particular subgroup if a pregnant patient were exposed to Zika virus by blood-borne transmission. To address the transfusion question, we do know that other flaviviruses that are arthropod-borne have been implicated in transfusion transmission and most notably here West Nile virus. So we would expect that it would be a risk and they have, indeed, been - at least one report coming out of Brazil with transfusion transmission possibly occurring in that case. So we expect that it could occur. Whether that would pose any additional risk or how that might affect a pregnant patient is unknown at this time.

Warner Hudson:

Thank you. I was actually asking about a simple needle stick, pregnant woman, say a healthcare worker caring for a Zika patient gets a needle stick exposure from a Zika patient.

Dr. Ingrid Rabe:

So again there are few data to be based on. We do know that there's a risk laboratory transmission and potentially the same would hold true for percutaneous transmission as we had other arboviruses, but again what that might translate to in terms of risk for a pregnant patient particularly is not clear.

Warner Hudson:

Thank you very much.

Coordinator:

The next question is from Virginia.

Laurie Forlano:

Hi, this is Laurie Forlano from the Virginia Department of Health. My question is for an asymptomatic pregnant woman who had relevant travel to an infected country, the algorithm is that fetal ultrasounds should be conducted. Is there a recommendation as to how early that first fetal ultrasound should be conducted or just according to standard patient prenatal care?

Dr. Dana Meaney-Delman:

So this is Dana Meaney-Delman. Thank you for that question. Unfortunately we really do not have data to inform when to perform that ultrasound. We don't know how long after infection that the findings on ultrasound could occur. We don't know what the risk of maternal to fetal transmission is. So it's really a challenging area, and as more data emerge and we have more information we will share that and make those recommendations clearer. But right now it is - we are in a data free zone and it really is I think up to the individual patient and her healthcare provider.

Laurie Forlano:

Thanks. And just one quick follow-up question. How, just for any cause, due to any cause, how early could microcephaly even be detected by ultrasound? Is there any...

Dr. Cynthia Moore:

Hi, this is Cynthia Moore. And we have been doing quite a bit of studying and talking with our experts who do prenatal diagnosis to try to answer this question, and again I think unfortunately we don't know of - for certain. We do have case reports that -- anomalies such as microcephaly--were missed on the mid-pregnancy ultrasound -- which would be the 18 to 22 week, and subsequently was identified on 28 to 30 week time period. I think it depends on the severity - it may depend on the severity of the actual microcephaly or any of the problems with the structure of the brain. But again, we don't have a firm answer that we can back up with a lot of data.

I will say that our experts in this area say it is challenging at 20 weeks and often if they see anything, it needs to be followed up with serial ultrasounds until they can be certain of what's going on.

Laurie Forlano:

Thank you.

Coordinator:

Next question is from Anne Sarkis.

Ann Sarkis:

Hello, Ann Sarkis here, Washington, D.C., the IAED Bank Travel Clinic. I have a question on how would adults be treated coming back from a zone and showing symptoms and would quarantine be part of the treatment if they were full-blown symptomatic and all of that ?

Dr. Ingrid Rabe:

This is Ingrid speaking again to address this question. And with regard with a returning symptomatic traveler, we would again advise the consultation or presentation to a healthcare provider. If they have clinical features consistent with potential Zika virus infection that they again be evaluated potentially for - to be able to treat for dengue and other possible infecting viruses as well to optimize clinical outcome. But as far as testing is concerned, that would need to be discussed with a healthcare provider who would in turn discuss with state or local health departments to facilitate appropriate testing. And we do encourage patients who are symptomatic to avoid mosquito bites during the first week of illness so it's not a viremic source for potential human to mosquito to human transmission. But it is bite-prevention per se.

Ann Sarkis:

Okay. So quarantine would not be part of the treatment?

Dr. Ingrid Rabe:

No.

Ann Sarkis:

Okay, thank you very much.

Coordinator:

Next question is from Priscilla.

Priscilla:

I'm from Michigan, Beaumont Health System. I'm just calling regarding women who want to travel to these areas say for a service trip or whatnot, and they would like to get pregnant within the next month, my question is could they be carrying the virus in their blood and would that affect a future pregnancy, if we know anything?

Dr. Dana Meaney-Delman:

So this is a question that has come up...thank you for the question. We don't have any evidence at this time to suggest that it would impact future pregnancies. With other infections, once the viremia has been cleared from the blood, it doesn't pose an issue. But again for Zika virus specifically, we have not collected data on this issue.

Priscilla:

All right. Thank you.

Coordinator:

Question is from Ernest Visconti.

Ernest Visconti:

Have there been any travel or any endemic-related cases in North America to date?

Dr. Ingrid Rabe:

This is Ingrid speaking. So we have had some imported cases as well from travelers who have been to endemic areas, yes.

Ernest Visconti:

Okay.

Dr. Ingrid Rabe:

No reported for the local transmission within the continental U.S.

Ernest Visconti:

Okay. Is it a large number of cases or just sporadic at this point?

Dr. Ingrid Rabe:

At this stage, sporadic, not a large number.

Ernest Visconti:

Thank you.

Dr. Ingrid Rabe:

As travel increases, we will see increasing numbers.

Ernest Visconti:

Thank you.

Loretta Jackson Brown:

And we'll go to the webinar system for a question. So presenters we have someone wanting to know the technical information on blood and amniotic fluid, the process for sending that, could you share that with our audience on how they can send samples, I guess, to their state and local or to CDC?

Dr. Ingrid Rabe:

Yes. So at the moment we are advising healthcare providers to contact their state or local health departments to facilitate testing. As I mentioned, we are limited in the number of laboratories that are currently able to provide the testing, so much of it is being done at CDC and then a few state health departments that have capacity to do so. However, we would encourage clinicians to contact their local health department or state health department to facilitate how best to arrange for transfer of those samples to them and then on our lab or to the state lab, as the case may be, and they will be able to provide guidance on which particular samples should be submitted and, yes, the - if there are remaining questions upon discussion with the state and local health department, we are certainly available to discuss with them and provide it as well.

Loretta Jackson Brown:

And I think, Dr. Rabe, they also want to know you know, taking from Ebola, are there any special handling precautions that they need to be aware?

Dr. Ingrid Rabe:

Not at this time. It would be similar to the submission of other arboviral testing.

Loretta Jackson Brown:

Thank you. Operator, we'll take another question from the phone.

Coordinator:

All right. Thank you. The next question is from Mary Milanga.

Loretta Jackson Brown:

Go ahead, we can hear you.

Mary Milanga:

Sorry. My question is should there be concerns for newborns as far as exposure? Hello?

Loretta Jackson Brown:

Dr. Moore will probably take that. Dr. Moore?

Dr. Cynthia Moore:

I will, but unfortunately to tell you that we really don't have any data on that. We have a couple of newborns that have I believe transmission during the birth process and one did have some symptoms and the other did not, so we can't really base any recommendations or conclusions on small numbers like that, but we hope to get more data on that, also.

Mary Milanga:

Additionally, what if an infant was to be bitten by a mosquito, are they at risk developmentally in the early neonatal or in infant phase?

Dr. Cynthia Moore:

Again, a wonderful question, but we don't have any information to give you on that, but it is a question that we're discussing and thinking about how we can gather that information.

Mary Milanga:

Okay. All right. Thank you for your help.

Coordinator:

Okay. Next question is from Mark Geher. Mark Geher, go ahead.

All right, going to Diane Rabinski.

Diane Rabinski:

Actually, Priscilla asked my question, but I did have a question on the incidence rate in Brazil. I read somewhere that they've had 3500 cases of microcephaly in the last 4 months. Is that correct?

Dr. Cynthia Moore:

This is Cynthia Moore. We're working with the Ministry of Health to try to get a better handle on that. What they're reporting now is a process of seeing how many babies are identified with microcephaly, but as I said earlier there are many causes for microcephaly. So it's an evaluation process to see how many of those children actually appear to have had Zika virus versus other types of infections or other etiologies of microcephaly. So that's a work in progress.

Diane Rabinski:

Okay. And I have a lot of people traveling overseas from our agency in Washington, D.C. If women have been immunized for yellow fever and then they get pregnant and have a baby, can they test the baby then for the Zika or will the yellow fever have affected the baby's antibody response or whatever you're testing?

Dr. Ingrid Rabe:

Sorry, this is Ingrid speaking again. So this is presumably somebody who has received yellow fever vaccine prior to pregnancy?

Diane Rabinski:

Correct.

Dr. Ingrid Rabe:

Then the newborn is being tested, it should not interfere with IgM presence or PCR that is being tested. There may be presumably IgG transfer, neutralizing antibody transfer as well present in the mother's circulation.

Diane Rabinski:

Thank you very much.

Coordinator:

Okay. Our next question comes from Dr. Janet Andrews.

Dr. Janet Andrews:

Yes, hi, this is Dr. Janet Andrews; I'm from Norwalk Hospital, Norwalk, Connecticut. And my question was partially answered before, but the question would be on a woman of childbearing years who is considering pregnancy and she goes to an area, comes back is asymptomatic. How long should she safely wait to try to attempt to get pregnant, is it a 2-week period, is it known how long, you know, that clientele should wait?

Dr. Dana Meaney-Delman:

So the first most important thing is Zika virus usually remains in the blood of an infected person just for a few days and up to a week, and we don't believe that the virus will cause infections after the virus has been clear from the blood. So to give you a definitive time, we don't really know, but the time frame for viremia is short-lived.

Dr. Janet Andrews:

Okay. So that's a good basis. So we begin two weeks or so, the virus should be out of the system?

Dr. Dana Meaney-Delman:

I don't know that we can know for every individual how long it will take. Remember we need to consider both incubation period and then if they were viremic how long that would last, but we are working to get an answer to that question more specifically because I'm sure it's coming up quite a bit.

Dr. Janet Andrews:

Great. Thank you very much, very good presentation. I really learned a lot.

Dr. Dana Meaney-Delman:

Thank you.

Coordinator:

Our next question is from Etuma Menjat.

Etuma Menjat:

Hi. One of the questions I had was the previous caller's which you answered, but the second I have is of all the microcephaly babies from Brazil, have they looked at other co-morbidities which can cause microcephaly and what they pretty much chalked up to only potentially Zika virus is the only etiology and in that case was it due to any kind of mutation? Because obviously in the East African area there were no reported - it was unreported or underreported or have the virus mutated?

Dr. Cynthia Moore:

Hi, this is Cynthia Moore. I'm not sure about the last part of your question, maybe Ingrid could talk about that. But my understanding and in a recent MMWR last week we had 35 babies reported from Brazil. There was I believe 1 or 2 babies that had cytomegalovirus, but they are trying to do as complete workup as is possible for microcephaly. But speaking as a clinical geneticist, sometimes you just can't find the reason. They are doing the things that are available to try to sort this out.

Etuma Menjat:

I see. I see.

Loretta Jackson Brown:

And I think the other part of that question, Dr. Moore, was did they see the microcephaly in other regions of the world? So I think we had a webinar question similar to that, was it seen in Africa as well and Asia?

Dr. Cynthia Moore:

We don't have direct information on that. We had the report that I think was mentioned in the presentation of a retrospective look back in French Polynesia after an outbreak of Zika virus where it appeared that a small number of babies had the same sort of problem that they're seeing in Brazil. Brazil was the first front of the infection, and to my knowledge, the - I may not know about it, I know, at least no other babies in other countries have been reported in medical literature, but as the infection moves on we'll have to gather information and see.

Loretta Jackson Brown:

Thank you. Operator, we have time for one more question.

Coordinator:

All right. And the next is from Annie Fein.

Annie Fein:

Hi. Can you hear me? This is Annie Fein in New York City.

Loretta Jackson Brown:

Yes, go ahead.

Annie Fein:

Okay, great. I actually have 2 questions, sorry about that. One is I wondered if you could clarify what the definition of microcephaly is that we should be using, and in particular including low birth weight or small for gestational-aged babies? And the second question is for example, is there some kind of a reference chart or really good reference for all gestational ages, et cetera? And the second question is do you know when a commercial test might be available for either PCR or a serology for Zika virus? Thank you.

Dr. Cynthia Moore:

Maybe I'll take the first part of that and, Ingrid, you can address the second. So you're asking about standard definition for microcephaly or what kind of tools could be used to know if a child has microcephaly. I think that's one of our challenges. It's a very good question because if you start looking in the literature, microcephaly is defined sometimes less stringently, sometimes more, sometimes by percentiles, sometimes by standard deviations. So that makes it difficult. I think the standard growth curves -- and I haven't looked at the premature charts in quite some time, I think they're based on percentiles. And if the definition is based on percentile, it's usually less than a 1/3 percentile, but on standard deviations sometimes it's minus two, sometimes it's three...it's quite difficult.

Dr. Ingrid Rabe:

And, Annie, this is Ingrid. Just to address your question about a commercial test, at this stage there is none and we do not have a specific timeline and obviously there's mounting interest and need for testing which is why obviously within the PubMed Health Med there's great interest to expand testing capacity, but we don't have specific timelines or information on that.

Annie Fein:

Thank you.

Loretta Jackson Brown:

So on behalf of COCA, I would like to thank everyone for joining us today with a special thank you to our presenters Drs. Rabe, Meaney-Delman and Moore. We invite you to communicate to our presenters after the webinar. If you have additional questions for today's presenters, please e-mail us at coca@cdc.gov, put January 26 COCA call in the subject line of your e-mail and we will assure that your question is forwarded to the presenter for a response. Again the e-mail address is coca@cdc.gov .

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Coordinator:

Thanks for participating in today's conference. This will complete today's call, you may disconnect at this time.