Findings correlate with clinical observations of more fetal abnormalities and other Zika-related health problems in late versus early pregnancy

Tampa, FL (Feb. 2, 2021) — A preclinical study by a University of South Florida Health (USF Health) Morsani College of Medicine research team has discovered a new mechanism for how Zika virus passes from mothers to their children during pregnancy – a process known as vertical transmission.

The researchers showed, for the first time, that specialized cells lining the uterus (maternal decidual cells) act as reservoirs for trimester-dependent transmission of the virus through the placenta – accounting for both the fetus’s greater susceptibility to first-trimester Zika infection and for the more serious congenital defects observed in early versus late pregnancy. They also report that the agent tizoxanide inhibits ZIKA virus in maternal decidual cells grown in the lab, offering promise for preventing perinatal transmission that can cause devastating malformations and brain damage in developing fetuses and infants.

The findings appeared Dec. 1, 2020 in the Journal of Immunology.

The study was led by co-principal investigators Ozlem Guzeloglu-Kayisli, PhD, a USF Health associate professor of obstetrics and gynecology, and Charles J. Lockwood, MD, USF Health senior vice president, dean of the Morsani College of Medicine, and a professor of obstetrics and gynecology specializing in maternal-fetal medicine.

“If we can better understand Zika virus vertical transmission and successfully block infection in maternal (decidual) cells early in the pregnancy, the virus will not pass through the placenta to reach the fetus and it is less likely to cause severe abnormalities,” said Dr. Guzeloglu-Kayisli, the paper’s lead author.

Ozlem Guzeloglu-Kayisli, PhD, USF Health associate professor of obstetrics and gynecology, was the paper’s lead author.| Photo by Allison Long, USF Health Communications and Marketing

Charles J. Lockwood, MD, dean of the USF Health Morsani College of Medicine and a professor of obstetrics and gynecology specializing in maternal-fetal medicine, was a co-principal investigator for the Zika study along with Dr. Guzeloglu-Kayisli. | Photo by Freddie Coleman, USF Health Communications and Marketing

The widespread global alarm caused by the spread of mosquito-borne Zika virus throughout the Americas in 2015-2016 dissipated after the virus all but disappeared in 2017. Yet, resurgence remains possible in areas where the Aedes aegypti mosquito is prevalent, and there is no treatment or vaccine available for Zika virus infection.

While most Zika-infected adults show no symptoms, the virus can cause minor flu-like symptoms, and in rare cases has been associated with Guillain-Barre syndrome. However, Zika poses the most concern for pregnant women, because up to one in 10 newborns of affected mothers suffer Zika-associated birth defects, including smaller than normal head size (microcephaly) that can lead to developmental disabilities and other health problems. Zika has also been linked to pregnancy complications, including preterm birth, preeclampsia and miscarriage. Moreover, timing appears important. Mothers infected in the first trimester are much more likely to have babies with severe Zika birth defects than mothers infected in the third semester.

The placenta, the organ supplying maternal oxygen and nutrients to the growing fetus, has ways to prevent most pathogens, including viruses, from crossing its protective maternal-fetal barrier. A subtype of fetally-derived placental cells known as syncytiotrophoblasts, in direct contact with maternal blood, are assumed to be the site where the Zika virus enters the placenta, leading to potential fetal infection. However, Dr. Ozlem Guzeloglu-Kayisli said, these particular trophoblasts resist Zika virus attachment and replication.

Above and close-up below: A model for mother-to-fetus transmission of Zika virus (green particles) through maternal decidual cell-mediated infection of villi attaching the placenta to the endometrium (uterine lining). | Images courtesy of USF Health first appeared in the Journal of Immunology: doi: 10.4049/jimmunol.2000713

To learn more about how Zika gets through the placental wall, the USF Health team began by investigating the cellular and molecular mediators of Zika virus replication. Among their key findings, the researchers:

–  Showed that specialized uterine cells from both pregnant and nonpregnant women were highly infectable by Zika virus. These immunologically active decidual cells, which line the uterus in preparation for and during pregnancy, form the maternal part of the placenta closest to the fetus.

–  Identified a more than 10,000-fold higher expression of the Zika virus attachment-entry receptor in the maternal decidual cells than in the fetal trophoblasts. Once inside the maternal cells, the Zika virus (an RNA virus) hijacks the cellular machinery to make proteins needed to copy its genetic material and churn out new viral particles. The proliferation of viral particles released from the maternal cells are then transmitted through branch-like vascular projections (villi) on the placenta’s surface layer where they can infect fetal trophoblast cells otherwise resistant to Zika virus.

–  Found that the efficiency of viral replication was significantly greater in first-trimester decidual cells than in those from term pregnancies.

–  Concluded that maternal (decidual) cells likely serve as the source for initial Zika virus infection and enhance subsequent transmission through the placenta to the fetus. “Moreover, trimester-dependent responses of decidual cells to Zika virus help to explain why pregnant women are susceptible to Zika infection and why the subsequent effects are more detrimental in the first trimester than in late pregnancy,” the study authors wrote.

–  Demonstrated that tizoxanide, the active metabolite of FDA-approved antiparasitic drug nitazoxanide, effectively impeded Zika virus infection in both maternal decidual cells and fetal trophoblast cells. The drug has been shown preclinically to inhibit a broad range of flu-like viruses and is being tested clinically against coronavirus. The finding warrants further testing of tizoxanide to block perinatal transmission of Zika virus and thereby protect the fetus from harmful outcomes, the researchers conclude.

The team’s work was supported in part by a Zika Research Initiative grant from the Florida Department of Health.

Center connects pregnant women and their families, and the region’s medical professionals, to USF experts in preventing, diagnosing and treating the mosquito-borne virus

Zika virus can be transmitted from a pregnant mother to her baby during pregnancy.

The photos seen worldwide after the Zika epidemic gripped Brazil and spread across the Caribbean were compelling — depicting infants born full-term yet with small heads and blank stares, held by mothers with faces full of concern and resolve.

But when the Zika epidemic waned last summer, and the last of the Centers for Disease Control and Prevention (CDC) travel advisories to Miami-Dade lifted, these striking images of infants with microcephaly, one of the most severe potential neurological consequences of active Zika infection in pregnancy, faded into the background. So too did the ongoing news about how pregnant women could protect themselves from the mosquito-borne, birth-defect causing virus.

Still a threat

Florida should not forget the threat Zika poses and its unpredictability, USF Health experts said, noting that the virus still circulates in some countries, and travelers continue to return to the United States after visiting or living in areas at risk.

With vigilance in mind, USF Health recently contracted with the Florida Department of Health (DOH) to establish a Zika Referral Center.  Funded by $600,000 from the CDC through the Florida DOH, the three-year program launched in April. It connects patients and medical professionals with USF’s multidisciplinary team of experts skilled in providing diagnostic, treatment and prevention expertise to expectant mothers, fathers, newborns and infants affected by Zika.

Zika virus spreads through mosquito bites.

“Although there are some theories, we still don’t understand all the components of why congenital Zika syndrome burst onto the scene in Brazil in 2015. We do know pathogens are always evolving, so we need to maintain a heightened sense of alertness even when Zika cases decline,” said the center’s medical director Patricia Emmanuel, MD, chair of the Department of Pediatrics, USF Health Morsani College of Medicine.

“We will use this CDC funding to educate pregnant women and their families about transmission of Zika and its potential long-term impact on their infants, and to ensure health care workers stay aware of potential exposure in their patients,” Dr. Emmanuel said. “Doing that can help us detect and follow Zika earlier in pregnancy, so we might better understand the full spectrum of the disease.”

The new center establishes on Florida’s West Coast a complement to the existing Zika Resource Team operating out of the University of Miami Health System since 2017.  (The first identified outbreak of mosquito-borne Zika virus infection in the continental United States occurred in Florida in Miami-Dade and Broward counties during summer 2016.)

A multidisciplinary Zika response team

The USF Health center’s Zika response team includes pediatricians, a perinatologist, an obstetrician, a clinical geneticist, a neurologist, an infectious disease consultant, and a newly recruited nurse practitioner who serves as program and case manager.

USF Health and the University of Miami will share prospective data collected, including numbers of expectant women tested for Zika infection and information on the growth and development of infants affected, Dr. Emmanuel said. Starting with Tampa General Hospital, the center’s staff will also provide training for obstetric and pediatric health professionals at regional hospitals in Hillsborough and surrounding counties, as well as health care consultations based on current CDC evidence-based practices and guidelines.

Not all pregnant women exposed to Zika will pass the infection to their developing fetus. But, the most worrisome risk for those who do is that their baby will be born with microcephaly, a serious condition characterized by an abnormally small brain and skull that can lead to seizures, feeding problems, developmental delays and impaired vision and hearing.

Stephanie Ros, MD, director of obstetric services for the Zika Referral Center, says USF Health has played a leading role caring for pregnant women affected by Zika and is equipped with the multidisciplinary expertise and resources to address the complexities of birth defects, including congenital Zika syndrome, before and after birth.

Ready to diagnose, manage women at risk and their babies

“Because the long-term effects of Zika can be so far reaching, no one medical professional possesses all the expertise to properly diagnose and manage every aspect,” said Dr. Ros, assistant professor of obstetrics who specializes in maternal fetal-medicine.  “At USF we can provide one centralized location for patient referrals, where our team remains up to date on the latest protocols for testing and has access to the appropriate tools to take care of women at risk and their babies.”

USF Health is equipped with the multidisciplinary expertise and resources to address the complexities of birth defects, including congenital Zika syndrome, before and after birth.

The USF Health Zika Referral Center is modeled after the highly effective USF Perinatal HIV Program, a collaboration between USF Health’s pediatric infectious disease experts and the regional perinatal community that delivers complex care to help prevent mother-to-child transmission of the human immunodeficiency virus. In Hillsborough and Pinellas counties, no pregnant woman followed by this program has given birth to an HIV-infected baby since 2014, Dr. Emmanuel said.

“It’s a successful network that could be extended beyond Zika to other viral infections, such as hepatitis B or cytomegalovirus, which may seriously affect the health of newborns,” Dr. Emmanuel said.

For more information, visit health.usf.edu/medicine/pediatrics/zika-referral-center.

The University of South Florida will collaborate on a new $10 million grant from Center for Disease Control and Prevention (CDC) to study ways to help stop the Zika virus and other infectious diseases from spreading in the United States.

Led by the University of Florida, the grant teams investigators from UF, USF, the University of Miami and Florida International University to create the Southeast Regional Center of Excellence in Vector-Borne Disease: The Gateway Program.

Thomas Unnasch, PhD, distinguished university health professor and chair of the Department of Global Health at USF College of Public Health, will lead the USF efforts during the project.

USF Health’s Thomas Unnasch, PhD, is a co-principal investigator for the CDC-funded Southeast Regional Center of Excellence in Vector-Borne Disease: The Gateway Program.

USF researchers  are working on a way to block transmission of Eastern equine encephalitis (EEEV) by migratory birds, who winter in Florida and fly north in the spring.  These birds contract the disease from mosquitoes in certain locations and USF is working to target mosquito control in those areas to keep the migrating birds free of the disease.

“This Gateway Program will allow us to better understand and interrupt wintertime transmission of EEEV spread from infected mosquitoes  in Florida,” said Dr. Unnasch. “We’re first going to identify the habitats in Florida that support mosquito survival in winter…and then propose treatments to eliminate the small numbers of mosquitoes responsible for the winter transmission. This will allow us to implement an ‘ounce of prevention’ strategy to attack the virus during its most vulnerable period.

“Much of the research we are doing with EEEV may have implications for preventing Zika from over-wintering in Florida,” Dr. Unnasch added, “That may be critical to any effort to eliminate Zika from from the state” and prevent its spread northward, therefore protecting the rest of the country.

For more information, go to press release from UF here.

RELATED STORY: Mosquito species may be key to transmitting EEE virus in southeast U.S.

USF Health Morsani College of Medicine immunologist Kenneth Ugen, PhD, participated in a new study demonstrating how a synthetic DNA vaccine approach successfully protected against infection, brain damage and death caused by the mosquito-borne Zika virus in vivo.

Dr. Ugen, a professor in the Department of Molecular Medicine, was a co-investigator for the preclinical study, recently published in the journal Nature: npj Vaccines. David B. Weiner, PhD, executive vice president and director of the Vaccine Center at The Wistar Institute in Philadelphia, was the study’s lead author.

“The paper published presents a study demonstrating the ability of a gene-based vaccine against a Zika virus protein to successfully protect mice from infection with this virus and associated damage,” Dr. Ugen said.

In this multisite study, 100 percent of the animal models were protected from Zika after vaccination followed by a challenge with the Zika virus. In addition, they were protected from degeneration in the cerebral cortex and hippocampal areas of the brain, while the other cohort showed degeneration of the brain after Zika infection.

A microscopic image of the Zika virus.

The research was the first of its kind to analyze a vaccine in an animal model that is susceptible to the disease, providing information regarding the protective impact of the immune response in susceptible individuals. Prior studies of the Zika virus have tested vaccines in animal models that are naturally resistant to Zika. This study extends these prior research studies in an important manner.

In this latest study, Weiner and colleagues demonstrated how a synthetic DNA vaccine expressed specific antigens for Zika in vivo. They observed that this novel vaccine generated robust antigen-specific antibody and T cell responses that neutralized the virus in preclinical animal models. Moreover, they found that the vaccine provided protection against the disease and death in animal models while also being neuroprotective, meaning that the disease was unable to spread to the brain. This is especially important given the risk that infants born with the disease have of developing microcephaly, a birth defect resulting in an abnormally small head and that may prevent the brain from developing properly.

Ken Ugen, PhD

One important aspect of Zika and many other mosquito-borne diseases is that not everyone infected with the virus will actually become ill as a result. With Zika, only about 20 to 25 percent of individuals with the virus are actually impacted by the disease, according to previous studies from the U.S. Centers for Disease Control (CDC). However, there is no way to know for certain who will be at risk for illness due to the virus, which is why it was crucial for this study to examine how a vaccine would operate in an infected, symptomatic host.

This Zika vaccine was developed by investigators at the Wistar Institute and Inovio Pharmaceuticals, with contributions from other investigators at multiple institutions. The vaccine has been approved by the FDA for clinical evaluation in Phase I clinical trials now being conducted in several U.S. and Canadian cities as well as in Puerto Rico.

Nearly 4,000 cases of Zika infection have been reported in the United States alone, according to the CDC. While most of these are travel-associated cases, more than 100 cases of Zika infection originating within the United States have been reported. Globally, more than 60 countries have reported mosquito-borne transmission of the disease.

***

This work was supported by the National Institutes of Health and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases grant NIH R01 AI092843. Weiner received funding from Inovio Pharmaceuticals Inc. and Gene One Life Science Inc.

//www.youtube.com/watch?v=NMiTKeEUh-U

Visit USF’s Zika at Our Doorstep website

Florida has become ground zero for the Zika virus – home of the first non-travel related cases of the mosquito-borne virus in the continental United States.

To put the current epidemic in context and discuss options for addressing this rapidly evolving public health and medical threat, experts from across USF Health gathered Aug. 19 for a half-day conference titled Zika at Our Doorstep: An International Public Health Conversation.

USF experts lead panel for Zika Conference.

Top researchers, elected and appointed government officials, and community leaders in the region’s tourism, transportation and health care industries filled the auditorium at the Patel Center for Global Sustainability to share the latest information about the virus. They also highlighted the need for more federal funding to support public health surveillance studies and biomedical research for early detection and new treatments such as vaccines and anti-viral agents, as well as studies to understand the development of Zika-associated fetal, childhood and adult brain effects.

The Patel Center auditorium was filled.

Also attending were federal legislators U.S. Rep. Kathy Castor and U.S. Rep. David Jolly, along with State Rep. Neil Combee.

The access to Zika experts also attracted extensive coverage by Tampa Bay area print, online and broadcast media, and the conference was picked up by additional news outlets, as well as other viewers, via online livestream.

The Zika Conference drew extensive media coverage.

Before the conference, Rep. Castor and Rep. Jolly toured the USF insectary where they saw firsthand the mosquitoes raised there. Research staff explained how they use the laboratory to better understand the insect and work on more effective treatments for devastating mosquito-borne diseases or develop vaccines to prevent infections. Currently the lab does not contain Zika-carrying mosquitoes, but it is designed to begin studying the virus.

U.S. Reps. David Jolly and Kathy Castor tour USF insectary with Dr. Thomas Unnasch. Photo by Ryan Noone.

The Zika virus has prompted worldwide concern largely because of its alarming connection to serious neurological birth defects, and its recent arrival in non-travel related cases is setting off alarms across the state. The conference featured topics that ranged from pregnancy and fetal effects to the importance of Zika risk communication. The following are highlights of what was said by the experts, elected officials and guests:

U.S. Rep. Kathy Castor.

U.S. Rep. Kathy Castor:

It’s important because, while the Congress is not acting, at least the folks here on the ground in the Tampa Bay area and at the University of South Florida are doing everything they can to educate the public and do some of the necessary research… This is a premiere university in the state and one of the top in the country for health innovation… We now know there have been 15 babies born with microcephaly and birth defects in the country. And there are hundreds of pregnant women known to be infected with the Zika virus being tracked right now. The Department of Health and Human Services says that, unless they receive supplemental funding, it will impact their ability to track these women, develop diagnostic tools and develop the vaccine… It’s much more cost-effective and efficient if you put the money into prevention — to prevent additional cases of birth defects and microcephaly.”

U.S. Rep. David Jolly.

U.S. Rep. David Jolly:

“This is a regional issue. The Florida delegation understands this impacts us more than other states. So as a delegation, they need to impress upon leadership and the broader Congress to actually pass the (funding) package… We still don’t know everything we need to know about Zika, the resources we need to control it and how to prevent it… We just took a tour of the insectary. This is one more remarkable thing that’s occurring at USF. A handful of research institutions are contributing to a national effort to learn more about mosquitoes and Zika so that, ultimately, we can contain it and hopefully, one day very soon, have a vaccine developed to eradicate the spread of Zika.”

Dr. Edmund Funai moderated the Zika Conference.

Edmund Funai, MD, USF System vice president and chief operating officer for USF Health:

“Rarely have I had the privilege of attending a conference that is so timely. And literally, just walking out of my house this morning, I saw two reports making their way through the media. One regarding another outbreak in Miami Beach, and another, far more concerning, about potential neurologic brain effects in adults. In this conference you’ll hear potential effects of this virus on unborn children. But now it’s becoming more clear that we may all be potentially at risk.”

USF System President Judy Genshaft.

Judy Genshaft, PhD, president of the USF System:

“We must be responsive and vigilant and willing to invest the necessary resources to stop Zika in its tracks and protect the most vulnerable among us from its devastating effects…By working collaboratively USF has a huge interdisciplinary team throughout the campus working on this particular response and on understanding Zika, whether it be maternal-fetal medicine, infectious disease, epidemiology, obstetrics, mosquito biology, public health, psychology, and chemistry… We want to be able to apply new knowledge to this virus and other tropical viruses that carry an increasing global threat. The investment in this is a wise one. The interconnected nature of our world means we all have a stake in fighting these kinds of outbreaks.”

Dr. Charles Lockwood.

Charles J. Lockwood, MD, senior vice president for USF Health and dean of the Morsani College of Medicine, a leading authority on Zika with expertise in maternal-fetal medicine, and a trustee on the March of Dimes National Board:

“This virus presents an extraordinary challenge to obstetricians and patients and it is the greatest threat to the well-being of American babies since polio…We just don’t have enormous amounts of data and that hinders our ability to predict an outcome… For a while we thought the third-trimester risk was not as bad, but now we know that, in fact, babies can appear to be perfectly normal in utero and up to term, and that microcephaly and other catastrophic consequences may not actually be discernable until early infancy, or even several months after birth. That is terribly frightening to obstetricians because it makes it very difficult to counsel women about the likelihood for fetal damage if they’re infected…There are enormous amounts of unknowns … As an obstetrician, maybe I’m a little biased, but it is absolutely critical that we have funding to improve our mosquito abatement strategy, to do a better job with surveillance and to develop a vaccine as soon as possible. The parallel with polio is apt and one of the reasons why the National Foundation for the March of Dimes has jumped on Zika like no other organization.”

Dr. Douglas Holt.

Douglas Holt, MD, director of Infectious Disease and International Medicine Division, USF Health Morsani College of Medicine:

“We hope (Zika) will be more like what we experienced with the Dengue virus in this state…The challenge is to not underestimate Zika. We just don’t know enough to have the confidence that that’s what will happen… We’re in for a tough fight. Zika represents a perfect storm. It’s a virus that is sneaky; a wolf in sheep’s clothing. It comes in and most people don’t even know they’re sick. In addition to this… it is unprecedented that we have a mosquito virus that also causes birth defects and is sexually transmitted.”

Dr. Thomas Unnasch.

Thomas Unnasch, PhD, chair and Distinguished University Health Professor, Department of Global Health, USF College of Public Health:

“Even though Phase I clinical trials for the vaccine are underway, it’s likely to take three to five years before the FDA approves a vaccine. So for the next three to five years we’ll still face a problem with the Zika virus and its transmission here… Most of the assays (tests) we have right now are not specific for the Zika virus. They cross react with Dengue. And given the fact that there are hundreds of thousands of cases of Dengue in the Caribbean every year, this creates a really large background for false positives of Zika virus. We need more specific tests to identify exposure to Zika virus, particularly among the at-risk populations.”

Dr. Deborah Cragun.

Deborah Cragun, PhD, assistant professor of global health, USF College of Public Health:

“In my experience as a genetic counselor, I often saw firsthand how risk perceptions can play a big role in decision-making and in emotional well-being… We see this with Zika, because we see concern amplified for several reasons. We know it can cause very serious birth defects.  Effective communication really needs to promote risk-appropriate actions to protect health, while at the same time not causing excessive worry or unnecessary action.”

Dr. Juan Pascale.

Juan Miguel Pascale, MD, PhD, deputy director of Gorgas Memorial Institute for Health Studies, Panama City, Panama, and professor of immunology, University of Panama School of Medicine:

“We have around 450,000 cases of Zika in Latin America, and we have 50,000 in Central America. We have around 1,800 babies with microcephaly in Latin America, so far. And 5,000 pregnant women have been exposed to Zika, and we are expecting microcephaly after they give birth. We have big problems… We are not efficient in controlling Aedes aegypti vector mosquitoes. We in Panama are beginning to use genetically modified mosquitoes and 93 percent of the mosquito population has been eradicated… Zika is not a Latin American problem or a U.S. problem – it is a global problem.”

Audience members posed questions for the panel.

Photos by Eric Younghans, USF Health Office of Communications
Video by Vjollca “V” Hysenlika and Ryan Noone, USF College of Nursing Communications

By Douglas A. Holt, MD
Andor Szentivanyi Professor of Medicine
Director, Division of Infectious Diseases and International Medicine
USF Health Morsani College of Medicine

(As of 8/04/2016)

What is known about the Zika outbreak in Miami?

• Mosquitoes in Miami have infected at least 14 people with Zika virus.
• A specific Miami neighborhood referred to as Wynwood has now been declared an area with active Zika virus transmission.
• This means that everyone who resides in or travels frequently to this area is at ongoing risk for being infected with Zika.
• The following steps are being taken to prevent Zika from spreading.
  1. Mosquito control is taking aggressive mosquito control measures within a minimum of an expanded 200 yards around the residence where a case of Zika infection has been reported.
  2. Mosquito control is testing mosquitoes for Zika.
  3. A medical advisory for the area has been issued through media, targeted outreach, health care provider notification and guidance targeted to OB/GYNs, midwives, Healthy Start, and others caring for pregnant women.
  4. Voluntary isolation will be recommended for infected individuals for 7 to 10 days from the onset of symptoms.
  5. The Florida Department of Health (FDOH) is going door-to-door to offer testing to identify more people infected, which will help determine the extent of the outbreak.
  6. FDOH will provide Zika Prevention Kits to pregnant women living in the area.

• Based on past experiences with dengue virus, also spread by the same mosquitoes, it is hoped that the outbreak will remain contained to this small area.
• However, Zika virus has proven to be very unpredictable, so we expect additional areas across the state to be identified as having active Zika virus transmission.

What does this all mean for Tampa Bay?

• Pregnant women are advised to avoid travel to the Wynwood neighborhood of Miami. If they have recently traveled to, or lived in, this area they should consult their obstetrician about being tested for Zika virus.
• Everyone should continue to take steps to prevent mosquito bites.
  1. Remove standing water from inside and outside your home or workplace. Check containers such as flowerpots, buckets, animal water bowls, and children’s pools. Scrub them clean and turn them over or cover them so they don’t collect water.
  2. Use an insect repellant, like bug spray or lotion, that’s registered with the Environmental Protection Agency (EPA). All EPA-registered bug sprays and lotions are checked to make sure they are safe and work well. If you use sunscreen, apply it first before bug spray or lotion.
  3. Wear a hat, a long-sleeved shirt, long pants, shoes and socks when outdoors. Treat clothes, shoes and other gear with bug spray called permethrin or wear treated clothes if you’re hiking, camping, or doing other outdoor activities.
  4. Use air conditioning and screens on windows and doors to keep mosquitoes out. Make sure screens on doors and windows don’t have holes or tears in them.

• Health care providers are being asked to remain alert for any patient with an illness that might be Zika fever and to notify the Health Department at 813-307-8010. Any two of the following clinical manifestations should suggest Zika fever: Fever, rash, joint aches and conjunctivitis or pink eye.

• Any pregnant woman should also now be asked about travel to the Wynwood neighborhood in addition to all the other countries outside the United States identified as having active Zika virus transmission. Additional areas will be included as they are identified by the FDOH. 

What is USF Health doing to respond if mosquitoes in Tampa Bay also spread Zika virus?

• Our physicians and medical providers have already begun screening our patients for symptoms suggesting Zika fever and all pregnant women for potential exposure to Zika virus.
• The Wynwood area of Miami has been added to the areas of concern and additional areas will be included as they are identified by the Florida DOH.
• We are working closely with the Department of Health-Hillsborough County to test patients who meet the criteria for Zika infection.
• Medical providers are following the recently released Centers for Disease Control and Prevention (CDC) guidelines on Caring for Pregnant Women with Possible Zika Virus Exposure.

Where can I get more information?

• CDC Health Alert Network (HAN) Health Advisory: CDC Guidance for Travel and Testing of Pregnant Women and Women of Reproductive Age for Zika Virus Infection Related to the Investigation for Local Mosquito-borne Zika Virus Transmission in Miami-Dade and Broward Counties, Florida https://content.govdelivery.com/accounts/USCDC/bulletins/15a36d4
• Update: Interim Guidance for Health Care Providers Caring for Pregnant Women with Possible Zika Virus Exposure — United States, July 2016  http://www.cdc.gov/mmwr/volumes/65/wr/mm6529e1.htm

• CDC Zika Page: http://www.cdc.gov/zika/index.html/

• CDC Travel Notices: http://wwwnc.cdc.gov/travel/notices

• FDOH Zika Page: http://www.floridahealth.gov/diseases-and-conditions/zika-virus/

• CDC Microcephaly: http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html

• CDC: Questions and Answers: Zika virus infection (Zika) and Pregnancy: http://www.cdc.gov/zika/pregnancy/question-answers.html

• Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities: http://www.nejm.org/doi/full/10.1056/NEJMoa1601824

• Zika Virus: http://www.nejm.org/doi/full/10.1056/NEJMra1602113
• Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00651-6/abstract

• Update: Interim Guidance for Health Care Providers Caring for Women of Reproductive Age with Possible Zika Virus Exposure — United States, 2016. http://www.cdc.gov/mmwr/volumes/65/wr/mm6512e2.htm?s_cid=mm6512e2_w

By Douglas A. Holt, MD
Andor Szentivanyi Professor of Medicine
Director, Division of Infectious Diseases and International Medicine
USF Health Morsani College of Medicine

(Updated June 24, 2016)

What more is known about Zika Virus Disease (ZVD) and birth defects?

• Additional evidence has been published confirming that ZVD causes microcephaly and other serious brain abnormalities.
• The risk of microcephaly is lower when the mother is infected during the third trimester of pregnancy.
• Asymptomatic ZVD can cause microcephaly.
• A study of pregnant women in Colombia over nine months during a ZVD outbreak is providing some preliminary data:

1. Nearly 12,000 pregnant women reported having experienced symptoms suggesting ZVD.
2. 1,850 of these pregnant women had ZVD that was confirmed by blood testing.
3. 616 of these women were infected during the third trimester of pregnancy and there were no cases of microcephaly or brain abnormalities.
4. There were also four cases of microcephaly in mothers who tested positive for ZVD but did not recall any illness.

• Further studies are ongoing to define:
  1. The full spectrum of congenital ZVD.
  2. Quantity of the risks of fetal microcephaly overall and based upon when during pregnancy the mother is infected.
  3. Whether current or past infection with another flavivirus like dengue influences the risk of congenital ZVD.

Will there be local transmission of Zika in Tampa Bay? That is, will people become infected with Zika by mosquitoes right here in Tampa Bay?

• Local transmission of Zika virus in Tampa Bay is probable.
• The type of mosquitoes that spread Zika are already here. We are entering “peak mosquito season,” which lasts about six months.
• The risk of mosquitoes spreading Zika in the United States is higher for Florida, especially Miami, Orlando and Tampa Bay, because we have more travelers returning from Zika outbreak areas.
• There will continue to be travelers who become infected outside the continental United States and return with live Zika virus in their bloodstream.
• Eventually sufficient numbers of mosquitoes will become infected and likely spread Zika to people here.
• This cycle continues and, as we have seen in other countries, can result in sustained and widespread transmission of Zika.
• What makes Zika especially concerning is that even after mosquitoes no longer carry Zika, women of child-bearing age or pregnant women can also become infected through sex by their partners. Thus, the public health threat of Zika to our community could continue for months after the Zika outbreak ends.

What is being done to prevent having Zika spread by mosquitoes in Tampa Bay?

• Everyone should take steps to prevent mosquito bites:
  1. Remove standing water from inside and outside your home or workplace. Check containers like flowerpots, buckets, animal water bowls, and children’s pools. Scrub them clean and turn them over, or cover them so they don’t collect water.
  2. Use an insect repellent, like bug spray or lotion, registered with the Environmental Protection Agency (EPA). All EPA-registered bug sprays and lotions are checked to make sure they are safe and work well. If you use sunscreen, apply it first before bug spray or lotion.
  3. Wear a hat, a long-sleeved shirt, long pants, shoes and socks when outdoors. Treat clothes, shoes and other gear with bug spray called permethrin or wear treated clothes if you’re spending time hiking, camping, or engaged in other outdoor activities.
  4. Use air conditioning and screens on windows and doors to keep mosquitoes out. Make sure screens on doors and windows don’t have holes or tears.
• Travelers returning from a Zika area are advised to report to their health care providers any symptoms of illness that might be ZVD:  Fever, rash, itching, muscle or joint aches, headache, conjunctivitis or pink eye.
• Anyone infected with Zika should be monitored for two weeks until the virus is no longer in their bloodstream.

What will happen if people become infected by Zika in Tampa Bay?

• A coordinated community action plan will be implemented.
• The Hillsborough County Emergency Operations Center would be activated.
• Florida Department of Health (FDOH) will notify mosquito control of a confirmed local transmission. Mosquito control will then conduct aggressive mosquito control activities within a minimum of an expanded 200-yard zone around the residence.
• Mosquito control will conduct enhanced mosquito surveillances and control activities around the residence at least weekly for six weeks.
• FDOH will organize outreach activities in neighborhoods within 1/8 mile of confirmed cases using FDOH employees and community volunteers such as the Medical Reserve Corps.
• State blood banks will be notified to screen blood supply and availability of Zika free products, particularly for pregnant women. Individuals from the impacted zip code(s) will be excluded from donating blood until six weeks after the last identified case of local transmission from the zip code.
• Following confirmatory testing at CDC, a medical advisory for the zip code(s) will be issued, with public notification through media, targeted outreach, health care provider notification and guidance targeted to OB/GYNs, midwives, Healthy Start, and others caring for pregnant women.
• Voluntary isolation will be recommended for infected individuals for 7 to 10 days from the onset of symptoms.
• FDOH will implement active case findings to identify additional infections including door-to-door outreach, enhanced syndromic surveillance, medical record review, and testing additional suspect cases.
• FDOH will provide Zika Prevention Kits to pregnant women through distribution at OB/GYN practices, Healthy Start Programs, CHD clinics and the community outreach activities described above.
• Active surveillance and response will continue until no additional cases are identified for at least six weeks.

During a local Zika outbreak, what will be advised for women who are pregnant, planning to become pregnant or might become pregnant?

• Pregnant women should take all precautions to avoid mosquito bites.
• Pregnant women should not have unprotected sex.
• Ideally couples (especially if the women is under age 35) should delay becoming pregnant until the Zika transmission ends.
• Women should practice safe sex and consider methods to avoid pregnancy such as Long Acting Reversible Contraception (LARCs) such as IUD’s and implantable devices.

Where can I get more information?

• CDC Zika Page: http://www.cdc.gov/zika/index.html/

• CDC Travel Notices: http://wwwnc.cdc.gov/travel/notices

• FDOH Zika Page: http://www.floridahealth.gov/diseases-and-conditions/zika-virus/

• CDC Microcephaly: http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html

• CDC: Questions and Answers: Zika virus infection (Zika) and Pregnancy: http://www.cdc.gov/zika/pregnancy/question-answers.html

• March of Dimes Zika Information: http://www.marchofdimes.org/

• Zika Virus Disease in Colombia – Preliminary Report: http://www.nejm.org/doi/full/10.1056/NEJMoa1604037

• Zika and the Risk of Microcephaly: http://www.nejm.org/doi/full/10.1056/NEJMp1605367

• Zika Virus and Birth Defects – Reviewing the Evidence for Casualty: http://www.nejm.org/doi/full/10.1056/NEJMsr1604338

• Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities: http://www.nejm.org/doi/full/10.1056/NEJMoa1601824

• En Español: http://nacersano.marchofdimes.org/embarazo/el-virus-del-zika-y-el-embarazo.aspx

The Zika virus pandemic continues to expand. As of March 23, 2016 there were 39 countries included on the CDC’s Travel Alerts (http://wwwnc.cdc.gov/travel/notices). In a remarkably short span of time, research focusing on the mosquitos that spread Zika, its pathogenesis (the virus’ effects on the body), clinical consequences, and available diagnostic testing has made rapid progress and provided new insights. This information is already being translated into guidelines and algorithms being used by the medical community to help patients, especially in the clinical management of women who are or want to become pregnant. On March 25, 2016 the Centers for Disease Control and Prevention (CDC) released updated guidance about caring for women of reproductive age with possible Zika exposure and the prevention of sexual transmission. USF Health is committed to meet the needs of our patients, through research initiatives undertaken both globally and locally. Dr. Douglas Holt’s update to the Zika virus question-and-answer document has been posted to the USF Health News site below,  including USF Health’s efforts to contribute to scientific discoveries and advancements associated with the Zika virus pandemic.

Sincerely,

Charles Lockwood, MD, MHCM
Senior Vice President, USF Health
Dean, USF Health Morsani College of Medicine

Zika Virus Update: Q&A

By Douglas A. Holt, MD
Andor Szentivanyi Professor of Medicine
Director, Division of Infectious Diseases and International Medicine
USF Health Morsani College of Medicine (MCOM)

(Updated April 8, 2016)

How is USF Health responding to the research efforts targeting Zika?

• USF Health is building on a strong foundation of basic science expertise that Dean Donna Petersen, ScD, established within the College of Public Health (COPH) under the leadership of Dr. Tom Unnasch, chair of the Department of Global Health. Dr. Unnasch and his faculty, including Dr. John Adams and Dr. Dennis Kyle, are internationally recognized as leaders in malaria, leishmania and arboviral diseases.
• In response to the call by Dr. Charles Lockwood, senior vice president of USF Health and dean, Morsani College of Medicine, to expand research even before the Zika outbreak, Drs. Unnasch and Holt began a joint recruitment effort for National Institutes of Health-funded researchers in infectious diseases.
• USF Health has longstanding partnerships with academic institutions, ministries of health, science and technology, and nongovernmental organizations in Panama through the USF Health International Education Foundation Office established in the City of Knowledge. Faculty from the COPH Department of Global Health and the MCOM Division of Infectious Diseases are working with scientists from the Gorgas Memorial Health Institute in Panama to respond to the Zika outbreak in that country.
• These efforts include medical students Key Yan Tsoi and Michelle Lippincott as well as their faculty advisors, Dr. Lynette Menezes from MCOM Infectious Diseases, Dr. Nestor Sosa, director general of the Gorgas Institute, and Dr. Dimelza Arauz, a Gorgas scientist, who are conducting an epidemiological study of current Zika cases in Panama.
• Drs. Adams, Holt, Anthony Odibo (Ob/Gyn) and Unnasch are working with Dr. Sosa to submit grant proposals to the NIH for Zika research.
• As part of National Public Health Week and World Health Day, the USF COPH hosted a panel discussion on Emerging Vector-Born Diseases, including Zika virus. Speakers included Dr. Robert Novak, professor of global health, infectious disease ecology and medical entomology, COPH; Dr. Sarah Obican assistant professor of obstetrics and gynecology and Dr. Douglas Holt, director of the Division of Infectious Disease, MCOM.

Does Zika virus cause microcephaly and other birth defects?

• On April 1, 2016 the CDC declared that  strong evidencence now exists that Zika virus causes fetal birth defects, including microcephaly, incomplete brain development, eye problems, and impaired fetal growth.  Studies are being done to better understand how Zika virus affects pregnancy.
• A retrospective review of a Zika outbreak in French Polynesia from October, 2013 to April, 2014 suggests that if a mother is infected during the first trimester, the risk of microcephaly is about 1%. This is a 20-fold increase in the syndrome compared with rates observed before the Zika outbreak.
• The risk of symptomatic congenital disease from Zika virus may be less in comparison to rubella and cytomegalovirus (CMV). When mothers are infected in the first trimester with rubella there is a 34-90% risk that the baby will have symptomatic congenital rubella syndrome. The fetal risk associated with CMV is 13%. However, up to 70% of the population will be infected during a Zika outbreak, far more than occurs with rubella and CMV infections. This explains the large number of microcephaly cases now being reported in Brazil.

What happens when a pregnant woman becomes infected with Zika virus?

• Most babies whose mothers had Zika during pregnancy are not born with major birth defects. However, researchers cannot rule out widespread though more subtle neurodevelopmental abnormalities. Researchers are working to better understand how often  Zika during pregnancy causes problems and precisely what those problems entail.
• Initially, there is a brief period when the virus circulates in the mother’s bloodstream and spreads throughout the body.
• The virus can be passed from a woman to her fetus during pregnancy or around the time of birth.
• The fetus becomes infected as the Zika virus passes from the mother’s bloodstream across the placenta.
• Early evidence from Brazil suggests that the greatest risk of Zika infection to the baby occurs when the mother is infected during the first trimester of pregnancy. This is also similar to what is known about other viruses associated with congenital conditions such as rubella and CMV. However, third trimester fetal deaths have been reported.
• The fetus is also less able to immunologically contain and control a Zika infection resulting in a prolonged and more profound infection. Zika virus from the infected fetus has been detected in the mother’s blood for up to two months.
• Zika virus appears to have a predilection for infecting and damaging developing neural cells, resulting in a potentially profound impact on brain growth and development. The pathophysiology and clinical findings of congenital Zika syndrome are very reminiscent of that seen with congenital rubella infection.
• What is still unknown about Zika infection during pregnancy:

1. We don’t know if sexual transmission of Zika virus poses a different risk of birth defects than mosquito-borne transmission.
2. We don’t know whether the risk to the fetus is different if the mother shows signs of Zika infection or is asymptomatic.
3. We don’t know how often the fetus becomes infected by the mother.
4. We don’t know which infected fetuses will develop birth defects.

I am pregnant and am worried I may have been infected by Zika virus. What will my doctor do?

• They will first ask questions to determine whether you might have been exposed to the Zika virus. Have you traveled to any area with Zika transmission at any time when you might have been pregnant? Has your partner?
• If so, the doctor will try to determine the most likely time you could have been infected.  When did you travel? What did you do?  Do you recall being bitten by mosquitoes, or having any of the following signs or symptoms suggestive of Zika infection: fever, rash, muscles aches or conjunctivitis?
• If your partner traveled without you, have you had unprotected sex since his return, and does he recall a “Zika-like” illness?
• If you are at risk, contact your local health department to arrange Zika testing.

What are the recommendations if I am pregnant and a blood test indicates I am positive for Zika?

• An initial fetal ultrasound will be performed around the 16^th week of gestation. Even if the results show no abnormalities, your obstetrician will recommend serial ultrasounds.
• Unfortunately, ultrasounds may not always detect abnormalities associated with congenital Zika syndrome. This is especially true for an ultrasound done early in pregnancy or soon after the fetus is infected with Zika.
• In some cases, a fetal brain MRI might be used to better assess the risk, but even this test cannot completely exclude congenital Zika syndrome.
• Amniocentesis can also be used to screen for the presence of Zika virus RNA.

What should couples do before attempting to become pregnant?

• Consult with your physician.
• If neither of you has traveled to any area with Zika transmission in the last six months, there is no need to delay.
• At this time couples who want to become pregnant cannot get tested for Zika virus to determine if they were infected. It is unknown what the test results would mean, and the CDC does not have enough tests to be used for this purpose.
• Men who become infected with Zika can spread the the virus to their partners during sex. There are six cases of this happening in the United States so far.  All the men recalled being sick and had sex within a few weeks of being ill. We know that live Zika virus can be found in semen beyond two weeks. Semen has also tested positive for viral particles using RT-PCR for up to 62 days.
• A man who has traveled to a area of Zika transmission could have been exposed to the virus, so the following precautions are recommended:

1. If the man did NOT show any symptoms of Zika disease, the couple should wait at least eight weeks before attempting to become pregnant.
2. If the man did show symptoms of Zika, the couple should wait at least six months before attempting to conceive.

• A woman who has traveled to a Zika area should delay attempts to become pregnant for at least eight weeks, whether she developed symptoms of Zika or not.

Did the CDC report that Zika will come to Florida?

• On April 1, 2016, the CDC released recommendations that states prepare to manage cases of Zika virus. The Florida Department of Health has been doing this since October, 2015.
• Health care providers and the general public have been educated about how Zika is spread, where you might get infected, and the symptoms of Zika.
• The Hillsborough County Health Department has investigated and arranged for testing of anyone suspected to have been infected with Zika virus, including pregnant women who had traveled to a Zika infected area.
• Any person who tests positive for Zika virus is interviewed about their risk of exposure to Zika and for any possibility that they were infected in the United States. To date, all acquired the infection while traveling in an area affected by Zika, except for  six cases involving sexual transmission by men infected outside the continental United States.
• If someone is identified as infected but has not traveled to, or had sex with a man who has visited, a Zika infected area, then they will be the first person infected in the United States by a mosquito.
• The Florida Health Department initiates investigations to identify anyone who might have been bitten by an infected mosquito.
• These potentially exposed people would be asked if they had any recent illness and to report the onset of any illness suggesting Zika infection.
• Mosquito control efforts would target affected neighborhoods.
• Quarantines would not be used and are ineffective, since, other than by sexual transmission, Zika does not spread from person to person.

Will the Zika pandemic end?

• A time will come when most of the population will have been infected with Zika. In the French Polynesia outbreak an estimated 70% of the population became infected.
• Zika infection results in lifelong immunity. Eventually a community develops “herd immunity” whereby the virus does not have enough people who are susceptible, so its spread becomes limited.
• Zika virus then becomes endemic to that area. This means that Zika will join other diseases like dengue that are regularly found in certain areas.
• Travelers to Zika areas  are advised to avoid mosquitoes. Women of childbearing age should take steps to prevent pregnancy.
• A Zika vaccine would be very useful, especially for women in his situation. 

Where can I get more information?

• CDC Zika Page: http://www.cdc.gov/zika/index.html/

• CDC Travel Notices: http://wwwnc.cdc.gov/travel/notices

• FDOH Zika Page: http://www.floridahealth.gov/diseases-and-conditions/zika-virus/

• CDC Microcephaly: http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html

• CDC: Questions and Answers: Zika virus infection (Zika) and Pregnancy:
  http://www.cdc.gov/zika/pregnancy/question-answers.html

• Zika Virus Infection with Prolonged Maternal Viremia and Fetal Brain Abnormalities: http://www.nejm.org/doi/full/10.1056/NEJMoa1601824

• Zika Virus: http://www.nejm.org/doi/full/10.1056/NEJMra1602113
• Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00651-6/abstract

• Update: Interim Guidance for Health Care Providers Caring for Women of Reproductive Age with Possible Zika Virus Exposure — United States, 2016.
  http://www.cdc.gov/mmwr/volumes/65/wr/mm6512e2.htm?s_cid=mm6512e2_w