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Zika Virus Infections
Perspectives Past, Present… and Future
MUSC -- April 8, 2016
Eric Brenner, MD
Department of Epidemiology and Biostatistics
USC School of Public Health
Topics (flexibly construed)
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Emereging Infectious Diseases
Introduction to ZIKV
ZIKV Epidemiology, Mosquito entomology
New Information – CDC, NEJM etc
ZIKV analogies to WNV, dengue and malaria
ZIKV: Public Health and Politics
Remaining Questions (and prognosis!)
Questions and Discussion
ZIKA Flash Summary
Basics I: Of interest, but not so Alarming
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ZIKV discovered in 1947 in a Uganda forest
A Flavivirus related to WNV, YF, JE, DENG,
CHIKV etc.
Known transmission by Aedes sp mosquitoes
Little impact or interest until recently…
Infection in children and adults
– ~80% no symptoms at all
– ~20% generally mild self-limited “viral
syndrome”
– Occasional post-infection complications
(e.g. GBS)
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Explosive impact 2015 in Brazil, with…
Rapid spread across South & Central America
& Caribbean
Infection in pregnancy => transplacental fetal
infection
Devastating consequence => microcephaly
(+attendent neurological and developmental
problems)
Rapid spread in a new large “non-immune”
population:
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Tools:
– No Dx. Tests (until last few months)
– No Rx. (as is case for most viral infections)
– No Vaccine (but likely to be developed)
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Basics II: Extremely Alarming
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Anxiety in USA as (i) epidemic spreading North
from Latin America and (ii) summer “mosquito
season” approaching
Medical / public health complications:
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100s of thousands or millions of new cases… in which
Many will occur in pregnant women
Risk of thousands of fetal infections => miscarriage / fetal
death / microcephaly
Now found to be sexually transmitted
Likely transmissible by blood transfusion
Frequent travel between US and Latin America
Complex Societal issues, for example:
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Mosquito control: What resources? How effective?
Access to contraception & abortion
June 2016 Olympic Games in Brazil!
Test of society’s preparedness for certain future grave
Emerging Infectious Disease threats!
http://jme.oxfordjournals.
org/content/51/1/104
Zika Forest
www.sciencemag.org/news/2016/02/zika-s-long-strange-trip-limelight
Account of the 1947 discovery
of the Zika Virus in Uganda
On 18 April 1947, a rhesus monkey that researchers identified as 766 ran a fever of
39.7°C, about 2°C higher than normal. The monkey was part of a study hunting for yellow
fever virus and was living in a cage on a platform built into the tree canopy in the 1.5kilometer-long Zika Forest, which runs adjacent to an arm of Lake Victoria in Uganda.
Three days later, the investigators took a blood sample from Rhesus 766 and injected it
into the brains of Swiss albino mice. The mice “showed signs of sickness” after 10 days,
and the researchers harvested their brains, from which they isolated a “filterable
transmissible agent.”
Come January of the following year, the same researchers trapped mosquitoes from
these canopy platforms and took their bounty back to the lab, hoping to isolate yellow
fever virus. Others had shown that one of these species they caught, Aedes africanus,
shuttled the yellow fever virus, so the investigators put 86 of the insects in a refrigerator
to “render them inactive” and then ground them up in a blood-saline solution, which they
again injected into the brains of mice. The animals “appeared inactive” after 7 days, and
tests showed they harbored the same transmissible agent that had sickened Rhesus
766.
www.sciencemag.org/news/2016/02/zika-s-long-strange-trip-limelight
Yellow Fever Transmission Cycles
www.cdc.gov/yellowfever/transmission/
Zika Tower
Video (CNN!)
A Simple 3-Part Model for Thinking
about Spread of Infectious Diseases
Susceptible host
Reservoir
Mode of transmission
Environment
(e.g. tetanus, legionella)
Animal
(e.g. rabies, WNV)
Human
(e.g. measles, TB, Zika)
Direct contact
Droplet spread
Airborne spread
Vectorborne
Common vehicle
Vertical
Auto-inoculation
Susceptible = “lacking
immunity”
Immunity may be:
1. Active or passive
2. Natural or artificial
3. Humoral (antibodies)
or cell-mediated
CMI=cell-mediated immunity,
(rather than antibodies) important
for TB!!
Going Further then with a 5-part Model
More Instructive for Vectorborne Diseases
1. The agent (pathogen)
2. The reservoir
3. The Mode of Transmission
4. Susceptible hosts
5. The Environment in which
the eco-transmission cycle
takes place:
• Natural environment:
(e.g. temperature,
humidity, breeding sites,
etc)
• Human environment:
home screens & AC, etc
etc.)
Oops…. ↑temperature  ↑mosquitoes  ↑certain diseases! A good time to start to
consider potential impact of global warming on the spread of these infectious conditions!)
Examples of “vectors” of
“vectorborne diseases”
and a few of the diseases
they can transmit!
Tick
Mosquito
(e.g. Malaria, WNV, Zika)
(e.g. Lyme Disease, RMSF
Fly
(e.g. Onchocerciasis)
Louse
(e.g. Typhus)
Flea
(e.g. Plague)
Aedes aegypti
Anopheles albimanus
Malaria
Yellow fever, Dengue
and Zika
WNV
Vector for
Culex quinquefasciatus
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Would
You
Drink
or SIP
Juice
at the Zoo?
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WNV
Yellow Fever
Dengue
St. Louis Encephalitis
Japanese Encephalitis
• Zika
Important Flaviviruses
• Though not Coke
• And certainly not Milk
• Chickungunya
• Malaria
Further Perspectives on Zika:
1. From Other Infectious Diseases Acquired
Abroad
2. From Past Experience with Introductions of
Other Tropical Mosquito-born Diseases into
the United States
Results: CDC received 1,691 reported cases of malaria, including
1,688 cases classified as imported, one transfusion-related case,
and two cryptic cases, with an onset of symptoms in 2010 among
persons in the United States. The total number of cases represents
an increase of 14% from the 1,484 cases reported for 2009.
Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were
identified in 58%, 19%, 2%, and 2% of cases, respectively. Thirteen
patients were infected by two or more species. The infecting
species was unreported or undetermined in 18% of cases. Among
the 898 cases in U.S. civilians for whom information on
chemoprophylaxis use and travel area was known, 45 (5%) reported
that they had followed and adhered to a chemoprophylactic drug
regimen recommended by CDC for the areas to which they had
traveled. Forty-one cases were reported in pregnant women,
among whom only two (5%) adhered to chemoprophylaxis. Among
all reported cases, 176 (10%) were classified as severe infections, of
which nine were fatal.
Results: CDC received 1,691 reported cases of malaria, including
1,688 cases classified as imported, one transfusion-related case,
and two cryptic cases, with an onset of symptoms in 2010 among
persons in the United States. The total number of cases represents
an increase of 14% from the 1,484 cases reported for 2009.
Plasmodium falciparum, P. vivax, P. malariae, and P. ovale were
identified in 58%, 19%, 2%, and 2% of cases, respectively. Thirteen
patients were infected by two or more species. The infecting
species was unreported or undetermined in 18% of cases. Among
the 898 cases in U.S. civilians for whom information on
chemoprophylaxis use and travel area was known, 45 (5%) reported
that they had followed and adhered to a chemoprophylactic drug
regimen recommended by CDC for the areas to which they had
traveled. Forty-one cases were reported in pregnant women,
among whom only two (5%) adhered to chemoprophylaxis. Among
all reported cases, 176 (10%) were classified as severe infections, of
which nine were fatal.
Cholera has been diagnosed in three New Yorkers - the first known cases in the city since last
year's outbreak in Haiti. Three adults developed the disease after travelling to the Dominican
Republic for a wedding on January 22, city health officials confirmed today. The victims began
experiencing classic symptoms of dehydration and diarrhoea soon after returning home.
Typhoid Fever Globally in
the United States
• Estimated 21 million cases of typhoid fever
and 200,000 deaths occur worldwide.
• Each year in the United States, approximately
300 culture-confirmed cases of typhoid fever
More than 80% of reports of typhoid fever are
of travelers to southern Asia.
www.cdc.gov/nczved/divisions/dfbmd/diseases/typhoid_fever/
Introduction of WNV into the
USA: A look-back to fall 1999
NY Times Sept 4, 1999
Unusual Encephalitis Cluster
in Northern Queens, 1999
www.floridahealth.gov/diseases
-and-conditions/dengue/
• So… YES, we do have occasional US outbreaks of “locally acquired
malaria”.
• These are of interest, but are always self-limited and in recent
decades have never bloomed into true “large-scale” public health
problems.
Zika and Politics
US Zika Funding Video
www.scdhec.gov/Library
/CR-009025.pdf
South Carolina 2016 List of Reportable Conditions (continued)
Zika... where are you?
www.examiner.com/article/cdc-activates-emergency-operations-center-response-to-zika-virus-outbreak
www.cdc.gov/zap/
US Zika Action Plan Summit - CDC – April 1
(Selected Participants)
• Tom Frieden – CDC Director
• Amy Pope - White House Homeland Security
Advisor
• Nicole Lowry – DHHS Assistant Secretary for
Preparedness, Health and Response
• Representatives of State Governors and State
Commissioners of Health
www.cdc.gov/globalhealth/security
Contextual Points
• W. African Ebola Outbreak: 2014-2015
• Obama Administration 2014 request for $1.8 billion (? Over 3-5 years)
• ~$600 million for international outbreak response
• ~$600 million for domestic preparedness
• ~$600 million for longer term development of “Global Health Security”
http://www.npr.org
Newscast Video: In face of Congressional
inaction, administration to use Ebola Funds
for Zika Preparations
WHO: Zika may infect “as many as 4 million people…”
Globally, dengue infects ~ 400 million annually.
Slide courtesy of Dr. Eric Brenner
TheState Jan 29, 2016
R. Ball, MD MPH FAC
WHO Declares Zika virus an international “Public
Health Emergency” (pandemic) 2.1.2016
www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/e
CDC EOC → Level 1 (highest) on 2.8.2016
R. Ball, MD MPH FAC
12. Some Epidemiologic Perspectives
regarding Zika and its Potential
Quantitative Impact on Public Health
www.mayoclinic.org/diseasesconditions/microcephaly/basics
/causes/con-20034823
www.cdc.gov/zika/public-health-partners/microcephaly-case-definitions.html
Given ~ 4million births per year in the USA, instructive to do some mental arithmetic
How common is Mental
Retardation” ?
Or much better…
What is the Prevalence of
Mental Retardation” ?
http://cirrie.buffalo.edu/enc
yclopedia/en/article/144/
Some Epi-conclusions
• Even one ZIKV-related microcephalic or retarded
child likely to “make the news” and alarm the
public
• Will be important to communicate broader
numeric epi-perspectives regarding actual
“numbers” in the USA
• Matter reminiscent of public and media furor
regarding any individual mass shooting… but
overlooking / accepting the thousands murdered by
firearms every year
14. Key Zika Studies now Underway... to
help us really understand the biology and
epidemiology of just what is happening!
A Major Zika Epi-Study Underway
• Follow-up of hundreds pregnant Brazilian women.
• Will be delivering over the next several months
• Newborns will become microcephaly “cases” or
“controls”
• Collection of extensive biological,serological, medical
history and other data will allow for quantitative
estimation of “risk” of Zika-induced microcephaly (ZIM)
• This, and other studies now underway will put our
understanding of the current Zika epidemic on much
firmer ground!
P.S. Also need to clarify whether ZIM is either:
(i) a rare but expected problem just not noticed before as previously affected
populations were small in size? … or
(ii) a new phenomenon (perhaps due to viral mutation)?
Example of Possible Zika Microcephaly
Case-Control Study Design
Pregnancy Outcomes
Clinical or Serological
Evidence of Zika
during pregnancy
1. OR = ad/bc
Microcephaly +
Cases
Microcephaly Controls
Yes
a
b
No
c
d
Standard analysis of a case-control study
2. OR as a good estimate of Relative Risk (especially with relatively rare diseases)
3. Hence RR~OR
Pe (RR-1)
4. PAR% =
Pe (RR-1) +1
Provides information regarding existence and magnitude of
association between Zika infection in pregnancy and subsequent
birth of a child with microcephaly!
Then, with data to estimate Pe e.g. (from a pre- and post-pregnancy
Zika serologies in a cohort of pregnant women), this calculation can
provide an estimate regarding what proportion of microcephalic
births are in fact actually “due to” Zika virus infection in pregnancy!
www.nytimes.com/interactive/2016/health/what-is-zika-virus.html?_r=0
http://www.cdc.gov/chikungunya/resources/vector-control.html
Some Summary Points
• Zika virus spread just the latest in what is now essentially incessant occurrence
of Emerging Infectious Diseases (EIDs). (cf. HIV, H5N1 and H1N1 influenza, SARS,
MERS, Ebola, Nipah, MDRTB and much more!
• EID occurrence due to multiple factors including:
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Increasing global population (now 7+ billion)
Increasing urbanization (>50% global pop now urbanized)
Increasing opportunities for pathogen “spillover” from zoonotic reservoirs to humans
Incredible increase in human travel (disease anywhere today can be a disease
elsewhere tomorrow)
– Global warming (e.g. with increasing likelihood of increased incidence of so-called
“tropical mosquito-borne diseases” in previously considered “temperate climates”.
– Changing economic and social behavior (e.g. wish of populations to have permanent
access to food produced elsewhere [=> increase in global foodborne outbreaks]
– Reluctance of populations and governments to invest in the epidemiological and
laboratory infrastructure needed for (i) prevention, (ii) rapid detection, and (iii) rapid
effective response.
• Recommended EID readings
– Googling “Emerging Infectious Diseases”
– CDC’s free on-line Emerging Infectious Disease Journal, now in its 21st year.
www.cdc.gov/eid
www.cdc.gov/eid
And re Zika’s Short-term future in
North America…. ?
• This presentor’s sense is that:
– Zika outbreak will be intense for a whole initial year in Latin America…
– then will become less intense as increasing proportion of the population will be immune
– In USA transmission will be limited because of (i) limited range of Aedes aegypti, (ii)
increased local mosquito-control efforts, (iii) use of screened windows and air-conditioning
more widespread in USA than in Latin America
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Some sexual transmission will occur (most directly or indirectly travel related), but
incidence will be but a tiny fraction of overall burden of STIs (syphilis, GC, chlamydia, HPV,
HSV etc etc.) in the USA.
Transmission by blood transfusion may occur, but rarely. Blood banks will be able to limit
such by (a) deferring donors with recent travel or other possible exposures, and (b) if
necessary, starting to screen donated blood for Zika just as they have now done for years
for WNV.
Some newborn microcephaly and/or death may occur, will be uncommon but any
occurrence will nonetheless attract great public attention. Such cases will represent
but a fraction of the microcephaly which occurs annually in the US in any case,
and even Zika-related infant deaths be small in number compared to numbers of
pediatric deaths due to prematurity, influenza and other conditions.
• The Zika epidemic may have paradoxical salutary effects as press, public and
politicians acquire increased public health and epidemiological perspective from
inevitable further events and discussions surrounding them
The End ! Thank You!
Questions? Discussion ?