Opening Session: Forum on the Diagnosis, Evaluation, Management of Zika Infection among Infants

Opening Session: Forum on the Diagnosis, Evaluation, Management of Zika Infection among Infants


>>Good morning. My name is Henry Walke, and
I’m the Incident Manager for the CDC Zika Response. It’s my pleasure to
introduce our CDC Director, Dr. Brenda Fitzgerald. Dr. Fitzgerald brings to CDC a
state public health perspective. She served both as
a Commissioner of the Georgia Department
of Public Health and as the State Health Officer. She also brings a clinical
perspective as someone who served as a practicing
obstetrician/gynecologist for three decades. Welcome, Dr. Fitzgerald.>>Thank you so much, and
thank you so much everyone for being in the room. I apologize for not
being there in person. I am in D.C. because of
[Hurricane] Harvey. But I cannot tell you how
important I think this work is, and I cannot tell you
how much I appreciate all of you being in the room. As you all know, Zika is
the first time in 50 years that we have had a virus that’s
associated with a birth defect. And as that new entity,
there are a lot of things that we know we have to
do and a lot of things that we know we do not know. And that’s the reason
for bringing the public and private partnership
together, because it’s now time to move on to the next phase of
our understanding about Zika. The important thing is
that we know already in the United States that there
are over 2,000 pregnant women who have lab evidence of Zika, and of the 2,000, there
are 93 infants born with known birth defects. In the territories,
especially Puerto Rico, there are almost 4,500 pregnant
women with evidence of Zika, and of them, we know that 128
have obvious birth defects at birth. But we also know at this point that the microcephaly
is terrible, but it is not the only birth
defect that may be evident with a Zika infection. We now know that Zika
virus attacks nerve tissue particularly, and we know that
there are cases of blindness and deafness or problems
associated with the optic nerve and with the nerve tissue
associated with hearing that have been affected. A significant number. My concern, quite
frankly, is that we know that there is tremendous
brain development, early brain development,
that’s occurring in this very crucial
part of a child’s life. So our concern, and
my particular concern, and I know concern of a
lot of you in the room, is what is this going to do for normal neurologic
development of children? At this point, of course,
the testing has picked up these children, but we do not
know if there are some women, especially in Puerto Rico,
who may not have been tested, because there’s widespread
evidence of the mosquito that carries Zika in the
island, and there are about 30,000 live births a year. We know that, again,
about 3,000 of them have — their mothers have
evidence of Zika infection, but not all the women have
been tested, and some of those that were tested
may have not been in an ideal time
for the testing. So we have a huge
clinical need ahead of us. What we have asked you
here today for two reasons. One, to help us come up with
some schedule and some thought about what is the best way
to monitor these infants. We certainly are committed to
having a Zika Pregnancy Registry
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and we certainly are —
want to be open and continue the dialogue between the physicians who will
now be caring for these babies and the people that have done
the original testing to see if any other very
obvious defects occur. So it really requires to
activate as a private community to figure out how often we need
to be monitoring these babies, and also if there
are other things that we need to be monitoring. We also are concerned
particularly with Puerto Rico because of the large
number of babies there and certainly Dr. Walke
can tell you about. He’s recently gone to
Puerto Rico, can tell you about the onsite
activities there, and certainly the medical
community there stands ready to work with all
of us to make sure that those babies are cared for. But we predict that it will
be an overwhelming task. I believe we’re up for it and I
especially believe that we are up for it if we get
together at this early time and have thoughtful planning
and thoughtful ideas about how to evaluate when new
evidence emerges. I’m particularly happy to
introduce as the next person to speak to you,
Dr. Karen Remley. Dr. Karen Remley is a
pediatrician by trade. She has been the State
Health Officer of Virginia, so she certainly understands
the public health arena. And she is currently the
Executive Director and CEO of the American Academy
of Pediatrics, and we know that her leadership
will be a tremendous asset as we all try to do the
best thing for these babies that may have been exposed. So, Dr. Remley, we’d love
to hear your comments.>>Thank you very much. It’s particularly fun
to follow Dr. Fitzgerald because we’ve been
good friends for years. So I think, as everybody in
the room knows, whatever we do, relationships and
thoughtful, trusted, and caring relationships are
what always make the biggest difference for children
and for our communities. I apologize I’m not with you. I’m at — actually, I have
a daughter getting married in two days so I’m — as soon as I finish this phone call
I’m heading to St. Louis to be the mother of the bride. So it’s nice to have something
wonderful to celebrate. And it is hard for me to
believe it’s been a year since you all got together and
developed guidance for caring for pregnant women
and infants with Zika, and how much we’ve learned,
and how much as Dr. Fitzgerald said, the gaps
and knowledge of what we have. It has been, I have to say —
I know that there are a large of number — as I look
through the list of attendees, I see many incredible
researchers and clinicians and friends and members
of the Academy, and it is just a
privilege to be able to speak to all of you today. I want so share briefly some of the activities the
Academy has been involved in over the last year. We have project Echo Zika, which is a telementoring
program connecting AAP experts, many of whom are around
the room, with clinicians in Puerto Rico, American Samoa,
and the U.S. Virgin Islands, knowing that some
of the specialties that are needed are scant
in those communities. And to be able to
connect in that way, clinician to clinician, I think
I would say that the people who are doing the telementoring
are learning just as much from those very capable
and astute clinicians on the ground. We’ve been doing
educational outreach, which is particularly focused on parental psychosocial support
videos that are being done in just — in both
English and Spanish. Resources for parents, a
webinar series, and websites. And then also support for
our chapters, particularly in those parts of the country that may be most likely
to see Zika cases. And then, last, we’ve
been doing support for the CDC local health
department, Zika field assignees in those affected areas,
connecting our chapters with those local
health departments, and making sure that, again,
those relationships develop. That’s just a few highlights
of the work we’ve done. I wanted to also particularly
recognize the incredible partnerships and
integration of work that have occurred
in Puerto Rico. I know Drs. Valencia, de la
Vega, and Ysern are there. I’ve had the opportunity to
know Dr. Ysern very well. I’ve heard wonderful
things from Dr. — about Dr. Valencia and Dr. de
la Vega, and I just am humbled by the way you have
shown leadership in this important
health issue for all of our children in the future. I know there’s also
many ACOG leaders there. And I think, once again, this demonstrates the
incredible commitment that ACOG and AAP have to women and
children which are our future. And the last thing I will say — as Brenda said, I have the
advantage, as she did, of being able to be a state health
official, and understand that it is crucial that
not only do clinicians and researchers partner
with public health, but that we have mutual respect and we fully integrate
the work we do because it is the
clinician at the bedside who is truly the most
trusted source of information. And that’s true whether it’s
Dr. Ysern taking care of a patient in Puerto Rico or
Dr. Kimberlin taking care of a patient in Alabama. It is that doctor/patient/family
relationship that is really going
to help us with this. And I stand ready
to hear from Fan [Tait] and everyone else
how the day went. And I’m excited that some
of the work they’re going to be doing will be
very Zika-focused, but may help push us even
farther in terms of how we look at innovative ways to
screen children, regardless of whether it’s for a Zika
infection or from other causes, to make sure we have early
identification of problems. And with that I’ll turn it back
over, I think to you, Henry. And, Brenda, have a good day
in Washington and advocate for all those people in Texas.>>I absolutely will. Thank you so much, Dr. Remley.>>Thank you.>>Right. Thanks to both of you. So next I want to introduce
Dr. Christopher Zahn. Dr. Zahn represents the American
College of Obstetricians and Gynecologists as
their Vice President of Practice Activities. He’s been a critical
leader and partner to CDC during the Zika response. So, welcome, Dr. Zahn. [ Applause ]>>Well, thanks, Henry. Thanks to Dr. Fitzgerald and
everyone at CDC for inviting us to participate in this, and
certainly also to be here with the partners
in this, with AAP. ACOG has clearly worked
with AAP, the CDC, Society for Maternal-Fetal
Medicine in addressing this crisis
ever since early 2016. And I think importantly, although probably not
a great reason for it, but Zika’s really propelled
maternal and child health to the forefront of health
issues around the nation. So, really drawing
attention to that. I think it’s been an amazing
relationship in working with the CDC, as well as AAP
and SMFM, in addressing this. We’ve been on call
sometimes several times a week with folks at the CDC. And it’s really been incredibly
important in developing that partnership to put the
recommendations out there, particularly done so
in an anticipatory and a proactive manner
as opposed to reactive. So it’s really bidirectional
where the CDC provides us with information
that we can build into our practice
advisories to get the message out to the obstetric providers. But it also provides a
way for us, as clinicians, to get the message back to the
CDC, particularly from folks in our recently-formed
Zika Expert Workgroup — several of the members
are in the room today — to really look at what
are the practical aspects, what are the implementation
challenges of these recommendations. And I think some of the examples of the most recent
communication, even surrounding testing of
asymptomatic [pregnant] women in the most recent updated
guidance, really demonstrated that ability to talk about those
challenges before the guidance is released, as opposed to
afterwards, and then scrambling to figure out what to do. As mentioned, probably our
biggest collaboration is in development of the
practice advisory. The practice advisories were
developed a couple of years ago as a way to have information
out there relatively quickly until we were able to come out
with more established guidance. The practice advisory has been
updated 10 times since January of 2016, so it just reflects
how rapidly things are changing. And it gets a lot of views. It’s been viewed
over 160,000 times since it was initially
published. It’s translated into Spanish
for those folks who can benefit from that information. So, again, it’s a key way for
us to try to get the message out to the providers as well as
for the implementation piece. As Karen mentioned, we’ve
worked closely with the AAP. In fact, we’re working
with the AAP on several activities
including toolkits that have been distributed to over 35,000 of
our members twice. And it’s been incredibly
well-received. We’re in preparation of a survey
to look at what people know, and more importantly, what
they don’t know about Zika, what are some of the challenges
in a clinical practice, and what tools they need,
what resources they need to help better inform
the providers such that they can take care
of the patients, which is — this conference, this forum
is critically important to inform that process as well. We’ve also been working with the
CDC’s local health department initiative in connecting our
ACOG district and section folks at the local level with those
local health departments, because it’s really the boots
on the ground at that point. And that’s where the
true implementation of these guidelines
are in effect. So what can we do
to help with that? And then, finally, we also,
Zika Care Connect, I think, we think, is a critically
important resource to try to make the members available so when they do have those
questions they have a place to go to answer some
of those questions. And I think this collaboration
really emphasizes an important point, is this is just the
most recent example of a — of a biggest — of our — of a
significant health challenge, particularly one
that’s impacting women, and even moreso, pregnant women. But we don’t have to think that
long ago about Ebola, H1N1. And it’s Zika today, and it
will be something else tomorrow. And at some degree, I think
it’s fair to say that all of us in the room, whatever
organization we’re representing, have had to scramble whenever
these emerging issues come up. Things get dropped, people have
to drop what they’re doing, and it’s got to be
rush to get this done. And ideally, based on this
progression, and again, there’s going to be
more in the future, ideally we could have
resources, better structured, better prepared,
better ready to go, so we can mobilize more quickly,
thoroughly, and efficiently, as opposed to having to reinvent
the wheel every time something comes up. So, hopefully, we can all learn
a lesson from this exercise, as well as some of
the past ones, to be able to take that on. So, again, it’s been an
amazing collaboration. We very much appreciate
the opportunity to be here. So looking forward
to the next two days. Thank you. [ Applause ]>>Okay. So, good
morning, again. And I’m Henry Walke,
the Incident Manager for the CDC Zika Response. And I just wanted to thank
our partners, American College of Obstetrics and Gynecology,
and American Academy of Pediatrics, and, of course,
our Director, Brenda Fitzgerald, for joining us in this
important discussion. And thanks all of you
for joining us today. We’re now in the 586th
day of activation for the Zika response. It’s really an unprecedented
engagement of thousands of CDC staff. Countless more federal, state, and local staff have
worked alongside of us. And our coordination with HRSA and CMS has been especially
essential to the provision of services to Zika
virus-affected individuals, especially pregnant mothers in
the U.S. and the territories. And we’re very happy that HRSA and CMS colleagues
are here today. Throughout this response CDC has
relied upon all of its partners to ensure up-to-date
guidance is disseminated. And that our experts get
practical feedback from practitioners on the ground,
such as you, so we can improve
the work that we do. This response has brought
together diverse groups such as pediatricians engaging with emergency preparedness
specialists, and policy advisors working
alongside epidemiologists and vector-borne or
vector-control practitioners. This cooperation with
you and within CDC across multiple centers has
helped ensure their efforts were coordinated and that, when
we made big decisions, we heard multiple perspectives. You’ve heard Dr. Fitzgerald talk about the magnitude
of the epidemic. More than 42,000
symptomatic cases of Zika virus infection
have been reported, and more than 6,500
cases in pregnant women. Certainly there’s been a
decline, and Dr. Fischer, I’m sure, will talk more about
his, a decline in the number of new reported Zika
cases in 2017. However, we’re still in mosquito
season, and it’s difficult to predict when and
where local transmission or outbreaks will occur. This week I’m very
happy to announce that the CDC’s Emergency
Operation Center has transitioned from a Level Two
to a Level Three response. Level Three is the lowest level of our Emergency Operation
Center’s activation. So it goes Level One, Level
Two, and then Level Three. And after Level Three
is Deactivation. As the cases continue
to decline, CDC is in the processing
of transitioning staff and important activities back to
their home offices and programs. A decrease in activation
level does not mean that people are no
longer at risk from a Zika virus infection. Zika virus continues to
be a public health threat in the U.S. and abroad. And CDC continues
to support efforts to protect pregnant
women and their babies. There’s still much to
learn about Zika virus. I certainly have learnt a lot
in the past few months for sure. CDC and its partners are working
to improve diagnostic capacity, develop better tools
to prevent infection, and understand the full range
of potential outcomes in babies with congenital Zika infection. Babies will continue to be born
with congenital Zika infection in 2017 and beyond, underscoring
the need to stay committed to following these
infants and ensuring. I think this slide illustrates
a useful way to think about the follow-up care of infants potentially
affected by Zika virus. At the top of the pyramid there
are a small number of infants with Zika virus associated
birth defects, about 250 in the U.S.
states and territories. In the middle tier, there
are infants born to women with laboratory evidence of
possible Zika virus infection. These are infants without
birth defects, and there are about 5,000 infants in the
U.S. states and territories. On the bottom tier, there are
infants with congenital exposure to Zika virus without
any laboratory evidence. There are many more of these
infants in Puerto Rico alone where there was a high level
of Zika virus transmission through about 30,000
live births a year. We’re following these
infants in the top two tiers through Zika pregnancy
and infant registries. And we have published
guidance on the evaluation and management of these infants. For the bottom tier of
infants, we have questions about the appropriate
follow-up of these infants, questions we hope
to discuss with you in the next couple of days. So this forum is incredibly
important to us to continue and advance our understanding
of the clinical care of pregnant women and newborns. Thank you all again for joining
us here in Atlanta this week, to lead these discussions, and learn from our
colleagues altogether. CDC cannot do the work we do without your collaboration
and support. Thank you. [ Applause ] You’re going to see
a lot of me today. So I’m pleased now to introduce
Dr. Dana Meaney-Delman, Co-Lead of the CDC’s
Zika Pregnancy and Birth Defects Task Force. Dana is an
Obstetrician/Gynecologist, and who has served with Zika
response from the beginning, since January of 2016. She will outline the goals
and objectives for this forum, and help set the
stage for what we hope to accomplish in
the next two days. Welcome. [ Applause ]>>So, welcome. Again, good morning. A lot of friendly faces. I’m very excited to see
folks that I’ve known or that I’ve gotten
to know over the phone over the past 20 months. So, really excited that
we’ve all come together. A sincere thank you to
Dr. Fitzgerald, Dr. Remley, Dr. Zahn, and Dr. Walke
for their opening remarks. I want to acknowledge and thank
our colleagues from ACOG and AAP for all their collaboration
and dedication to the Zika response
these past 20 months. And as co-hosts of this forum,
we are grateful for their help as we identified all of you
and as we all come together. We are honored to have such
a wonderful and diverse group of nationally recognized
experts here with us. Thank you all for
travelling to Atlanta. We realize that many of you
have had to cancel your clinical or your professional obligations and have left your
families to be here with us. And we recognize that travelling
during a hurricane response may be particularly challenging. Our thoughts and
prayers go out to those who have been affected
by Hurricane Harvey. As Dr. Fitzgerald mentioned, the Zika response has
demonstrated how important it is for the clinical and
public health communities to partner during
emergency responses, and together we have
a lot to be proud of. We have undoubtedly impacted
the lives of pregnant women and families throughout the
U.S. and throughout the world. And we may never
know how many cases of congenital Zika virus
infection we have prevented. We have invited all
of you to this forum for these main objectives. First, to ask that you share
your individual expertise and experience with Zika. Your input will greatly
assist CDC as we consider potential
future updates to our guidance for infants with congenital
Zika virus exposure. Second, to help us review
the data that has emerged since our last pediatric
meeting in July of 2016. And, third, we are
hoping to work together to identify strategies
to enhance communication and coordination
of care for Zika, but also for other conditions that affect pregnant
women and infants. And we think we will
all learn a lot from each other in
the next two days. So briefly I’d like to
outline the plan for today. This morning we’ll
have a series of talks to ensure we’re all
starting from the same page. We will have presentations
in our initial session that covers Zika
virus epidemiology, diagnostic testing, our
existing recommendations, and the emerging evidence. We will also hear from
Dr. Miguel Valencia, our close collaborator
in Puerto Rico, and he will describe how
Puerto Rico has actively sought to increase access to services
for families affected by Zika. This afternoon we will divide
into preassigned topic sessions as shown on this slide
and in your agenda. We have done our best
to preassign experts in a balanced manner to these
preassigned topic sessions, and we also are mindful
of space constraints. If you don’t remember
what session you’re in, you should have a little
colored dot on your nametag that can serve as a reminder. At the end of the day we’ll
reconvene in this room to briefly present themes from
concurrent topic sessions. This will provide an opportunity
for others who are not part of a given topic session to provide individual
expert feedback. What will happen
after the forum? CDC and colleagues will
compile the individual input from our experts here today. And this input will help CDC as they develop potential
future updates for guidance. We hope to have a draft
updated guidance document within the next six to eight
weeks before the Zika response deactivates, as you
heard from Dr. Walke. And our plan would be to
acknowledge all of those who participated in the forum in future clinical
guidance updates. Now for some logistics. For those participating
by webcast, so this morning’s session is
webcast, if you have questions or comments please send them to
the email address listed here, and please include your name
and professional affiliation. And we will respond to questions
over the next several days. From media questions,
please email [email protected] We are pleased to
have Paul Decknick — can you stand up Paul —
from Deloitte Consulting. He will be here to help us
facilitate our discussions and, most importantly, to keep us
on time so we can get to lunch. He will also help to remind us
to focus on the forum objectives and to avoid group think. This forum is not about
achieving consensus. It is for us to hear about
the pros and cons, advantages and disadvantages,
of any future changes to the existing recommendations. And, lastly, please remember to disclose any new
competing interests. You all filled out a form
for competing interests, but if any new competing
interests have arisen, please let us know. And please make sure you
identify yourself when speaking. We all want to know who you are. We all want to get
to know one another. For CDC participants, we
have invited experts all over the U.S., and we
want to hear from them. So please be gracious
hosts to our guests and let’s let —
let’s hear from them. For our non-CDC forum attendees, there are some housekeeping
details. There’s a form in your folder
that goes through these. But there’s some I must say. First, you’re considered
visitors to the CDC Campus, so you’ll need to be
escorted between buildings. You don’t need to be
escorted to the bathroom. We do have a large number
of designated escorts. These are people who are
relatively new to CDC and we’d love to
hear your experience, so as they’re escorting you
please feel free to engage in conversation with them. These are folks who are very
excited to talk with you. All visitors must enter and
exit through the Security Desk that you came through
in the Visitors Center, so please don’t come
out through other ways. And everyone at CDC
must wear a badge that you’ve all received
in plain sight. And when you are moving
from building to building, the green topic session,
you will need to have your government I.D.
Please bring your name tents with you if you are
moving from room to room, and please bring them
home with you tonight and back with you tomorrow. Restrooms are located
down here to the left. They’ll be pretty easy to find. An escort can help you
if you need assistance. In case of an emergency,
an escort will direct you to the appropriate
assembly area on campus. And then, finally,
picture-taking on campus is not allowed
outside of CDC buildings, and specifically not on the
third floor in Building 21 which houses the
Emergency Operations Center. Sorry, those were
a lot of logistics. There’s more in that
page in your folder. So, now I have the
pleasure and honor to introduce Dr. Marc Fischer,
who will provide an overview of Zika virus epidemiology. Dr. Fischer is a Medical
Epidemiologist and Pediatrician with CDC’s Arboviral
Diseases Branch, and during CDC’s Zika response,
he has served as a lead of the Epidemiologic Task Force. Welcome, Dr. Fischer. [ Applause ]>>Good morning. Thank you, Dr. Meaney-Delman. As Dr. Meaney-Delman said, I’m
going to give a brief overview of the Zika virus epidemiology. So in May, 2015, the first
locally-acquired cases in the Americas were
reported in Brazil. And as of August, 2017, local mosquito-borne
transmission has been reported in 48 countries or
territories in the Americas. The only countries without
reported local transmission in the Americas are Bermuda,
Canada, Chile, and Uruguay. This table shows
numbers of suspected and confirmed Zika virus disease
cases reported by country or territory in the Americas
from the 2015 through 2017. A few important points. So suspected cases are
generally defined as cases with clinically compatible
illness. They may vary by
specific country, although PAHO [Pan-American
Health Organization] has a specific definition of specific
symptoms for suspected cases. Confirmed cases are
suspected cases that have some laboratory
evidence of disease. As noted in the first
column, overall 48 countries from the region have reported
locally transmitted cases. Overall, about a
little over 787,000, or almost 788,000 cases
have been reported over this time period. As you could see at the bottom
in the footnote, about a third of those cases have some
laboratory evidence of disease. So there may be cases
suspected that are actually due to other causes and certainly
there are under-reports of cases. By country, you can see that
by far the most cases have been reported from Brazil with
over 350,000 cases making up about 45% of the total, followed by Colombia
with 108,000. Those two countries together
make up almost two-thirds of all the cases reported. This shows an epidemiologic
curve of the suspected and confirmed cases reported to
PAHO from the entire region. A couple of import
caveats here as well. So, first I’d like you to note
the Y-axis which has a total of 40,000 cases, and
that will change in some of the other slides I show. The X-axis shows cases by
week for 2015 through 2017. It’s important to note that Brazil did not make Zika
virus reportable until 2016, so they did not start
reporting cases as Zika virus until that time. In addition, the cases here are
per the date they were reported, not the date that they
necessarily occurred. So there’s a shift
in the epi curve. But overall, as you can see,
as far as reported cases, there was a substantial peak
of cases in early to mid-2016, which then decreased
over time through 2016, and then has a small
peak again in 2017, but at a much lower level
than the previous years. You can also see by region,
and there’s a color arrow there for South America,
but the vast majority of cases have been reported,
as we saw, from South America, notably Brazil and Colombia, followed by Central
America and the Caribbean. This now shows the epi curve
for Brazil alone which, as you can see, really mirrors
the cases for the region. The Y-axis now is 25,000 cases. And as you can see, there’s an
abrupt reporting starting 2016. As we know, there was a large
epidemic of Zika virus in 2015, and that’s where it
was first recognized. Many of those cases were
initially reported as dengue. And then cases were reported
as Zika virus starting in 2016. And some of those cases, again, will be reflected
from previous years. But you can see again
a peak in early 2016, then a dramatic decrease as you
move to the middle of the year, and then a small increase
again in early 2017. I want to contrast that to show
that there are still some areas that are having Zika
virus activity in 2017, albeit at much lower levels. So this shows suspected and
confirmed cases reported from Ecuador for the
same period of time. As you can see now, the
Y-axis is 1,000 cases, so substantially lower than
the two previous epi curves that I’ve shown. But what I wanted to show is
that Ecuador had a small peak with upwards of 300 reported
suspected and confirmed cases in mid to early 2016, then a
decrease at the end of the year. But to have then seen an
increase similar to their peak in 2016 and early in mid-2017. And then, similarly, I wanted to
show Peru which gives an example of another country,
an epi curve. This also has a Y-axis
level of 1,000 at the top. Peru had very few
reported cases in 2015/’16, but then started having
outbreaks reported in late 2016, and had their peak
upwards of 800 or so suspected cases
reported in early 2017. So there are still small
focal areas in the Americas that have reported
outbreaks or sporadic cases of Zika virus in 2017. Moving on to the United States. From 2007 to 2014, there were
14 Zika virus disease cases identified in U.S. travelers. These were people
returning from parts of Asia and the Western Pacific
that had sporadic or outbreaks of disease. However, following the
introduction and spread in the Americas, cases among
U.S. travelers increased substantially as
you might predict. And then in 2016, there was
limited local mosquito-borne transmission identified in
two states, Florida and Texas. And in 2016 large
outbreaks occurred in three U.S. territories,
Puerto Rico, the U.S. Virgin Islands,
and American Samoa. This shows the number of
Zika virus disease cases. So these are all symptomatic
disease cases as well as presumptive viremic blood
donors, so those are persons who donated blood
and were identified through the screening. These are all laboratory
confirmed, so unlike for PAHO reports, these will have some
laboratory evidence. And these will be reported
based on their date of onset, not the date of report. So in 2016 there were
a total of a little over 41,000 disease cases
reported from the United States, with 5,102 of those being from
U.S. states, and over 36,000 of those being from
U.S. territories. By contrast, in 2017,
there’s been a total of 770 cases reported as of last
week. Two-hundred-fifteen of those
being reported from U.S. states and 555 from the
U.S. territories. The bottom part of the table
shows presumptive viremic blood donors identified through
the routine screening of the blood supply. And as you could see, the numbers are substantially
smaller but reflect the same trends. So in 2016 there were overall
359 blood donors reported, 37 of them from U.S. states,
and 322 from the territories. In 2017, as of last week, there
were 12 positive blood donors, nine reported from U.S. states, and three reported
from territories. And I want to point
out the footnote there which is important, that these
cases do not include congenital disease cases, so these are postnatally
acquired Zika virus infections. So as far as breaking down the
laboratory-confirmed Zika virus disease cases reported from
U.S. states and the District of Columbia for 2016
and ’17 — 2016, as we saw, there were a little over 5,100
cases, the vast majority, 95% of those were reported
as travelers to other areas, mostly areas in the Americas. In addition, there were 224
locally-acquired cases presumed to be through local
transmission — 218 of those from Florida,
and six from Texas. And then there are a few cases
reported from other routes of infection, which include
sexual transmission, one case of laboratory
transmission, and one case of an unknown likely
person-to-person route. In contrast, in 2017, the
215 cases reported thus far, 213 of those have
been in travelers. There have been no locally
acquired cases reported thus far from U.S. states. And two sexually-transmitted
cases have been reported. This shows the cases from
the U.S. states and District of Columbia reported by
month of disease onset, with the Y-axis being 2000 here, which you’ll see again the
contrast with the territories. The main point, again, as we
see, a peak in the reports of cases of both
travel-associated and local transmission in
mid-2016, with a sharp decline by the end of the year,
and a small number of cases reported
as of this year. The locally-transmitted
cases are shown in yellow. This shows a breakdown of those
cases by states of residence. And overall you see
about 22% of the cases — this is travel-associated
or local transmission — were reported from Florida,
and 20% from New York, 8% from California,
6% from Texas. So, again, about 50- to 60%
of the cases are reported from those four largest states. This shows a breakdown of the
cases reported from U.S. states and District of Columbia by sex. And you can see two-thirds of
the cases are reported among women. This is likely somewhat due to
surveillance and testing bias — testing and identification
of pregnant women or women of reproductive age. It’s unclear whether sexual
transmission plays a role in addition to this difference. But, in general, probably more
a surveillance testing bias. And this shows a breakdown
of these same cases by 10-year age groups, again
from states and District of Columbia, with a peak
between 20 and 49 years of age, which primarily reflects
both the age of travelers predominantly,
and as well surveillance bias where we look for cases and
testing of pregnant women and persons of reproductive age. Finally, this slide
shows the numbers of possible Zika virus
infections reported to the U.S. Zika Pregnancy
Registry from states and District of Columbia
from 2015 through August 8th of this year, and these numbers
were already referred to. But among pregnant women,
there have been 2,100, a little over 2,100 possible
Zika virus infections among pregnant women reported
to the Pregnancy Registry. There have been 93 live births of infants with birth defects,
and eight pregnancy losses with birth defects
reported to the Registry. Now, I’m going to show
a series of slides, basically the same slides,
but for U.S. territories. So these are
laboratory-confirmed cases of symptomatic Zika virus
disease, non-congenital, reported from U.S. territories. As we saw in 2016, there were
over 36,000 cases reported. Less than 1% were
among travelers. And the vast majority,
almost 36,000, were reported as locally-acquired,
presumed local mosquito-borne transmission. There are no cases
reported among other routes, but in endemic areas it’s
really not possible to separate out the possibility of, for
example, sexual transmission from local mosquito-borne
transmission. Contrast in 2017, as we saw,
there were 555 cases reported. All of those are reported as local mosquito-borne
transmission. This shows the month
of illness onset again. And you can see the
Y-axis is now 10,000, so five times higher
the Y-axis maximum that I showed for the states. But it shows the same pattern;
that is, a peak in the number of cases reported by month
in July and August of 2016, with a dramatic decline in
the fall and winter of 2016. And, as we saw, there have
been cases reported in 2017, but just because of the scale of
the curve, you can’t note them on this particular slide. This shows a breakdown
of those disease cases by territory of residence. And you can see that
overall the 97% of those cases reported
have been from Puerto Rico, 1,000 cases or 3% from
the U.S. Virgin Islands, and 168 from American Samoa. This shows the breakdown by
sex which, again, is similar or very close to the same
for states, and that is 62% of the cases reported from
the U.S. territories were among women. And this shows the age group
breakdown for U.S. territories which is a little different. So here you have
endemic transmission in these areas among
a naive population without previous immunity. So you could see a
broader distribution across all age groups, although
you still see a peak among the 20-to-39-year-olds,
probably, again, reflecting somewhat testing and surveillance bias among
persons of reproductive age. However, also possibly
representing exposure. You can see about 10% of the cases were reported
among children less than 10 years of age. And then this shows the
numbers of pregnant women and live-born births
reported to the Zika Registry, the U.S. Zika Registry, with possible Zika virus
infections among pregnant women. There were 4,418 possible
Zika virus infections report to the Registry from
U.S. territories. Live-born infants with
birth defects are 128, and pregnancy losses with
birth defects, there are seven. So, in conclusion, in
summary, the Zika virus, we’ve seen large outbreaks in
the Americas that peaked in 2016 and have substantially
decreased in activity in 2017. However, smaller outbreaks and sporadic disease
continues to occur. Some focal areas of some
countries, and we showed Ecuador and Peru as two examples
of that. The incidence and disease
risk among U.S. travelers has basically followed the
epidemiology of the outbreaks in the Americas due to
travelers going to those areas. And a similar decrease
over time in Puerto Rico and U.S. Virgin Islands. And the U.S. territories
have markedly decreased their incidence in 2017, but continue to have sporadic
infections that are reported. Thank you very much. [ Applause ] Next I’d like to introduce
Dr. Wendi Kuhnert who will provide an overview of Zika virus laboratory
diagnostics. Dr. Kuhnert is the Co-Lead of
the CDC Zika Lab Taskforce and has helped lead
the development of CDC’s laboratory testing
guidance for Zika virus. Please welcome Dr. Kuhnert. [ Applause ]>>So, thank you, Marc,
for that introduction. Good morning all and
thank you for coming. For my presentation, as
mentioned, I will be focusing on summarizing the limitations
of the current Zika testing. This information is applicable
to all of the existing assays, and is not limited to the assays
that are manufactured by CDC. So objectives for my portion of
the talk today are to, first, provide an overview of
Zika testing in general. I’d then like to look
at the limitations of both the nucleic
acid testing as well as the Zika serologic testing. I’d like to look at some
additional challenges to a definitive Zika diagnosis, some limitations
of infant testing. Then I’d like to move on
to looking at this season, the bigger picture, looking
at some of our emerging data and how this, again, will impact
our — the results of our tests. And then, finally, a
changing disease prevalence and how we start to look at
our assays in that light. Of note, some of this
information is provided within the healthcare provider
fact sheets that are associated with the FDA documentation
for all of our assays, and for the two CDC assays, the
Zika MAC-ELISA and the Trioplex, we have placed some
copies of these fact sheets on the resource table outside. So before I move on to the
specifics of the assays, I did want to provide
an overview of testing so that we are all starting
with the same information. It is important to understand
that at this time none of the Zika tests
are FDA cleared. There’s a large number of tests that are currently
approved for emergency use. And more currently are underway
and under review with the FDA. At this time there are
14 nucleic acid tests and three serologic assays
that have been cleared. This FDA process for emergency
use authorization is intended to strengthen the nation’s
public health response during an emergency and, thus, is
far less stringent compare to the routine 5-10(k) process
for most diagnostic assays. This abbreviated process allows
the FDA to approve of the use of uncleared medical products
for use in an emergency to diagnose, treat, or
prevent serious disease. This is meant to happen when there are no adequate
approved alternatives. For all Zika tests, timing
of the testing is critical for optimal assay performance. Samples should be collected at optimal times following
infection or exposure. Additionally, optimal assay
performance requires close attention to the
populations to make sure that they meet Zika clinical and epidemiologic
criteria for testing. Intended use is another
important aspect of laboratory testing
in general. For the Zika serologic assays, all existing performance
data has been based on symptomatic cases. Without data on asymptomatic
screening we are more cautious in our interpretation
of these results. So, as pointed out
in my last slide, timing of testing is critical. Here I would like to look more
at the markers of infection and how they can
impact test results, depending on when the
samples were collected. This diagram shows an example of an IgM response
following symptom onset. We know that IgM starts to
come up soon after infection. However, this graph is only a
representation of the timing of infection and
is not definitive. Additionally, IgM duration,
while shown on this graph to end at approximately three
months, is not well-defined and can vary within individuals. This graph shows how,
for symptomatic cases, it is much easier
to see how timing of the testing can be targeted. For the asymptomatic testing, this is obviously a
much larger challenge. Since the timing of infection
is impossible to determine for an asymptomatic patient,
there is a much higher chance of specimen collection
falling outside of the expected duration
of IgM detectability. Additionally, with the decrease
in IgM levels, as we can see, tailing off months after
infection, the results or the tests ended —
the IgM levels may linger within the equivocal zone
for a longer period of time which also creates a
challenging interpretation. Next, I’d like to
talk specifically about the testing limitations
of nucleic acid performance. As mentioned previously, timing of the test is
critical to diagnosis. Zika RNA is only detectable
during the acute phase of infection. While we have seen some
reports of longer duration within pregnant women,
generally it is only detectable for about two weeks
following infection. Data on asymptomatic
patients is unknown. Another limitation is the
potential for false positives. In general, these
assays are designed to minimize the occurrence
of false positives. These design elements for the
nucleic acid tests include limited cross-reactivity as
well as well-defined cutoffs and assay validation processes. However, contamination
within the laboratory or elsewhere during the
specimen life cycle is possible. False negatives are another
potential assay challenge. A negative result does
not rule out infection as the sample may
have been collected when viral RNA was not present,
or potentially the test was used on samples, such as
amniotic fluid, for which the assay
has not been validated. As stated previously,
viral RNA is only present for a limited duration in time. Overall, I would like to stress
that it is important to remember that the absence of
laboratory evidence of Zika virus infection cannot
definitively rule out infection with the Zika virus in persons
with epidemiologic risk factors. Next I’d like to focus on the
serologic assays and, again, review some of the limitations
of these serologic tests in ways that they might be different
from nucleic acid tests. Serology assays are
also not always able to provide a definitive answer, and results should be
interpreted within the context of the assay limitations. However, a negative IgM test,
if performed at the correct time in the setting of a
negative nucleic acid test, does provide some
reassurances of the absence of infection during
the current pregnancy. Anti-IgM antibodies are
not detectable immediately after symptom onset. Plus duration is
unknown, and the duration, as I said previously,
can be inconsistent. Another challenge is that the
current serologic assays are not able to distinguish
between recent infection versus infection that occurred
six or more months ago. I also want to mention the
plaque neutralization test. This assay is included
within our testing algorithm and is recommended to be used to confirm an initial
IgM positive result. A negative PRNT, when
performed during the recommended timeframe, along with
negative nucleic acid testing, does indicate no lab evidence
of Zika virus infection. This assay measures neutralizing
antibodies, but can’t be used to determine the
timing of infection. An additional limitation
of this PRNT is that is does not have
value in some areas. The cross-reactivity issues that
occur during PRNT analysis mean that it is not useful in
regions with high levels of circulating Flaviviruses,
such as Puerto Rico. Like nucleic acid tests, serologic assays also have the
potential for false positives. Here we would like to
emphasize that the positive or equivocal results are not
definitive for diagnosis. False positives can occur due to closely related
Flavivirus infections as well as non-specific reactivity that
is unrelated to the infection. These cross-reactive antibodies
make it difficult to identify which Flavivirus is
causing the current illness. Serology can also have false
negatives like any other assay. Absence of lab evidence of infection can’t
definitively rule out infection if the patient has
epidemiologic risk factors. A false negative, therefore,
in an infant would result in cases that are missed. Overall, for Zika serology
testing, it is recommended to be conducted soon
after symptom onset, but within 12 weeks
post-infection in order to ensure the best results. Other challenges exist
and can hamper efforts to obtain a definitive
laboratory diagnostic result for Zika. As stated before, the
Zika MAC-ELISA is approved for emergency use only. The data provided for this
approval, and contained within the assay’s
instructions for use, are actually quite limited. In an ongoing effort to improve
this assay, we have looked at how the selection of
either a negative control or the negative calibrator can
affect the assay’s performance. We have found that even
when calibrators are used, that are within the parameters
of the EUA performance, that results can be impacted. This slide shows how when two
laboratories chose different calibrators with different
optical density ranges, that the final results of
these tests were different. Here we show that Laboratory
One has a calibrator that actually runs higher
within the approved EUA range. And, as you can see on the
far right, they have ended up with fewer number
of positives. Here we see that that
lab has 31 positives within this collection
of samples. The other lab chose
a lower calibrator and actually has almost double
the number of positives, or actually, more than double. And here shown, we can see that this labor has a total
number of 70 positives. This emphasizes the need to
evaluate assay performance with well characterized samples. The laboratory with
the higher number of positives has achieved
an assay that is performing with higher sensitivity
compared to the other lab. And as shown from this table,
the lab tests would vary based on a simple selection of
calibration material and points to the need for a
well-characterized gold standard as well as confirmation
of the initial result. As mentioned, CDC is continually
evaluating the performance of our own assays as we
learn more about the virus. This slide provides an
overview of our current efforts to standardize the
CDC’s Zika MAC-ELISA. We have, as part of this effort,
developed a three-phase plan to improve both the precision
and the accuracy of the assay. Phase One, which was
completed in August, included the distribution of additional quality control
guidance for both primary or plate acceptance
criteria and secondary or clinical sample
acceptance criteria. Phase Two, which we are
targeting for completion in October of this year,
includes the evaluation and distribution of a
calibration control serum, as well as a negative
control serum. And as pointed out
in the last slide, these reagents are key reagents that contribute to
assay precision. This process will include a
fully updated emergency use authorization submission
to the FDA as well as updated instructions for use. Finally, Phase Three, which
we hope to complete by the end of calendar year 2017, will
include the manufacturing and distribution of a completely
new Zika MAC-ELISA kit. We will submit to FDA a new
packet for EUA approval. And, obviously, this kit will
require full validation prior to manufacture and distribution. So, while testing in general can
present diagnostic challenges, maternal and infant testing has
some issues, specific issues, that are worth mentioning. Passive transfer of
maternal antibodies to the infant has the potential to complicate serologic
test interpretation. IgM antibodies, in general, do
not cross from mother to infant. This has not been
well studied for Zika. Another potential complication
is the lack of information on detection of maternal
neutralizing antibodies within these infants born
to Zika-positive mothers. Similar to Zika diagnosis
overall, the role of nucleic acid testing in infants is not
well characterized. And the duration of IgM and neutralizing antibodies
is not well-studied either. Finally, a positive
Zika test in a placenta or a cord blood does not
necessarily indicate congenital infection and could reflect
maternal infection alone. Studies have reported that
infants with clinical findings of possible congenital virus, but also have negative
Zika virus testing. Some potential causes
of this could be that the finding are due to
infection by another cause. It could indicate
that the testing, as we previously indicated,
was either incomplete or not performed within
the optimal timeframe. It could indicate that the
infant perhaps did not mount an IgM antibody response. And, finally, it
is also possible that a negative result can
be due to the limitations of the test that is being used,
as we have discussed here. Overall, as we look at
this upcoming season, the emerging data has
significant implications for Zika testing
during pregnancy. This season has shown declining
numbers of reported cases. And this situation results in
a lower pre-test probability as well as a higher proportion
of potential false positives. Along with the declining
numbers, we have noted that IgM antibodies can
persist for six months or more in some individuals. This prolonged response
can make it difficult for healthcare providers
to use Zika IgM results to determine whether an
infection occurred during the current pregnancy versus
prior to conception. This graph shows pregnant women
with evidence of Zika infection in the U.S. territories. We are looking at this
by date and test type. Here it’s a little
more complicated in that we’re looking at — in red we see that this is
showing the nucleic acid positive tests. The blue area is actually
showing the IgM positives. So most of the infections,
as we have seen in previous presentations,
in 2016, were all identified
through PCR testing. And you can see with the large
increase in red within 2016. However, in 2017, what we
noted is that the majority of infections were only positive
with IgM, as you can see on the far right,
the increase in blue. This larger proportion
of IgM positive results versus the nucleic acid
positives prompted us to review existing results
and confirm initial testing. We believe that this increase
in IgM positives is evidence that the IgM response has
been prolonged in a time when very little
virus was circulating. So, again, looking
at this new season, we have seen that
infection prevalence is low. But here, this slide shows how
the positive predictive value of the test can actually change
depending upon the prevalence of disease. This slide uses an example
test that shows an assay with very high sensitivity
and specificity. Both are shown at 98%. In a situation in which
the disease is circulating and has a high prevalence, we can see that the
positive predictive value of the test is also high at 94%. However, in a time when the
disease prevalence falls, for example, looking at
1% disease prevalence, the positive predictive value of the test is actually
quite low at 5%. And the false positive rate
rises to approximately 95%. So, in summary, even the best
performing assays do not perform to the same standard
when the prevalence of the disease is low. So, in summary, I
have provided, I hope, an overview of the current
Zika assay limitations. We know that we still have
knowledge gaps related to optimal infant testing. And this is information that we
will use to document evidence of congenital Zika
virus infection. I have also shown that as
the outbreak has changed, we have looked at
emerging data and found that this has required changes
to the testing algorithms. This need was clearly
demonstrated in our review of how disease prevalence
can impact assay performance. And, finally, CDC will continue
to review our existing assays and look at ways to
improve how they function within this changing
outbreak landscape. Thank you. [ Applause ]>>Okay. So now is the
time that we’re hoping to have more discussion,
maybe a raucous discussion. So let’s have some questions
and comments from the audience. And, Dr. Fischer, if we
can use the microphones, that would be helpful so
that everyone can hear. We have some microphones set up
in the middle of the room. Just announce your name.>>Hi. Thank you. That was excellent. This is Rich Beigi from
MaGee Women’s in Pittsburgh. I have a quick question
about the lab testing. So that definitely
was very thorough. It was definitely
wonky, but so important. For other infectious diseases,
a lot of the obstetricians who take care of those patients, I think share the
same experience where there — it seems
to be a higher rate of false positive serologies
from the pregnancy itself, such as — we have a higher
rate of HIV false positives, parvovirus, the list
kind of goes on. So I wonder if that’s
been investigated. Separate from the false
positive issue you have in the whole population,
I’m wondering if pregnancy actually increases
the false positivity rate by virtue of the
pregnancy itself. And it seems that you
may have the data to look into that I suppose.>>Okay, thank you. Thank you for the question. So I’m going to turn
to Wendi or Marc. I know this is a tough question, and I’m not sure how much
data we have on this.>>So it’s a very good question. I don’t think we have
data specifically to answer that for Zika virus. But as you point out,
particularly with regard to serologic testing, there
are antibodies, proteins, made during pregnancy which can
cause false positive results either in the pregnant women
or potentially in the infant through passive transfer. But I don’t have a specific
answer as to whether that occurs or to what degree
with Zika virus.>>Bill.>>Meg Fisher, no
relation, from New Jersey, the Unterberg Children’s
Hospital. And, actually, my question
though is for Marc. On our last Echo call
with American Samoa, they gave us their results. And interestingly,
although they had a couple hundred pregnant women, they’ve had not a
single affected baby. So the question then came
up, is there an ethnicity or a racial difference
in outcomes? And do we know this?>>We do not. So for Zika virus there
are essentially two types of genotypes that
circulate primarily in Asian and African strains. And we’ve seen primarily
Asian strains here, and that’s what’s
circulating there. There have not been known
differences by the virus itself, although, obviously, we have
limited amounts of data. And there have not been, as
of now, described differences in the phonotype or due to
the population or ethnicity. So I think we’re primarily
talking about a numbers game, because of the population
that’s under surveillance. But that’s probably the
best we can do right now. One other point which
I thought you might ask about for American
Samoa, is it does bring up the issue of dengue. So American Samoa is having
a dengue outbreak right now, and has had dengue
outbreaks in the past. And so that is an example of substantially complicating
the diagnostic issue because when they test people
they are seeing IgM antibodies, but those are really due
to previous infection or passive continued
IgM antibodies. They are not having any
positive PCR results for Zika at this time.>>Thanks.>>Yes, hi. Ivan Gonzales from the
University of Miami. It’s just a comment
because as a clinician and also the background of
pediatric infectious diseases, you know, I totally understand
the false positive rates for the IgM’s and the
positive predictive value, especially in our area that
we’re having decreased numbers of positive Zika cases. However, I want to just kind
of share with you something that we saw from before where
there was a woman that came from Venezuela and if it wasn’t
because she was actually tested for IgM and the baby was
born without microcephaly. And when we — because of the
IgM it actually triggered the full work-up on the baby, and
that case was actually reported. Dr. Berrocal, who’s with us
here today, she was the Latino author
that published the — it had all the case
— all the findings, so the baby had calcifications
in the brain and also had the
hyperpigmentation in the eyes. So I’m not — I don’t have
an answer for you in terms of what we need to do. But I think that without
having a screening tool that we can still use, it’s
going to be very challenging because not all the
cases are microcephalic. So we don’t know when
you will trigger a workup on these babies. Thank you.>>Thank you for the comment. Others?>>Hello, Alberto de la Vega. I am from Puerto Rico. With last slide you showed
regarding the positive predictive value
and sensitivity with the huge drop
we’ve had in cases, wouldn’t that negate completely
the use of these tests?>>I think that’s something
that we had discussed obviously with the asymptomatic cases,
and that’s why, you know, there is no longer
the recommendation. I think that also goes
to our lack of knowledge of how this assay performs in
the asymptomatic population. But I think that that’s part
of what we continue to discuss, you know, as an agency,
with, you know, our external colleagues, because
I think it is a challenging decision process.>>David Kimberlin, University
of Alabama Birmingham. To follow on that, I
found the last talk to be quite discouraging
in terms of the performance
characteristics or lack thereof. Can you just tell us,
is this a good test, a bad test, a medium test? What is — give me some
[laughter] relation to other viruses or
bacteria we test for.>>So I think it’s not a — I
would never call it a bad test. I think if it was a bad test
we shouldn’t have pursued an EUA. I think it — at the time
it was the best test we had, and I think — I hope that we
have documented a continued effort to improve the test. I think serologic testing
in general is very different from nucleic acid tests. And I think it is
not, as I pointed out, it’s just not as definitive. So I think we’re improving, but I think it is a
continued struggle with this decreased prevalence. I don’t know, Marc, from the
Fort Collins perspective, I don’t know if you
have anything to add.>>No, I agree. It’s a — I think it’s
a — the tests are good, but need to be used and interpreted carefully,
as with any test. Similar to other
things you test for. David, you know, if you test
for influenza, Rotavirus, outside of the season, you
don’t get the performance characteristics that you might
expect when you test for them when those outbreaks
are occurring. And so, particularly
with serologic testing, I think we’re dealing with the
same issues of interpretation. We have some additional
challenges with regard to the cross reactivity that
you don’t necessarily have for other viruses. This is common to Arboviruses
and is not unique to Zika. But the challenges of
where these are occurring, the level of Zika, dengue, other cross reactive viruses
makes the interpretation particularly of serologic
testing challenging. The PCR, I think, performs as
expected with any other PCR, but again has the
limitations of the epidemiology when you’re testing for it in an
area where it’s not occurring. So you’re going to
have a majority of tests even though you
have very high specificity, the majority of the tests
will be false positive.>>Hi, I’m Debbie
Levine from Boston. With all of the issues that
arise with the serologic tests, and I know imaging will
be a whole, you know, area that’s looked at later, prenatal ultrasound
is its own area. .But neonatal head ultrasound is
going to give you a huge amount of information and it’s an area that really hasn’t
been pursued well. Especially, if we look
at asymptomatic infants who might have been exposed
in utero and I would just like to see data on a large
population of these exposed. Because there is a very specific
finding that we don’t see in other infections and
that’s the calcification of the gray-white
junction and you can see that very easily
with head ultrasound.>>Thank you for the comment. Let’s move — yeah.>>Lisa Hunter from
Cincinnati Children’s Hospital. I’m really wondering
about surveillance efforts in the missing countries. In particular, Mexico,
where there’s so much travel between Mexico and the U.S.
Are there really no cases in the missing countries or are
there surveillance differences that are — that
need to be looked at or need to be investigated?>>Right, so let
me clarify that. So the slides that I showed
just show the largest — the table showed the countries with the largest numbers
of cases reported. As mentioned, there
are 48 countries, almost all of the
countries and territories in the U.S. have reported cases. And then the individual
country epi curves that I showed were just a
given example of the patterns. There absolutely have been
cases reported from Mexico. There are some differences
by country. So as an example, Mexico reports
only laboratory-confirmed cases similar to the United
States and Canada, and a few other countries. Whereas the other countries
reported suspected plus confirmed cases so
they have cases without any laboratory testing
or evidence of infection. Mexico, as an example, has a
very good surveillance system for arboviral diseases including
dengue, chikungunya and Zika. But the cases that are reported
all have some laboratory evidence of disease.>>I would just add to that. That we are following
closely the cases in Mexico especially
along the border — the border of Texas and New
Mexico, Arizona, California and to look for transmission
patterns. And Texas certainly,
for example, has heightened their
surveillance along the border.>>Hi, I’m Bonne Maldonado
of Stanford University. So I was interested
in and obviously, we’ve been quite overwhelmed
by the degree of homology — high degree of homology between
Zika and dengue in particular. About 80%, I guess,
homology between the genomes. And I guess — my
question is how — are you working with
other laboratories, in particular, NIH. I know Tony Fauci has
been talking about trying to optimize his assays. And I imagine you are but will
we be talking a little bit more about this later and
what are the prospects for future testing capacities?>>I would say, yeah. We are actively working
with NIH. We were actually just up there a
few weeks ago and then a couple of months ago, they
came and visited us. We actually have routine
laboratory calls with them and then there’s other calls,
you know, from other aspects. So, you know, we have
been working with them. Most of the NIH studies are
actually being performed with a version of
the CDC MAC-ELISA. They work with some of the lab
experts out in Fort Collins to develop that assay using
very similar reagents. So a lot of the testing that
they’re doing is quite similar. But we totally agree. You know, looking forward, I think from an assay diagnostic
perspective, the other thing that we have done is, you know, we did a broad agency
announcement and put some funding out. So we do have some additional
collaborators in addition to NIH outside of the agency who
are we are also working closely with to look at future
assays and diagnostics.>>I’m Flor Munoz from Baylor
College of Medicine. I just have maybe a couple
of quickly related questions. One is regarding that epidemiology whether there
are any other similar countries where you see an uptake
this year compared to previous year other
than Peru and Ecuador? And related to the dengue
and other sensitivity issues with the assay, how do you
assess for infant infection in that scenario when you
have already potentially a lot of positive tests
from the mother? So how do you differentiate
maternal versus infant infection? And just last thing
related to that, how do you assess
prevalence when the majority of people are asymptomatic
in the U.S. in terms of just knowing what
the infection rate is? Is it based on just the blood
donor data that was shown or is there any other way
to assess true prevalence of infection in the U.S.?>>So in answer to your first
question, I selected Peru and Ecuador to show because
they’re really the best examples of countries that have had
similar or higher numbers of cases reported in
2017 although most of these were in early 2017. There are some other countries
that have had increase in reports again in ’17 but
they are not at the levels that were reported
from ’16 or ’15 so there may be some other
countries out of the 48 but those are the
two best examples that have reported
focal outbreaks. Then I don’t know if you
want to address the other?>>Well, let me take, sorry,
the prevalence question, I guess and then I’ll see —
so yeah, it’s difficult for arboviral diseases in
general and particularly, flaviviruses and
Zika in particular, to establish a prevalence
of infection because of the cross-reactivity
issues and some of the duration of antibody levels
that Wendy spoke to. So the plaque reduction
neutralization test which is measures
predominantly IgG antibodies that neutralize should
be present for a very long time,
if not lifelong. The problem is you
can pick up low levels of cross-reacting antibodies
to other dengue or to other flaviviruses. So if you measure that
in a population of people who have been exposed
to other flaviviruses which could include dengue,
West Nile viruses, for example, or even had been vaccinated
with a flavivirus vaccine, Yellow Fever, Japanese
encephalitis — you will get sort of, you
can see levels of antibodies. So it’s difficult. A negative result — so if
you have a negative PRNT for Zika virus is
very good evidence that the person has not been
infected either recently or in the past with
Zika virus infection. But because of that
problem, it’s difficult to do a prevalence study. There are antibody assays
that are being developed that target different
parts of the virus. That may be more
specific and the hope is that those could potentially be
used for prevalence-type studies but those still need a little
further evaluation in particular for the IgG component.>>I think we have time for a
few more questions, before we break.>>I think there
was a third question about the maternal infant? Sorry, sorting through the –>>Okay, the third question
that you asked about was about distinguishing antibodies. So, you know, IgM
antibodies as Wendi mentioned and everyone knows here, typically do not
cross the placenta. So typically, if IgM antibodies
are detected in a young neonate, we presume they were
developed by the fetus in response to infection. As was brought up as far
as problems in pregnancy, we don’t really know whether
there could be situations where the IgM could cross,
unusual situations, abruption or previa, for example or
potentially contamination. But in general, we believe
IgM may reflect, you know, the infant’s antibodies. Neutralizing antibodies are
IgG, if such an assay was used, clearly reflect maternal
antibodies and maternal infection and
those will decrease over time as they do for other congenital
infections, but we’re not clear on the exact timing
when those will decrease if the infant was not infected and it just reflects
maternal infection. Presumably though,
after a period of time when maternal antibodies fall,
say to nine, 12, 18 months — those antibodies would
reflect fetal infection or congenital infection. One other caveat,
you do have obviously in endemic areas is
they could reflect, you know, postnatal infection. As we’ve seen, there have not
fortunately been a lot of those. But certainly, neonates or
young infants are susceptible to infection. So right now, we’re
in a time period of very low infection rates
and so it would be unlikely to reflect that but
that’s an issue over time that in those areas, you would
have to always consider that.>>Here.>>Yeah, thank you. Ellen Lee from New York City. Thank you so much
for those really informative presentations. This goes along the lines
of all the lab questions. Would you be able to
comment about Zika testing in the commercial sector and
specifically I’m thinking about DiaSorin Zika IgM test
which has become available through some commercial labs?>>So I can comment briefly. I think that, you know, the DiaSorin assay is a
new assay on the market. It is the first NS1
targeted serology assay so it does have a
different target. Both the InBios and the CDC
MAC-ELISA target the envelope. We have done some preliminary
assessment of that assay. Unfortunately, we do not have
the platform at CDC so we’ve had to rely on colleagues. What we have done is
we have sent a panel of well-characterized
samples to DiaSorin. And we actually found
that this panel in their hands performed very
well and showed some, you know, a high amount of equivalence
to the CDC MAC-ELISA but also showed a
very good sensitivity. It also showed a
high specificity and did not show the
cross-reactivity with dengue. That is one of the advantages of the NS1 target
is it doesn’t seem to have the same
cross-reactivity. We are also working with
three public health labs and they are doing sort of
a retrospective analysis of between 100 and 150 samples,
some positive, some negatives, and some other, you know, potentially cross-reacting
viruses. Again, that information has
shown a low cross-reactivity or none with dengue. We have seen some
cross-reactivity with hepatitis C but I actually
think that was acknowledged within the DiaSorin
package insert. Unfortunately, we don’t
have the data yet. We’re working through
some IRB issues with the public health labs. But that’s still coming. I think that overall, some
of our challenges and I guess to speak to the question of
commercial labs in general, is that not all of these
samples really follow the true case definition. I think that, you know,
that most of their — maybe not most but
a high percentage of these samples
may not be samples that the public health
lab would accept. So I think we are actively
working with the commercial labs and in fact, I have a call
with them later this week to discuss how we can better
enforce some specimen criteria on these collections because
I think that does contribute to some of these potential false
positives that we have seen from the commercial labs. Is that –>>Yeah, thank you.>>Okay.>>We have time for just one
more question. No virtual questions at this
time.>>Thanks. Meg Fisher again and this — I’m getting clearer
on the serology. But I still have, you
know, obviously normally, we would say, well,
just measure the IgG. And if the IgM doesn’t work, we’ll just follow
up with the IgG. And I know that there is the
flavi-reaction and original sin. Does IgA help? Has anyone looked at IgA? I mean, you know, it
seems like we need IgG against something
else, the envelope? I don’t know what but
— or some other kind of IgG, not neutralizing? There ought to be some way that
we could get to this better.>>This is not a new problem
although it’s new to Zika. It’s been an issue
for flaviviruses for a very long time and
people have tried to solve it. It has not been solved. IgA has been looked
at, I believe, in some limited degree
not by our laboratory. I don’t know of that
as being an answer yet so I guess you’re
talking about along the lines of toxoplasmosis, some
combination of IgA. That doesn’t appear
to be an answer. The NS1 or targeting of
other parts of the virus that may be more specific
is one of the possibilities that look — is being
looked at in addition to blocking antibodies, something that removes the
cross-reactive is another approach that several
labs are taking. But I think right now, it
still is the same challenge of balancing the type
of test you’re doing in the epidemiologic sort
of setting and the timing of infection and the expected
risk of infection at the time.>>I guess it’s time
for a break. Yes, I have 15 minutes
scheduled for a break. [ Applause ]

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