Welcome: Clinical Evaluation & Management of Infants with Congenital Zika Infection

Welcome: Clinical Evaluation & Management of Infants with Congenital Zika Infection


>>Good morning, everybody. Welcome. Welcome to Atlanta. It’s going to be 99 degrees
today, so it’s good that we’re in here where the
air-conditioning is and I think we’re going to
have a great day-and-a-half. Just by word of sort of
introduction as to who I am, I’m Georgina Peacock,
I’m the Division Director for Human Development
and Disability within the National
Center on Birth Defects and Developmental
Disabilities here at CDC. And I’d like to welcome you on
behalf of my Center Director, Dr. Coleen Boyle, as
well as the staff here that have been working on this
issue, to this meeting sponsored by CDC in collaboration with the
American Academy of Pediatrics. The National Center
on Birth Defects and Developmental Disabilities
has a long history of working with AAP on emergency and
non-emergency situations, all with the common goal
of bettering the lives of babies and children. We work every day at our Center
around birth defects prevention and research, understanding
developmental disabilities, protecting people with blood
disorders and improving health for people with disabilities. And the Zika response, as we’ll
learn over the next two days, really embodies all
of these areas. We’ve been all hands on deck at
the Emergency Operations Center since this was activated
early this year. We have, from our Center
have had almost half of our staff either detailed
fulltime or part-time in efforts working
on this response. And, in addition to the work of
our Center, the National Center on Birth Defects and
Developmental Disabilities, there are of course many
Centers and offices, in fact, probably every single
one of them here at CDC working on this response. Our purpose over the
next day-and-a-half is to discuss the clinical
evaluation and management of infants born in
the United States with congenital Zika
virus infection, from birth to one year, and
to inform the interim guidance on appropriate care and support for vulnerable infants
and their families. Today’s Zika outbreak
us unprecedented. Never before in history
has a bite of an infected mosquito resulted
in a devastating birth defect. Zika virus infection is a
recognized cause of microcephaly and other serious brain
anomalies, however, the full spectrum of the affects of Zika virus infection
during pregnancy has not been fully recognized. As of July 7th, 2016 there
are 346 pregnant women in the United States and
D.C. and 303 pregnant women in the US territories
with laboratory evidence of possible Zika
virus infection. Nine infants with birth
defects have been born to women who had Zika infection in
pregnancy in the United States. We are literally learning
more about Zika every day and the CDC continues to
evaluate all available evidence and to update recommendations
with new information that becomes available. As more infants are identified with congenital Zika virus
infection interim guidance is needed to help healthcare
providers to determine appropriate medical
and developmental evaluation and management of these
infants and, of course, that’s why you all
are here today because we need the expertise
here to help inform this. We value the input
and collaborations of our stakeholders and
partners and are happy that you can join us here
today and look forward to the important conversations
that are going to go on over the next couple days. And now I’d like to introduce
my friend and colleague, Dr. Fan Tait, she’s the
Associate Executive Director at the American Academy of
Pediatrics and the Director of the Department of
Child Health and Wellness. Thank you.>>Thank you, Georgina. Wow. She gave the
background on that. I’m here to say thank you from the American
Academy of Pediatrics. I will tell you I work with CDC
and with other Federal partners, with other organizations
around Zika. It has been a great privilege. It’s so important, and I think
you all being here speaks to the importance, right? Just so you know, to pull off
a meeting like this in what, three weeks, four weeks max,
we started talking about that, takes a remarkable amount
of work from the CDC, also from our staff
at the Academy. But what I’ve been most, not
surprised but most honored by is when we asked you all
to come you said, yes. You know, and in a three-week, essentially a three-week
period of time. We know you have day jobs, night
jobs, weekend jobs, families. And we actually talked about
whether we could ask people to come in this short
period of time. At the Academy we are
always trying to give – we don’t always, but we’re
trying to give two months, three months’ time when you’re
scheduling something like this, and I tell you when
Laura put out the call or we all did I would say
unless there was an emergency from the people that
we asked, you’re here. So I am so honored to be a
part of not just the Academy and the pediatricians
here, but all of you here. So this is so important. I was thinking about what I
might say for just a minute or two, and we need to get
to work so it’s not going to go much longer,
not much longer. But I also wanted to just
call out family voices, right, because when we have any meeting
like this we’re so grateful to have family – wave your
hand, Jennifer – family. This is why we’re here, right? It’s for the children
and for the families. And, Jennifer, we’re so grateful
that you’re here to help us to see that North Star of what
we can do that would be the best for the children
and families, right? I’d also like to thank you
all for being on calls prior to this meeting, right, to get
here, but there’s so much to do. We thank you. If I haven’t had a chance,
I’m pretty much a hugger, if I haven’t hugged you or
at least had the opportunity to shake your hand please
know how much it means to all of us that you’re here. And, Sonia, thank you and so
many others for the leadership. Thank you, all, we’ll
be talking.>>Thank you to Georgina
and to Fan and to all of you for being here today. I’m just going to give
a few brief remarks and then we’re going to get
started because, as Fan noted, we have a lot of
work to do today and we’ve already been working
hard before this meeting. So our top priority
at CDC as part of the Zika response efforts is to protect pregnant
women and their babies. And many of these
efforts have been focusing on preventing Zika
infection in pregnant women. We’ve issued travel
guidance, encouraging women or asking women not to travel
to affected areas, and for women who must travel to or
who live in an area with active Zika transmission
we have given guidance on ways to prevent mosquito bites and
to prevent sexual transmission. However, as of July 7th, and
there will be new numbers coming out today and they
are bigger than this, but already there are more
than 650 pregnant women who have evidence of
possible Zika infection in the United States
and its territories. So we have a lot of work to do. Because of this there
is an urgent need to develop interim guidance for
the evaluation and management of infants born with
congenital Zika virus infection to give these children
the best chance to reach their full potential. CDC in collaboration with our
partners and other investigators across the globe are working
as quickly as possible to collect data on the affects
of congenital Zika infection. However, at this time these
data are severely limited. Therefore, it’s essential
that we work with experts in children’s health
and development to gain individual input to
inform this interim guidance. We are grateful to colleagues
from the American Academy of Pediatrics, they’ve
been fantastic. I still remember the day we
called them and asked them about this and they
didn’t say are you kidding? So, who have worked with us
rapidly to plan this meeting. Together we have
invited you here today to convene a broad range of
nationally recognized experts who can provide us with
individual expertise to help us with the development
of this guidance. And before we begin I’d like
to join Georgina and Fan in thanking you for taking time out of your busy summer
schedules to be here. Briefly, I’d like to outline
the plan for the meeting. This morning we’ll have a
series of talks to make sure that we’re all familiar with
Zika virus, its epidemiology and what is already known
about the prenatal affects on the infants with Zika
virus, including the affects on the brain and the eyes. Then this afternoon
we’re going to assemble into breakout sessions
for discussion. So there’ll be three
breakout groups. Please stick with the one
that you’re assigned to. The rooms are really tight. We have just enough space, so
if you swap rooms you might have to sit on somebody’s lap. That’s not a good thing. And we will reconvene at the
end of the day for each group to briefly present the summaries
of their breakout discussions and also discuss any issues,
overlap issues or things that we’re concerned about. Then tomorrow morning we’ll
get back together again for a more formal
discussion with slides that summarize where we’re at. We’ll go back into
breakout groups, and then we’ll get together
at the end of the day. Because of the limitations on
breakout session space we had to place limits on
the number of people that could attend this meeting. There was a lot of people
that wanted to attend that weren’t able to attend. And, therefore, I wanted
to just make you aware that these full group
sessions are being webcast, live streaming on the web. So for those that are
participating by webcast if you have questions we’ll
be taking those by e-mail and we have someone here that
will be monitoring that box and we’ll be taking
those questions at the end of the morning. The e-mail box is
[email protected] When you send questions
please include your name and your professional
affiliation. We may not have time to
answer all the questions, but we’ll answer as many
as we can at the end of the morning session and
then we’ll answer the rest after the meeting. For media questions, there’s
a separate place for media. Please e-mail [email protected] After the meeting we’re
planning to compile and synthesize the individual
input that we received from experts here today and
this input will inform the development of interim
guidance that will be published in CDC’s Morbidity and
Mortality Weekly Report or MMWR. And we realize that these
will be interim guidance, that they’ll be updated as more
information becomes available. So just some housekeeping items. If you need to go
to the restroom it’s out that door there,
go to the right and then it’s the first
hallway to the right and then they’ll
be on your left. And with no further
discussion I want to introduce Doctor Marc
Fisher and he’s going to be giving the first talk
on Zika virus epidemiology. Marc is a Medical
Epidemiologist here at CDC’s Arboviral
Diseases Branch.>>Thank you, Sonia. Good morning, everyone. As Sonia said, I’m
an Epidemiologist in the Arboviral Diseases
Branch, and I’m just going to give a brief overview of
some information on epidemiology on Zika virus, which
probably everyone is already familiar with. So the objective is to update
the epidemiology of Zika virus in the Americas and
the United States. Just for quick review, Zika virus is an RNA flavivirus
that’s related to Dengue, Yellow Fever, Japanese
Encephalitis and West Nile viruses and it’s
transmitted to humans primarily by the Aedes Stegomyia
species, mosquitos. Typically causes
asymptomatic infection or a mild Dengue-like
illness, but recent outbreaks as we’ll discuss have identified
new modes of transmission and clinical manifestations. These are the principal vectors
of Zika virus in the Americas. Aedes Aegypti is the primary
vector, also the vector of Chikungunya and
Dengue and Yellow Fever. Aedes Albopictus is
also a component, although less efficient
vector likely for transmitting to humans for various reasons. These vectors also transmit
Dengue and Chikungunya. They lay their eggs in
peridomestic water containers and live in and around
households, and their peak feeding time is
during the day although they can also bite at night. Aedes Aegypti is more efficient
for transmitting the virus to humans because it tends
to live in and around humans, primarily it bites humans
more than Aedes Albopictus which bites other
animals, as well. And then Aedes Aegypti
is an interrupted feeder so it can bite multiple people
during a single blood meal and, therefore, transmit to
various people during a single blood meal. This slide shows the
approximate geographic range of Aedes Aegypti and Aedes
Albopictus in the United States. So this is not where the
vector necessarily is, but the possible range of that. And so the brown shows the
overlap of the two species of mosquitoes, the
yellow shows areas where Aedes Aegypti
might be alone, and then the blue shows areas where Aedes Albopictus
may be alone. In addition to vector
borne transmission, a number of other
non-mosquito borne modes of transmission have
been identified now, including intrauterine
transmission resulting in congenital infection, most
importantly for this meeting. Intrapartum from viremic
mother to newborn. Sexual transmission,
laboratory exposure, and likely blood transfusion. In addition, there’s possible
transmission through organ or tissue transplantation
and breast milk, and there’s also a
current investigation of possible transmission through
close personal contact during a fatal case currently in Utah. As far as clinical
course and outcomes, most infections are
asymptomatic and the clinical on this is usually mild. Most characteristic
findings are fever, rash, arthralgia or conjunctivitis. Symptoms typically last
for several days to a week. Severe disease requiring
hospitalization is uncommon and fatalities are rare,
although have been reported. The newly identified clinical
manifestations are microcephaly and other congenital anomalies, which we’ll hear a
lot more about today. Guillain-Barré syndrome and other neurologic
syndromes are being identified and reported, and then
thrombocytopenia has been reported in a small
number of cases. Distinguishing Zika from Dengue and Chikungunya viruses
is important. The viruses are transmitted, as
we said, by the same mosquitoes with a similar ecology. They can circulate
in the same area and likely rarely can
cause some co-infections. The diseases have
similar clinical features. Most importantly as far as
Dengue it’s important to rule it out because proper
clinical management with Dengue can improve the
outcome, and at the bottom of the slide there I
have the link to the WHO Dengue Clinical
Management Guidelines. So as far as Zika virus
diagnostic testing, RT-PCR should be performed
for viral RNA in serum that’s collected
less than seven days after illness onset and urine
collected less than 14 days after illness onset, and these
guidances are continually being revisited and updated as needed
as we have new information. In addition, evaluating RT-PCR
for viral RNA in amniotic fluid and semen appears to be useful,
but the full implications of finding the RNA in
those specimens is unclear. Serology for IgM and then
neutralizing antibodies can be performed in serum and
cerebral spinal fluid and immunohistic
chemical staining, or IHC, and RT-PCR can be performed
for viral antigens and RNA and tissues, including placenta. Serologic diagnosis
is difficult. The Zika virus serology can
be positive due to antibodies against some of the other
related flaviviruses, Dengue in particular,
and including somebody who has received Yellow Fever
vaccine or previously infected with the Yellow Fever virus. Neutralizing antibody testing
is more specific and may be able to discriminate between these
cross-reacting antibodies when it’s a primary
flavivirus infection, meaning the first time
somebody has been infected with any flavivirus,
however, it’s difficult to distinguish the infecting
virus, particularly in people who are previously
infected or vaccinated with a related flavivirus. So moving on to the
epidemiology, the virus itself was first
isolated from a monkey in the Zika Forest
in Uganda in 1947. Before 2007 there were only
sporadic human disease cases reported from areas of
Africa and Southeast Asia. And then in 2007 the first
outbreak was reported from Yap Island in the
Federated States of Micronesia. And after that there
were subsequent outbreaks in the Pacific, in particular
islands in the Pacific, and in 2013 to 2015
there were more than 30,000 suspected cases
reported from French Polynesia and other Pacific islands. As far as the Americas in May 2015 the first locally
acquired cases in Brazil in the Americas were
reported from Brazil with transmission
likely occurring for some time prior to that. And then as of July 14th, 2015 local transmission has now
been reported in 40 countries or territories in the
Americas and further spread to other countries in
the region is likely. This map shows as of
today areas with ongoing or active transmission with
primarily being in the Americas and then some other countries or territories outside
the Americas. Moving on to the
Americas specifically, locally transmitted cases from those 41 countries
and territories. As of July 14th, this
is from January 1st, 2015 through July 14th,
2016 there have been more than 500,000 cases
reported from the Americas. Only 20% of those cases have
been laboratory confirmed, the remainder are suspect cases. You could see that by
far the largest number of cases have been reported from
Brazil, followed by Colombia, and then a list of
several other countries. This shows a breakdown
of those suspected and confirmed locally
transmitted cases in the Americas by region, which you can see the
largest proportion are from South America, as you saw
with most of them accounted for by Brazil and Colombia. The next followed by
that the Caribbean Region and then Central America. As far as the United
States local mosquito borne transmission of Zika virus
has not been reported in the Continental
United States, although non-travel related
cases are currently being investigated in Florida. In 2011 through 2014 11
laboratory confirmed cases were identified in travelers
returning to the US from areas with local transmission and
then with current outbreaks in the Americas cases among
US travelers have increased substantially and these
imported cases may result in virus introduction and local
spread in some areas of the US that have the competent vectors
or through sexual transmission. This shows as of July 13th
the numbers of cases reported in US states and
territories from January 1st, 2015 through July 13th, so
there have been 1,316 travel associated cases, with 1,305 of
those reported from US states. Travel associated here includes
the travelers themselves, their sexual contacts or infants
who were infected in utero in a pregnant woman
who was traveling. As far as locally acquired
cases these are all so far from the territories, with
the bulk of them being from Puerto Rico, as
you see, 96% of those. These are presumed to be local
mosquito borne transmission, but obviously in a place where there’s active ongoing
mosquito borne transmission you cannot distinguish what
might be sexual transmission. In addition, there has been
one additional case reported from a US state that
was acquired through laboratory transmission
through a needle stick in a worker who was working
with a live viral culture. This shows the breakdown
of the state of residence of the US travel
associated cases. This is the 1,305 travel cases. You can see about 45% of
the cases are accounted for from two states, New
York State and Florida, followed by California,
Texas, New Jersey. And this shows the epidemiologic
curve of these cases over time. You can see that the cases were
still increasing through June and we imagine they will
still be up in July. This is just reporting
the artifact so far through the July 13th date, but
you can see cases where it began to be reported at
the end of last year, increased over the first
quarter of the year, and have now thus
far peaked in June. It shows a breakdown of
the sex of the cases, with about two-thirds
of them being female. Presumably this is somewhat a
testing bias, so people testing for women who are pregnant
or concerns about pregnancy, but requires further evaluation. This shows a breakdown of
the age groups of the cases, so you could see the majority
of cases have been in adults, in particular in
younger adults from 20 up through 60 essentially, which probably reflects
again mostly travel related and traveling age. A little over 100 cases
have been reported in people under the age of 20. It shows the clinical
signs and symptoms of those travel associated
cases, and you could see the two most
common symptoms reported being fever and rash, followed
by arthralgia, and about half the patients have
conjunctivitis and about a third of the patients, although
you can see about half of those patients have
unknown status regarding their arthralgia and conjunctivitis so the number may actually
be a little higher than that. So moving on to current
guidance, who should be tested for Zika virus infection? The current recommendations are
that patients with fever, rash, arthralgia or conjunctivitis
who may have been exposed to Zika virus through
travel to an area with ongoing transmission
or an epidemiologic link to another laboratory
confirmed case, either through vertical
transmission, sexual contact or association in time
and place should be tested for Zika virus infection. In addition, testing
should be offered to asymptomatic pregnant
women who have a history of either travel or
residence in an area with ongoing transmission or had
sexual contact with a partner who had symptoms of Zika
virus during or after return from travel to an affected area. CDC has worked with
State Health Departments to establish strategies to identify possible
local transmission in the United States. This includes doing surveys of
household members and neighbors of travel associated
confirmed cases. Blood donor screening
is being performed in some areas of
the United States. Investigations of
unusual clusters of rash illness may identify
some local transmission or expanded testing of people
who have had no known exposure but have a more specific
constellation of clinical findings is being
performed in some areas. So, for example, some
places will test a person who has not traveled
but have three or four of the typical symptoms
of fever, rash, arthralgia or conjunctivitis. In addition, when and
if there is a case of local transmission we’ve
worked with Health Departments to establish strategies to
identify additional cases and to define the geographic
scope of the outbreak. So this includes surveying of
household members and neighbors within a 150-yard radius
or so around the case, that’s basically
the flying radius of the primary vector
mosquitoes. Notifying local healthcare
providers and laboratories of the possibility
of local transmission to increase their awareness
and look for additional cases. Syndromic surveillance is
being performed in some areas for evidence of increased
febrile or rash illness and changes from the
status or baseline. Laboratory based
surveillance for Zika virus or other arboviruses
that may be mistaken for Zika virus is
being performed. Community outreach is being
performed in many areas to increase the communities’
awareness and to look for cases. As I mentioned, blood donor
screening is being formed in some areas. And mosquito surveillance
is performed secondarily, only essentially around the
cases to look for evidence of possible local transmission. So, finally, as far as reporting
cases, Zika virus disease and congenital Zika virus
infection are now nationally notifiable conditions. The Council of State and Territorial Epidemiologists
approved an interim case definition at the
end of February 2016 and a revised definition was
just approved a few weeks ago at their Annual Meeting
in June and will be posted on their website
hopefully very shortly. Healthcare providers
are encouraged to report suspected
cases to their State or Local Health Department
to provide assistance with investigation and
laboratory testing. And then State Health
Departments should report laboratory confirmed
cases to CDC according to those CST case definitions. And pregnant women and congenital infections
are being followed through the US Pregnancy
Registry, both here and US States and
in Puerto Rico. And timely reporting to these
Health Departments allows further assessment of
the risk of infection and possible transmission
to reduce further the risk of local transmission and to mitigate the
risk of further spread. I think that’s all.>>Questions, anyone?>>Yes?>>Micheal Sauer,
University of Chicago. I hope everyone can hear me. What about seasonality? Is the peak in Brazil, what’s
the peak of the season, how does that translate
into our tracking and surveillance efforts?>>Right. So obviously for the
experience we’ve had so far in the Americas we don’t
know the seasonality, we can only base it based on
when the vectors are most active and things like Dengue, for
which we have known seasonality. So basically in the
Continental United States and subtropical areas the
seasonality would be typical for other mosquito borne
viruses, so we’re in the peak of it now, would begin
at sort of late spring, transmission would peak around
this time into late summer and then presumably
wane towards the sort of late summer, beginning
of fall. In other more tropical areas
we really don’t know the seasonality right now. It usually varies by wet
and dry season rather than necessarily
temperatures, although in places like Brazil they
do have a winter and there is a seasonality
to Dengue and we’re in that low season currently.>>Do you think that’s
in part due to the low, the dropping incidents in
the States, the July data?>>Oh, no, I think the July
data is just where we haven’t yet had reporting
for July, you know, those data as of July 13th
there’s a several week delay in reporting into our National
Arboviral surveillance system. So I don’t think we can say
whether July will be higher or lower than June
at this point as far as travel associated cases.>>Thank you for
your presentation. Can you just comment
on breastfeeding and what we know about that? That was – okay.>>Sure. So Zika
virus RNA has been identified in breast milk and
there’s a report, I believe two case reports of
live virus being identified in breast milk out
of French Polynesia. There have been no documented
known cases of transmission through breast milk, but
that is a possibility. At this point we believe
that the risk is low enough and the benefits of
breastfeeding are high enough that we still are recommending
breastfeeding for women who are living in and
possibly exposed to or even infected
with Zika virus.>>Thanks, Marc. I don’t know if this is working,
but do you know anything yet about the characteristics
of the virus? I mean we’ve seen some
genograms about the split from the African lineage,
but is there anything that you know that’s
different about say the viruses that are involved so far
compared to baseline?>>So far, all of the viruses
that have been isolated in the Americas, including from
travelers in the United States, have been of the Asian lineage. They’ve been, all of
them very closely related with very few genetic
differences and they’ve all been
very closely related to previous isolates from the
Asian strain, mostly for example from that 2007 Yap
outbreak there have not been any differences. So at least right now there’s
no evidence of a change in the virus itself as far
from what we’re seeing. I think there’s a lot more to
be done on that, obviously. Yes?>>Does inspecting and testing
for the virus in Puerto Rico, we have found 80%
are asymptomatic. The social history
helps us a lot. And when you mentioned
the factors that sometimes the patient
comes with headaches and general malaise or
sometimes one of the things that can lead you to suspect,
and when you ask relatives if they have had the rash, the
fever or anything then if one of them is positive
we try to test them. Because due to the high
percentage of people who present no symptoms
you have to – the social history is
very important when trying to pinpoint who is positive.>>Thank you. Yes, and I think a point to highlight there is there
is likely, as with Dengue, clustering in households
because these mosquitos are so closely associated in
households, although the data for Zika specifically
are not there yet. But thank you. Question?>>I have two questions. One on what you said. I’m a Physician who practices in
Southern California and I care for pregnant women, and a lot
of patients either have traveled to Central or South America
right before they got pregnant or during pregnancy, but
they have no symptoms and their spouse as far as they’re aware
have had no symptoms. But you were talking
about that there’s so much asymptomatic infection, so I’m just wondering are we
going to move to some point where we actually just recommend
testing all pregnant women who have a travel history or a
partner with a travel history, even without symptoms, or
we’re not there yet or?>>So I think there’ll be
more discussion about testing of pregnant women and some
updates to the guidance of it, of testing pregnant women, but right now the
recommendations are to test pregnant women who
have a known exposure either through travel or through sexual
contact and to offer testing to asymptomatic women who
also have known exposure who have either pregnant
women who have traveled or again have sexual contact,
but not routine screening of all pregnant women
in the United States where there’s no known
ongoing transmission.>>Yes, I think there’s
not a whole lot more that I can say right now. The investigation is ongoing. Again, it was a very unusual
situation with a fatal case, which obviously is
very uncommon. So the primary case was
much sicker than most cases and had some other
extenuating circumstances, and that there is
an apparent case that had close personal contact
with that person and the mode of possible transmission is
still being investigated.>>Do you have evidence
that efforts that control Dengue
will also work for this?>>So there’s no data
to that effect, right, because the control
efforts are still ongoing, but there’s no reason to
believe that the same efforts for Dengue wouldn’t
control this as far as the mosquito borne
transmission, right? There are some unique aspects of this virus regarding
sexual transmission and congenital transmission,
which can occur with Dengue, but not to this extent. But for mosquito borne
transmission it’s the same mosquito, is the same ecology, so the same control
effort should be effective.>>So I asked this question to a
lot of people, is there any way to detect Zika virus exposure
in the newborn blood spots that would be collected as
a part of newborn screening?>>So that’s a difficult
question and I’m not a laboratory person. There are some difficulties
in performing the assays on the blood spot, itself,
which there are groups that are working on that. Beyond that there’s
the issues of, which will be discussed
here this afternoon, the interpreting, the
interpretation of those results. So that would not be any
different than performing it on a specimen collected from
venipuncture, but you need to interpret the
serologic and PCR results. But right now I think the
primary limitation is just the technical limitations of
performing the assays, in particular the serologic
assay on the blood spot. The assays are not validated
for that specimen at this time.>>If you could, obviously,
it’d be a great means for population based
surveillance or assessment of broad based exposure
in a pretty effective way.>>Correct.>>But you really
need to get tested.>>Yes, and the limitation
of the serologic assay, so for PCR testing I think
that would be very useful. That’s likely to be positive if the baby was infected
perinatally, possibly not if they were infected in utero.>>Currently we are
trying that in Puerto Rico because we have five years
back of that, that we could go to those tests and see if
Zika had come previously. And we’re trying to
see if it is possible because if it is
possible and that outcome and know we have microcephaly
and these things hadn’t shown up then it would change
the whole ballgame.>>Correct, and Puerto
Rico you’re going to have that particular problem of
cross-reactivity with Dengue if you’re doing a
serologic assay, yes.>>Yes.>>I just had a question
related to lab testing. What’s the general availability
of the PCR kind of in the US in terms of Health
Departments and commercial labs?>>Right, so PCR assays
were developed at CDC, one in Fort Collins
and one in Puerto Rico, and those assays have
been distributed to all of the State Health Departments and other public
health laboratories in the United States and there
are now commercial laboratories that are performing the testing. It changes very quickly so I don’t know exactly
how many currently, but the PCR assay is widely
available at this point in the United States both through public health
laboratories and through some
commercial labs. The serologic testing is
a little more limited, that’s being performed
currently only through public health
laboratories, but there are several commercial
laboratories that have assays that may be available soon. Yes?>>What is the cost associated
with testing pregnant women?>>I do not know that. Does anybody else know the – no,
there is no cost when performed at public health laboratories
I guess I can tell you. I don’t know the cost associated
at commercial laboratories. Sorry.>>I know you may not be able to
answer, but is there a strategy that one might do
urine testing for this, as well as other diseases
of STDs in populations that might be a strategy
for early detection in populations at risk?>>Right, so some of
the ongoing evaluation of laboratory diagnostics
is looking for better diagnostic specimens or alternative, which
includes urine. Urine appears to be a good
specimen for molecular testing, certainly in the first week to
two weeks after symptom onset or exposure and maybe
further beyond that there may be
other specimens that also could be
positive or useful for longer periods of time. So in that sense urine
is a recommended specimen for diagnostic testing
for the first couple of weeks after onset. Whether it could be used
for screening depends on how long somebody
would have RNA in urine, and we really just
don’t know that. So if you had a pregnant
woman who was several months out from her exposure or
onset we don’t know what the usefulness of doing
molecular testing in urine would be at this time.>>This may be covered later
on, but are there any efforts to look at the genetic
modification of the mosquito that carries the vector?>>So as far as for …>>Yes, so there are a number of
genetically modified mosquitos that have been developed
for Aedes mosquitoes to reduce transmission
of Dengue and Chikungunya and those are being employed
in certain areas and, again, because it is the
same mosquitos, same ecology it could
potentially be an effective use for Zika virus, but those
are really still in kind of evaluation and pilot phases
right now, are not being used in large scale prevention
efforts. Thank you very much. [ Applause ]>>So the next three
talks are going to be about clinical manifestations
in infants with Zika, congenital Zika infection. And this first one was put
together and was supposed to be delivered by
Dr. Cindy Moore and she got called to a meeting
at WHO, a WHO meeting in Brazil and so she’s unable to be
here today and so I’m going to be speaking on her behalf. I think what we’ll do is we’ll
give these three talks together – my talk, Dr. Trevathan’s and
Dr. Ventura’s and then we’ll all
answer questions, the three of us together,
if that’s okay. So I’m going to be talking
about congenital Zika syndrome, and as I think most of you know
the manifestations in infants that have been – for which a
causal relationship has been established are the microcephaly
and serious brain anomalies. So in April CDC, we published a
paper in the New England Journal of Medicine where we
stated that we felt that Zika virus is a
cause of microcephaly and serious brain anomalies. But what we know from other
teratogens, for example, Thalidomide, Accutane,
and Rubella, is that what you see
initially is usually the tip of the iceberg. And so we expect that
there will be other levels, other more mild features or
even some that are more severe, and we’ll be talking
about those today. This talk is going to
focus on the pattern, the recognizable
pattern of anomalies that has been seen
associated with Zika virus. So this is focusing on
that little narrow part that helped convince us
that Zika virus is a cause of these problems,
cause of birth defects, but today we’ll be
talking more broadly about other birth defects, developmental disabilities
alone, other adverse pregnancy
outcomes, et cetera. So, first of all, I want to
talk about the mechanism, the pathogenesis that
we believe is involved in prenatal Zika
virus infection. And so we believe that the
initiating factor is damage to those central nervous system
cells by the Zika virus, itself. So that leads to destruction of existing central
nervous system tissues, of brain tissues, and disruption of future developmental
processes. That leads to a loss
of brain volume, which ends up causing
severe microcephaly, and I’ll show you some
pictures, misshapen skull with overlapping suture and
redundant scalp skin and that’s because the brain was
meant to be bigger, it was growing bigger, and then
the skull appears to collapse on itself and, therefore, the
skin of the scalp is redundant. There’s also neurologic
dysfunction and severe neurologic
dysfunction in these kids has been
reported – hearing, vision, swallowing problems to
such an extent that they, some kids have needed a G-tube. Global developmental impairment,
limb contractures, hypertonia, epilepsy and extreme
irritability. And this is what we have been
calling the recognizable pattern or congenital Zika syndrome. So I’m just going to go through
some of the parts of that. I’m going to very briefly
discuss the brain and the eye since we have real experts
here to discuss that. This is the cranial morphology. The microcephaly, as I
said, has been severe. Most kids with microcephaly in Brazil have had head
circumferences greater than three standard
deviations below the mean. There’s been a partial
collapse of the skull with overlapping sutures. There’s been occipital
bone prominence. And you can see in this
drawing here how this appears in these children
with the prominence of the occipital bone here. They oftentimes have a small
or absent anterior fontanelle and sometimes so small
that it’s difficult to do a postnatal
cranial ultrasound. Scalp rugae and you can kind of see in the picture here and there are some
more pictures later on. This is consistent
with a condition known as fetal brain disruption
sequence, and this is something that was quite rare before Zika and I’ll show you some
pictures about that. Not all of the babies that have
had severe microcephaly have this fetal brain disruption
sequence phenotype, but a good proportion
of them do. So this is some information about fetal brain
disruption sequence. This is from a paper that
Dr. Moore published in 1990. She and I both published a
paper on this condition in 1990, which is very ironic
I think to both of us. It was first described in 1984
by Russell and colleagues, but had been noted
back as early as 1836. What appears to occur
in these kids is that there is destruction
of the brain which results in a collapse of the
fetal skull, microcephaly, that overlapping of the
scalp or scalp rugae or sometimes that’s called
Cutis verticis gyrata, and neurologic impairment. And the cases that
have been seen in the past have been associated
sometimes with infection. There’s at least one case of
cytomegalovirus or CMV infection with vascular disruption
where the baby had almost like a stroke prenatally
and with fever, but in most cases the
cause was unknown. And there was a review paper
that was published in 2001 that looked at all
the kids that up until that point
had been reported with fetal brain
disruption sequence and at that time there were 20 babies
in the medical literature. So this is really
rare before Zika. These are some pictures
that Cindy has gotten from her colleagues in Brazil. And here you can see the scalp
rugae, again scalp rugae, the prominent occipital
bone here and here and here, or you can see with the 3D CT
how impressive the overlapping sutures are, and then again
that occipital prominence here, overlapping sutures here. The brain anomalies I’m just
going to briefly discuss because Dr. Trevathan is going
to talk about this much more. These babies have
thin cerebral cortex. They have intracranial
calcifications. And, as you know, intracranial
calcifications are seen in other infections, as well, but these are in
different areas. They’re primarily
subcortical in location. There’s also been
hydrocephalus, hydranencephaly, gyral anomalies, polymicrogyria. Some people have
said lissencephaly, but experts that we’ve
talked to say it’s more like polymicrogyria by imaging. Absent or hypoplastic Corpus
callosum and then hypoplasia of the cerebellum
or cerebellar vermis. And here are some
pictures, these are images that are courtesy of
Dr. Bill Dobyns from the University of
Washington in Seattle and Dr. André Pessóa
from Brazil. Here you can see at the
top the calcifications, the subcortical calcifications, and you can see the large
ventricles and then extra fluid in the extra axial spaces and
very small cerebellum here. Ocular findings, there’s
been structural retina and anterior eye anomalies
and posterior eye anomalies, and I’m going to leave all
the rest of the discussion of the eye to Dr. Ventura. They’re also, these
children have also had congenital contractures. And some kids have had
isolated contractures. There’s been club foot. There’s also been kids that have
multiple congenital contractures or arthrogryposis. It can be large joints,
small joints, upper limbs, lower limbs or all of the above. And this hasn’t been
previously associated with the fetal brain
disruption sequence phenotypes, so this is something that
is different, it’s not seen in all kids with Zika infection
but it has been seen in a number of them even from the very
first reports from Brazil, the report that we
published in MMWR in January. They have been seen in
other congenital infections, like Rubella and Varicella. And here’s just some pictures, again from Dr. Pessóa
from Brazil. Here you can see lower
limb contractures here and the hips and the feet. Again, in the lower
limbs and hips, and then here you can see upper
and lower in this child here. There are other severe
neurologic sequelae that have been seen, and
there’s not really a lot known right now. These children are old
enough to know a lot about their long-term medical
and developmental outcomes and very little is
known about mortality. We know something about
mortality in children with fetal brain disruption
sequence, but not about – not for these children with
congenital Zika infection. There appear to be
of the children that have been reported motor
and cognitive disabilities, seizures, swallowing
difficulties, vision loss and hearing impairment,
hypertonia and spasticity with tremors, and irritability
with excessive crying. We’re really at this point at
an early stage and, as I said, this is something that’s been
seen with other teratogens when we identify something
that causes problems, when women are exposed to it
during pregnancy we recognize that early on we’re really
seeing the tip of the iceberg. And so we’re really at a time
where we’re learning a lot about Zika, congenital
Zika infection. We know that in some
cases there have been, and Dr. Ventura has
reported some of this, about brain eye anomalies
without microcephaly, but we don’t know how
often that occurs. There has been central
cranial nerve dysfunction only at birth versus later. Are there other neurologic
anomalies with origin in the embryonic period or are their non-neurologic
congenital anomalies. Those are all questions
that need to be answered. I do want to note that
there are other things that cause what looks like
congenital Zika syndrome, and so we really do need to do the laboratory
testing whenever possible. There are other infections that
can cause similar features, congenital CNV seems to be
the most similar phenotype and there are some very
rare genetic conditions that can cause features
that are similar to that of congenital Zika syndrome. So one of the ways that CDC
is working to get answers to what the spectrum
that is seen with congenital Zika
infection is the US Zika Pregnancy Registry. And this is a Pregnancy
Registry, this is to monitor pregnancy and infant outcomes following
Zika virus infection during pregnancy, and that information
is being used already to inform clinical guidance
and public health response. This is a registry
that is dependent on the voluntary
collaboration of state, tribal, local and territorial
health departments. And pregnant women with
laboratory evidence of Zika virus infection
and exposed infants born to these women, as well as sometimes the women might
not have been identified but if their infants
have laboratory evidence of congenital Zika virus
infection then their mothers would be put into the
registry, as well. Dr. Peacock mentioned
these numbers earlier, these are last week’s numbers, these numbers will
be updated today and are quite a bit
higher today, but this is last week’s numbers. So 346 pregnant women who
have any laboratory evidence of possible Zika virus
infection in the US 50 States and District of Columbia. Those are women that
have been reported to that Zika Pregnancy Registry. And then you can see 303 women
in the three territories, the three US territories
– Puerto Rico, US Virgin Islands
and American Samoa. I just want to mention that the
US Zika Pregnancy Registry is used for collecting
information on all those babies, except for the babies
in Puerto Rico and for that there’s another system
and you can see it’s written down here, the Zika Active
Pregnancy Surveillance System, or ZAPSS, that’s being
used in Puerto Rico. And I think Georgina also
mentioned these numbers, these are the numbers of
babies that have been noted as having poor outcomes. Most of the women have
not yet delivered and so for most women there’s
not information, but there have been
nine live born infants who have birth defects
who we believe are related to Zika virus infection in the
US and District of Columbia. As Marc mentioned,
those are all cases that were travel associated. There hasn’t been documentation of mosquito borne
transmission in the US. And pregnancy losses
with birth defects, six. And then you can see the numbers
for the pregnancy outcomes in the United States
territories. So I just want to
acknowledge, first of all, Dr. Moore for putting together
this talk and then the kind use of information, photographs
and imaging from Drs. Pessóa, Fonseca, Ventura and Dobyns. And I think we’ll
just go straight into Dr. Trevathan’s talk. So Dr. Trevathan is Professor
of Pediatrics and Neurology at Vanderbilt and he’s also
representing the American Academy of Pediatrics Section
on Neurology, and he’s going to be talking about
neurologic manifestations of congenital Zika infection. I’m going to get
your slides up, so.>>Thank you, Sonia. I’m going to dive
into some areas that I think have been
alluded to both by Dr. Peacock and Dr. Rasmussen and talk about how we may be seeing
just the tip of the iceberg. I know we all hope that the
iceberg we’re not seeing yet is not too problematic, but
I am going to take the liberty to do what we sometimes do
in neurology and take a look at some pathology and some
animal models and some of what we know already
from human data, that Dr. Rasmussen has
eloquently reported. And describe what I think is at
least likely, possible to likely that we will be seeing
as clinicians, as neurological manifestations
in children, not just the children that we
know about now but perhaps those that we’ll be seeing
in the future. I’ll be making some real
broad generalizations based on at least my review of the
literature and discussion with experts, but then also
drilling down selectively in some areas that I
think might be helpful for us to think a bit more. And I think consistent with what
Dr. Rasmussen has just presented the data that we have to
date are really consistent with the idea that there are at least two broadly defined
mechanisms that we’re seeing and it’s more complicated
than that. I mean I understand we have
geneticists in the room and there’s some evidence that
Zika actually is impairing some of the manifest gene
expression and that could be one of the important mechanisms. But in general there’s a
disruption of brain development that is taking place, in
addition to disruption of already developed
brain tissue. And these, there’s
evidence in the pathology that these two independent
mechanisms broadly speaking are occurring simultaneously
or at least in the same infant
at different times. I think there’s an impression that there’s some very important
immunologic mechanisms. Perhaps cytokines could be
playing an important role, and that’s important for
us thinking about some of the neurological
manifestations because having an
inflammatory response, in addition to disruption
of development, in addition to damage of previously developed brain
does have certain implications in terms of what we may
expect to see later. Now one of the reports that’s
come out, it’s a tragic report, that’s also there
have been other cases that have been shared with
several of us in Neurology from Brazil in which
there’s been hydranencephaly or just really a replacement of previously developed
brain by fluid. Tragically, many of us who trained clinically
years ago remember that before imaging this
was easy to diagnose, all you did was take the
baby into a dark room, put a flashlight up against
the skull and the head lights up like a lightbulb
because there’s really no or very little brain
tissue in there and the light is just
distributed through the fluid. And that is actually
what has been reported by Sarno and colleagues. Now I added the blue arrow
there, up there under the image in A to make a couple of points. That’s really the fluid that’s
replacing the brain tissue, but if you look you can see that there’s a dramatic
asymmetry, all right? So there’s one hemisphere that’s
been almost completely replaced by fluid, another hemisphere
that’s severely damaged, but yet there’s still
some cortex that’s intact and in spite of all of
the damage that’s there. And I think that there’s
a symmetry in some of the other developmental
findings we’re seeing or are going to be helpful in understanding what we’re
going to see in the future. Now a real breakthrough in understanding the
developmental abnormalities with Zika occurred with the
publication of the group from Hopkins, Tang and others, reported in cell, stem cell that the Zika virus actually
directly invaded human neuro progenitor cells and actually
reproduced within the cells. In some cases there was
actual inducing of cell death, in others there was disruption
of cell function, cell cycles, and then transcription within these human
neuro progenitor cells. Now, as an aside, this
type of abnormality in these human neuro progenitor
cells has been associated in other types of models
with disruption both globally and also more focally
of neuronal migration and cortical development, as well as subcortical
abnormalities. It’s also been the case that these findings have
already been reproduced. I think one of the happy sides of the Zika story scientifically
is the absolutely impressive rapid response of science
to address this problem. The eloquent research that’s
been published already in a short amount of
time is impressive. So Tang’s and colleagues’
findings have already been reproduced and actually
taken forward so that they’re seeing
now more specific findings in in vitro models of
brain development looking at how Zika impairs development
of human neurospheres and human brain organoids. One of those articles in
Garcez, just recently, and colleagues
published this, and even those of us who are not
basic neuroscientists, laboratory neuroscientists,
you can see the difference in the sphere there in the
A image, perfectly round, normal looking human
neurosphere, and then in B it’s
shrunken, malshaped and is just not forming
or developing adequately, and that is very clearly
an abnormality that is seen in models in which there’s
abnormal development of the neurons and migration
of neurons, both globally and in some cases more focally. Here’s another image
from Garcez looking at a human brain organoid
models, and it’s very clear in this model that
Zika virus disrupts and impairs the normal
development of this in vitro model of human
brain development. Now an article that also
is fairly recent in nature, Cugola and colleagues show that there’s an animal
model, a mouse model for causing microcephaly that’s
very clearly directly causally related to the infection
of Zika virus with invasion and disruption of
progenitor cells. And you can see in the
picture of the mouse fetuses that there’s not only
really microcephaly, but also just major
growth restriction and this has received
quite a bit of attention. But what I’d like to draw your
attention to is not just that, not just that there’s
overall small brain, small size of the body, but there is a very
specific disruption of cortical development
in the temporal lobe and in the motor cortex. I don’t know that they
did a survey of all areas of the cortex, but clearly
shown in the temporal and the motor areas
of the frontal lobes in these animals there’s
abnormal cortical development and also there appears
to be disruption of the normal cortical
morphology. Also, there’s been an article
from Lee and colleagues that, likewise, has demonstrated
this small brain, microcephaly, as
a model in mice. And in this case it was
not the Brazilian strain, it was an Asian strain of Zika
virus causing this abnormality, and they reproduced the
work of Tang and others, invasion of progenitor cells. But what they have done, too,
is to describe and report some of the neuropathology. And, again, what they’ve
demonstrated is not just a dropout in the total
number of neurons, but also disorganized
cortex, a thin cortex, an increased neuronal
cell death. Again, all these findings
that are seen in animal models that are predictive
of certain types of abnormalities in humans. Now moving to some
of the human data, this is from Driggers and colleagues’ report in the New England Journal
earlier this year of a fetus that was tragically
infected with Zika and they have fetal MRI, as
well as a fetal neuropath. And the MRI, one of the things
that’s really very clear is thinning, dramatic thinning
of the corpus callosum. Corpus callosum is very
clearly too small and is thin. This is a large structure
relatively speaking and something that’s more
obviously seen as a marker when there’s severe impairment of cortical development,
neuronal migration. And then in the neuropath
they show disorganization of the cortex and this, again,
is consistent I would say with the previous animal
data that’s been seen. For some of us in Neurology some of what we’re seeing here is
reminiscent of what we’ve seen in CMV, as has been
mentioned before. And this is from some
work published by White and in Pediatric
Neurology recently, really more of a review of the
type of imaging abnormalities that have been seen with CMV. And in this situation they’ve
pointed out in the images to your left really CMV
being causally associated with this congenital perisylvian
syndrome in which frontal and temporal lobes are
abnormally formed, the cortex and subcortical white matter, and that there is very typically
polymicrogyria in the cortex around the perisylvian region. This, again, is consistent
with some of the neuropathology from the animal studies on Zika and then I think also what we’ve
seen in some of the neuropath from some of the
early human data. There’s also to your
right there’s images that really emphasize a
cleft within the cortex and this is the type
of abnormality that also is associated with
polymicrogyria within the cleft and areas of abnormally
formed cortex and other ways around the cleft. These types of lesions are
extremely highly epileptogenic, and when occurring
in a focal area of cortex very often
people can appear and children can appear
normal initially at birth and then develop seizures
in the first several months or even later in life. Here’s another picture
of one of these clefts that has polymicrogyria
within the walls of the cleft, and as you can see it’s
dramatically asymmetric although neither hemisphere
is completely normal. But the reason I point this
out is that there are cases that neurologists
see quite frequently in which one hemisphere can
be almost completely normal and the other has a demonstrated
cleft with polymicrogyria within it and so forth, and sometimes these children
can be dramatically unremarkable developmentally for the
first several years of life and then present with
seizures later on or they develop infantile
spasms or hemispasms very early. And so they often are not
microcephalic at birth. Lastly, let me just show an
example of some of the fine work of Ruben Kuzniecky, who
is an Adult Neurologist and epilepsy Specialist at NYU. Ruben has been interested
in this for over 20 years and the reason is because
if in taking care of adults, young adults with
intractable epilepsy with onset of the seizures in adolescence. Well, Ruben has pointed
out time and time again over the last 20 years and
it’s consistent with what most of us have seen is that one
of the more common causes of intractable focal epilepsy
in young adults and adolescents who don’t even have onset of
any clear neurological symptoms until that age are these types of neuronal migration
abnormalities associated with clefts, polymicrogyria
and thickened cortex. And in the image that’s to the far right there’s
actually an asymmetry in which one hemisphere
is relatively normal and then another hemisphere has
dramatically abnormal cortex with large areas of
polymicrogyria and a cleft and multiple different
types actually of cortical migration
abnormality. So what Dr. Rasmussen
was pointing out that what we’re seeing
in some of the cases of Zika so far is actually
technically not as consistent with lissencephaly
as polymicrogyria. I agree it does turn out to be
a very important distinction and is more consistent
with mechanisms that can produce these initially
less severe malformations that don’t manifest
until later in life. And so I think one of the things
we’re going to have to think about in looking at Zika is
realize that manifestations of a congenital anomaly may not
be readily apparent for months or even years or longer,
and how do we deal with that as clinicians and
as epidemiologists, I think is going to
be quite a challenge. So here I’ve summarized at
least the way I would think about these issues
that lay ahead for us. I think the column on the left, the infants that are
clearly abnormal at birth, and I believe this is work
group two for us, correct? This is a tragic situation, but I think relatively
easy to predict. These are children and this
would include the abnormalities that Dr. Rasmussen described
in more detail than I did, children that really
have profound motor and cognitive impairment, most
of them will meet diagnosis for cerebral palsy, they’re
all going to have profound, with an emphasis on profound,
intellectual disability. One thing that we
don’t often talk about because these children
are so severely impaired is that they do tend to have
cortical visual impairment and cortical auditory
impairment. How that impacts recommendations
for auditory screening and visual screening I think
is something worth discussing. For the pediatricians, one of
the things that’s a real problem that also Dr. Rasmussen
brought up is that initially these babies
are often able to suck, but as they become several
months old they lose their ability to suck, lose their
ability to feed, they can appear to regress during that time,
and I would suspect that most if not all of these
children are going to have severe problems
with feeding. Hypotonia is usually truncal
hypotonia, goes along with a lot of these types of
abnormalities that we’re seeing, and you put that truncal
hypotonia problems with gag reflex, problems with
feeding together and seizures, that really presents problems with aspiration pneumonias,
respiratory problems. Very soon there’s pulmonologists
and hospitalists involved in the cure of those children. The classic situation
here is onset of seizures in the first few months of
life, infantile spasms tend to be rare, epilepsy syndrome, tends to be relatively
common among children with these types
of abnormalities. And so as we educate
clinicians about what to expect I think a focus
on infantile spasm and how to recognize those
abnormalities will be important. Now of those who are initially
normal appearing at birth and, again, I don’t want to
play epidemiologist here, but I know this has
got to be a discussion and a concern among
the epidemiologists because we don’t really
know the number of people who have been exposed
at this point. But nevertheless among children
who appear normal at birth but who have one of
these milder forms of developmental brain
problems that I’ve mentioned, they tend to develop
what we would classify as acquired microcephaly
even though the etiology is developmental. And actually some of these
children may actually not meet diagnostic criteria
for microcephaly, their head circumference may
be above the second percentile, but they can have a
deceleration in head growth and then also have
developmental delays that are in one or more domains. And then, of course, the domain in which they have their
developmental delay would be related to the neuroanatomical
location of the associated
brain malformation. It will take us quite some time to know whether there’s
a pattern there that we can predict. As with the children that
are symptomatic at birth, these children will be
expected to have a higher rate of myoclonic epilepsy
and infantile spasms, but as with the cases that have
been reported for many years from adult epilepsy centers I
think we can also expect people to be relatively
asymptomatic if there’s a focal or even abnormality
isolated to one hemisphere, may not really present
until later in childhood or adolescence with
seizures and what appears to be developmental regression, and then that developmental
regression is often associated with an increased frequency
of subclinical seizures. So I think epilepsy and
developmental delays are going to be important to
look for in those kids that look normal at birth. Those who are abnormal at
birth I think will be familiar to pediatricians who care
for children with severe to profound microcephaly
from multiple other causes. I don’t want to end without
mentioning what’s already been mentioned, which is we know
that Zika is causally related to Guillain-Barré, both in
Brazil and in French Polynesia, and very often we
think of Guillain-Barré as being an adult problem but Guillain-Barré can also
affect children, two year olds, three year olds can
have Guillain-Barré. And so we’ll need to make sure
our colleagues are well versed in Guillain-Barré. There’s been a report or two on
myelitis, how often this occurs. I do not know. I think that one of the more
common questions I’ve had has been what is the risk to the
developing brain among children after they’re born during
the first two years of life if they are infected by Zika? I do not have any data on this. I don’t know the
answer to the question. It’s one that I feel
certain will be a question that will be ongoing for some
time and I’d be interested to personally know if
people have data on that. I’ve relied very much
on the work of others, and although my conclusions
are not necessarily those that have been in
these publications that I’ve listed here I’d
be happy to share these with you if you would like. Thank you. [ Applause ]>>And our next speaker
is Dr. Camila Ventura. She is an Ophthalmologist at
the Altino Ventura Foundation in Brazil, and she’s
going to be talking about ophthalmologic
manifestations.>>Good morning. It’s a pleasure to be here. I’d like to thank CDC and Dr.
Rasmussen for the invitation. To start with I would like to
acknowledge my team in Brazil at the Altino Ventura
Foundation, for sure this is
all about teamwork. As well as all of our partners
from Brazil and abroad, they have been helping
us along our way. And for you to understand where
we are standing right now. It’s important for you
to understand where, how did we start, and how did we
get involved with Zika syndrome, congenital Zika syndrome. So by October 2015 we
already knew that we had cases of microcephaly in
Brazil since May, and that people were talking
about that it was related to Zika, but we did not
have anything to prove it. By November 2015 this
association was proven to exist, and as we can see here the
impact in our population in Brazil how the peak of
microcephaly just went up mainly between November and December,
October to December, I’m sorry, and it was really fast and very,
very important for our country. So this was where
we were standing. Also, it’s very important for
you to know that Pernambuco, which is the red state as you
see on the map, it’s located in northeastern Brazil, it was
the first state to report cases of microcephaly in Brazil and it’s still considered
the epicenter because it’s also the state that
has the most amount of cases of congenital Zika
syndrome, more than 25%. So Altino Ventura
Foundation, we are located in northeastern Brazil and we
are a nonprofit Eye Hospital and Rehabilitation Center, so we
are in the Capitol of Pernambuco and this is a nonprofit
organization. We see about 35,000 patients
every month for eye care and we perform about 2,000
eye procedures a month. So it’s quite a lot, that’s
why we’re a reference center in northeast. Also, as for the
Rehabilitation Center we cover, we rehabilitate patients
according to their impairment, visual, auditory,
motor and intellectual. Right now in our Rehabilitation
Center we have more than 3,500 patients and
from those 156 babies with congenital Zika syndrome. They are being treated
at our institution. And so how did we get involved
with congenital Zika syndrome? It started that in December 2015
we organized three taskforces. In total we saw 128 babies
and their mothers because at that point we did not know if
mothers had ocular findings, as well, or only the babies. We found out that only
babies had ocular findings. The ocular exam included
the otoscopy, motility, bio microscopy, which is the
anterior segment examination, the fundoscopy, the
posterior segment examination, and we performed fundus
photography of all 128 babies. So as for the ocular
findings, now we are seeing, because at birth you cannot
actually diagnose strabismus and these strabismus they vary until six months of age, but
now these babies are growing and we are actually
assessing the strabismus, but also the segments that
these babies did not have and now they’re presenting
with time. But mainly the fundus
alteration, so this is what we mostly
see in these babies, and we were the first
ones to report the retinal and optic nerve alterations,
but now we see that these babies also
have vasculature findings. So as for the retinal
alterations, basically, we see scars, chorioretinal
scars as you see in this image, but also we can have
pigmentary changes as you can see in
this other image. And as for the chorioretinal
scar or atrophy it’s very important
to know that it varies according to the location, so you can
have let’s say a macular lesion, you can have a nasal
lesion, the size also varies so you can have a very small
and maybe you can miss that out if you’re not being,
observing it really well, but it can also be a very
extensive lesion in the eye. The shape also varies, it can
be circular or oval lesion or it can have more of
a disky form aspect. And the number of
lesions also vary. You can have an isolated
scar or multiple scars. As for the pigmentary changes, we see that these
babies they can have more of a focal pigmentation
in the macular region, but they also can have
diffused, so it really varies, as well as the pigmentary
aspect, it can be something like very fine but also
gross mottling pigmentation. And it can be isolated so
you can see only the pigment or it can be associated
to the scar. So it really varies a lot, and we’re learning
from this very much. Also, the optic nerve findings, in this picture we see all the
three findings we can find. The optic nerve, hypoplasia,
the pallor that we see in the optic nerve, as well as the increased
cupping. So this is a very good
image to show that. The vascular findings
we are seeing with time, so this is one image which shows
the attenuation of the vessels, but we were not the first
ones to report the hemorrhages that these babies have. Miranda and collaborators, they have described
these hemorrhages, as you see inferiorly. And also the abnormal
peripheral vasculature that you can see superiorly, and
it was also reported by Miranda. As for the anterior
segment alterations, from our 256 babies we have
not seen any anterior segment alteration, but it has been
reported in literature, the iris coloboma, the lens
subluxation, and cataracts. And also in previous papers
we have seen people describing microftalmia like pelvit. So talking about since
we are here to discuss, this is what we are actually
doing nowadays in Brazil and trying to advertise
and make sure these babies, they have an exam at least
within one month of birth, but also we find
it very important to document these fundus
because many of these babies that they are born
without ocular findings. Because they have a central
nervous system impairment, many times the optic nerves
are changing along the way, so it’s good to have the
documentation of the baseline to have this comparison. And we are talking
about all babies born, especially in the epidemic
areas, like Brazil right now. It’s very hard to have this
done, but this is something, the ideal world, right? Also, it doesn’t really matter
if the mother had symptoms or not, we defend that all
babies should be screened really and, also, as Dr. Rasmussen
said, we published a paper with a baby that did
not have microcephaly but had other neurological
and ocular findings, so it’s very important to
include all of these patients. And we also say that if the
patient has an ocular finding it’s very important
to refer this patient to at least a pediatric
ophthalmologist. Right now we are
following these babies, the pediatric ophthalmologist
and the retinal specialist in our institutions, we
are following these babies. Because the treatment is
actually multidisciplinary and, also, you have the magnifying
glasses that you can use to stimulate these babies,
patching and therapy visual, therapy simulation, but
it’s also very important that the retina specialist will
see these fundus and will detect if there is any change. So we’re working
as really a team. But, also, we think it’s not
only about having a lesion or not, actually both, all
babies should be followed at least during the
first year of age. And we would say we are
trying to this in our region where the retina specialist will
follow these babies every six months during the first year
of life because it’s a scar and it’s a past infection and
all of that we expect it not to change much, so
that’s why the six months. And the pediatric
ophthalmologist because of the visual
development they are following every three months these babies. But it’s very challenging,
of course, like I said it’s a
multidisciplinary team. We have a lot of
therapists, neurologists, ENT working with us, and
it’s a very costly treatment. We are going through a very
difficult moment in Brazil with all the political
and economic crisis. That’s why we’re
gathering help from all over because the cause is really
big, these babies need our help. And it’s very touching,
like I said to many of you, it’s touching to deal
with these patients and see how they can do
better with treatment. So thank you so much
for your attention. [ Applause ]>>Justin Obatim, Augusta, Georgia. In the animal data you showed
it was striking the intrauterine growth restriction, but
that’s not been the phenotype in humans. Was there any data
on the placenta of those animal models?>>Are you asking from those articles I…>>Yes.>>I don’t recall seeing the percentile data there, now… There are some of these human
cases in which Zika was isolated from the amniotic fluid and
that was one of the ways that they documented
exposure, for example. But I don’t recall an actual
histopathology of the placenta, itself, in the articles. But I’m not the best
person to speak to that. Yes, sir?>>Yes, there was an article
recently in [inaudible] looking at placenta and then there
was an article that came out, I saw it yesterday. First author was T-A-B-A-T-A from “Human Placenta”, it was showing different cell types at different stages of development.>>I’m Sharon Lehman,
she had a section on AAP, on opthalmogy and I am really very pleased that both of you talked about cortical visual impairment. Just as a co-incident three weeks ago we had a pediatric cortical visual impaired review… and then this week [inaudible]spoke to a group of teachers of visually impaired early intervention people. And this was a
very big topic. And many times in children who have all these neuro
developmental problems the cortical visual impairment
gets overlooked, and I think that
it’s going to be – and the early intervention
people at this meeting were
also very concerned that the recommendations that we
make speak to early intervention and not just the
initial treatment. So thank you for
bringing that up. I think that we’ll have to
discuss the follow-up in Brazil and the follow-up at
least in the United States because as we spoke, you know, the retina specialists
are probably not going to be interested in seeing these
children in the United States. So I think we’ll
have to modify things to fit clinical care here,
but really thank you both for bringing that up because
it is so often overlooked.>>Yes, I totally agree
with what you’re saying, and that’s why we want to emphasize we are following
these babies and we see that many do not reach the
milestones for the age according to their age, you know, the
vision according to the age. And this for sure
has to do with CNS.>>Georgina Peacock
from CDC. Ed, you talked about the
loss of suck and the increase in feeding problems over time,
is that only in the children that would develop seizures? I know this is somewhat
speculation, or do you think there’s
a possibility of some developmental regression
in all of the babies regardless of the development of seizures?>>Yes, again, with
the disclaimer that I’m projecting
based on other types of situations that we’ve seen. I think that’s a separate
issue from the seizures. I mean the seizures can
exacerbate the overall situation because you’re having
a lot of seizures and you can’t control your
secretions you’re going to be more likely to aspirate. But in these children that
are severely microcephalic and I would say especially those that have severe frontal
lobe dysfunction, you know, as we’re all designed
over simplistically that as our brain
develops we shift from that reflex
sucking mechanism to more or intentional chewing,
swallowing activities that are more related
to higher structures. And so those higher brain
structures are not intact, then they tend to develop
those more severe swallowing and feeding problems after
a few months of life. So I think it’s more related
to the brain injury, itself, the loss of feeding ability than
it is actually the seizures.>>This is Susan Wiley from Cincinnati, and I want to mirror
thanking you about the functional vision
assessment and thanking about cortical vision. But my question is
actually for the babies who are not microcephalic at
birth, do we have any knowledge that there’s an asymmetry of
head circumference to the rest of the growth parameters or is
that not necessarily apparent to the degree that we know that? I mean so, you know, recognizing
that some kids are going to have a normal
head circumference, but is it disparate from their
somatic growth in those kids? So you would kind of put two
categories of children up?>>Yes.>>One with clear microcephaly,
those without microcephaly, and what we should do to
be thinking about them? But whether there’s data to suggest a relative
microcephaly compared to somatic growth?>>Yes, I don’t know that. Again, I’m projecting based on what we’ve seen
in other conditions. And I would say especially,
I mean it would be nice to know what you’ve seen in
Brazil, but since the pathology and the imaging that we’ve
seen can be quite asymmetric, both in terms of
brain destruction and then abnormalities of
actually brain development, you know, abnormalities in
migration, in other conditions that have that sometimes the
head size may not be technically abnormal or below
the second percentile because one hemisphere is normal
and then those children are not as easy to pick up early on.>>Now the case that we reported
actually there was a cranial facial disproportion and also
– but the head circumference, like I mentioned, was normal
but the brain findings, the baby had ventriculomegaly
classification. So he had the neurological
findings that has been reported, but you look at the baby and you
see that there is cranial facial for sure, it’s not something
that will pass by you and you do not realize it.>>So one side of the
face was a different size?>>One side is like
you see that it’s not – you would think actually that
the baby has microcephaly, but once you measure
it’s within the growth.>>Oh, I see.>>We are following this baby and the brain keeps
following the normal curve, not within like the 90%. It’s a little bit under, but
not considered microcephaly. Do you understand?>>Yes, yes.>>And it keeps in the curve,
but you look at the baby and you see, oh, it’s not, the proportions are
not normal for a baby.>>Hi I’m Yvonne Maldonado,
[inaudible]. And what’s striking to me and to all of us obviously are the dramatic Microcephaly and
[inaudible]. But when you look at other congenital infections as you pointed out, CMV and Rubella, which again are also [inaudible] we haven seen those dramatic findings. And yet my understanding is that there are Zika
disruptors throughout the brain, and not just in the neuro
genitor cells, and do you have any idea
why this is so profound? And would this virus
relative to, say, CMV and especially Rubella,
which can be quite devastating in terms of the same
cellular drop-off?>>Others may have a
different impression, but, no, I don’t know. And I would agree this is,
to me, the neuropathology and imaging that we’ve seen so far is actually much more
concerning, both in terms of the brain injuries to the
babies that are microcephalic but also I think the potential of what these mechanisms
could do to children that initially pass screens. So I would agree with you,
this is a new territory.>>So one other comment is that as you know there’s
also literature that suggests that antibody dependent
enhancements, for example when
he’s in vitro looking at adding Dengue virus
antibodies to cell in vitro models results in
higher cellular destruction. And whether or not there’s some
cross-reactivity with that, additional inflammatory
response. I think somebody else brought
up this issue of inflammation, but I think that may be another
cofactor that I don’t know if that’s been looked at yet. So, for example, women who
are – I know it’s hard to do but to distinguish between
Dengue co-infected women versus not and whether that
Aedes may actually lead to additional cellular drop-off?>>A question for
our epidemiologists.>>Yes, I knew Marc
would probably — [ Inaudible ]>>I’m interested as to why
this is being seen here now and whether previous
Dengue infections in an area could be contributing
at a population level. There is the one study that you
mentioned that looked in vitro and suggested that there could
be an increased severity, but I’m not aware of any data, and it is very difficult
serologically to find a population that is
not previously Dengue infected in these parts of South
America and suggest that there’s greater severity
of disease compared to or not. I think it’s an unknown.>>Yes, Fernando Cerna,
American Academy of Pediatrics, Puerto Rico. These soft signs that you have
mentioned on the neurological and ophthalmological they’re
not necessarily are just with microcephalic babies. Do you have any data on
when was the mother infected or when was the Zika
was diagnosed, if it was in the
first trimester, second or third trimester
of pregnancy?>>Yes, so one of our
publications we wanted to see what were the
risk factors associated with the ocular finding
and we actually saw that the first trimester
is related, so probably the ocular
findings, the infection occurred in the first trimester so that
the baby had the ocular findings and consequently I
believe the microcephaly. And also another risk factor
was the cephalic perimeter, so the smaller the
head circumference was at birth – oh, I’m so sorry.>>We had some signaling
from the back of the room and I think that’s what
he was trying to tell us.>>So also the head
circumference was also another risk factor. So what makes me believe that
the eye infection occurred in the first trimester, the head
stopped growing severely, right, and then the ocular
findings also appeared in the same moment. What we are seeing now as
ocular findings are scars. We are not seeing
active disease. And that’s why we are
not treating these babies with steroids or trying to find
some treatment for these babies because actually now
it’s a past infection and we believe it was
the first trimester. [ Inaudible ]>>I know that my
constituents are dying to know the answer to this. How did Brazil respond
to the parents? How did you support the numerous
parents that were having to deal with all, you know, the children
that they had to support? What – how did your state, your country support the
parents dealing with this?>>That’s a great question. We thought it was very important
to give parents support and since the beginning. We saw many mothers depressed, many of the families did not
want to show their babies, they would cover
their babies up. They would come with the babies
covered, would leave treatment with the babies covered. They could not handle the
pressure from media also and from people around,
the curious people. So because of that we have
formed a support group for the mothers,
basically mothers. We were actually
mentioning how fathers they in these moments it’s very
hard to maintain a family when you have a baby
that cannot stop crying. These babies have
a neurological cry. I actually have on my phone, I have recorded their
cry, it’s insane. And all the therapies
involved because the babies, these are 256 babies, we are
trying to see them weekly. It’s not easy. We have, like I said,
a political issue when we are not being
paid for these babies. But we are having
donations and grants. We’re trying to get as
many help as we can. And mothers have responded so
well to support, psychological, psychiatrists, as well as some
of them they need psychiatrists. But mothers are helping
themselves. So, okay, my baby
cannot swallow. Every time, like you said, they have swallowing
issues, they really do. So one mother discovered
a way of feeding the baby and they are teaching – oh, so we make every week while
the baby is being treated, stimulated, ocular, motor, the mothers are also being
treated with support group. So I find this very important. It’s not only about
seeing only the babies, but everything around them. It’s a whole family that
changes once you have a baby with congenital Zika syndrome.>>I am not aware of do you know
whether anyone has ever looked at congenital CMV and arthrogryposis?>>In what?>>Arthrogryposis? Because we’ve got so many. [ Inaudible ]>>It was really interesting
looking at onsite – oh, I’m sorry, Lisa Hunter, I’m at
Cincinnati Children’s Hospital in Pediatric Audiology
– and really interested in the congenital ophthalmology
anomalies and thinking about parallels with
the auditory system, but haven’t been able
to find data yet. And I’m wondering from
Brazil with the testing that is done there, there
are some really good ENT and audiology research
facilities, is there any data about to come out
or any knowledge about what the parallels may be? I’m worried about dual sensory
impairment, both hearing and vision in these children and the profound
developmental effects that may occur as a result.>>They certainly have auditory
findings, and we’re trying – this is something that the
next paper we’re working on is assessing. We have assessed
38 babies and all, these babies have been assessed
by ENT, neurology, orthopedics, ophthalmologists, all of them. And we want to – nobody
has, no publication has come out about the auditory findings,
and it’s very important. The tests, in the beginning
every – when we had 138 babies in the beginning we tested them
with – it’s a screening test. I don’t know in English,
but it also has errors so it’s not so precise. You have the same, when the
baby is born you screen first and then you have the
real auditory test. So we did not want
to rely on that test, that was why we during, like a long time we did
not publish those findings. It took a lot to have the real
tests, the more specific test.>>Diagnostic.>>Yes, the diagnostic,
exactly, but now we have for the 38 babies I
was telling you about, so this is something we
are working on for sure. And it’s mainly unilateral
what we are seeing.>>I’m curious.>>Unilateral.>>So I’m going to have the
questions stop so we can stay on time, otherwise, we will
get severely behind today. So we have a break right
now for 15 minutes. If you want to ask Dr. Trevathan or Dr. Ventura questions during
the break that would be great, and we’ll come back
at ten-thirty for the next series of talks. Thanks so much.

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