Zika Virus Infections Perspectives Past, Present… and Future

Eric Brenner, MD

Department of Epidemiology and Biostatistics

USC School of Public Health

MUSC -- April 8, 2016

Topics (flexibly construed)

• 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

• 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)

• Tools: – No Dx. Tests (until last few months) – No Rx. (as is case for most viral infections) – No Vaccine (but likely to be developed)

• 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: – 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

• Anxiety in USA as (i) epidemic spreading North from Latin America and (ii) summer “mosquito season” approaching

• Medical / public health complications: – Now found to be sexually transmitted – Likely transmissible by blood transfusion – Frequent travel between US and Latin America

• Complex Societal issues, for example: – 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!

Basics I: Of interest, but not so Alarming Basics II: Extremely Alarming

http://jme.oxfordjournals.org/content/51/1/104

Zika Forest

www.sciencemag.org/news/2016/02/zika-s-long-strange-trip-limelight

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 1.5-kilometer-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

Account of the 1947 discovery of the Zika Virus in Uganda

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

Reservoir Susceptible host

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!!

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.)

Going Further then with a 5-part Model More Instructive for Vectorborne Diseases

Oops…. ↑temperature ↑mosquitoes ↑certain diseases! A good time to start to consider potential impact of global warming on the spread of these infectious conditions!)

Mosquito Tick

Flea Louse

Fly

Examples of “vectors” of “vectorborne diseases”

and a few of the diseases they can transmit!

(e.g. Malaria, WNV, Zika)

(e.g. Typhus)

(e.g. Onchocerciasis)

(e.g. Plague)

(e.g. Lyme Disease, RMSF

Aedes aegypti Anopheles albimanus

Culex quinquefasciatus Vector for

Yellow fever, Dengue

and Zika

Malaria

WNV

• Would

• You

• Drink

• or SIP

• Juice

• at the Zoo?

• Though not Coke

• And certainly not Milk

• WNV

• Yellow Fever

• Dengue

• St. Louis Encephalitis

• Japanese Encephalitis

• Zika

• Chickungunya

• Malaria

Important Flaviviruses

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.

US Zika Funding Video

Zika and Politics

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

TheState Jan 29, 2016

Slide courtesy of Dr. Eric Brenner R. Ball, MD MPH FACP

WHO: Zika may infect “as many as 4 million people…” Globally, dengue infects ~ 400 million annually.

WHO Declares Zika virus an international “Public Health Emergency” (pandemic) 2.1.2016

www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/

R. Ball, MD MPH FACP CDC EOC → Level 1 (highest) on 2.8.2016

12. Some Epidemiologic Perspectives regarding Zika and its Potential Quantitative Impact on Public Health

www.mayoclinic.org/diseases-conditions/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

http://cirrie.buffalo.edu/encyclopedia/en/article/144/

How common is Mental Retardation” ?

Or much better…

What is the Prevalence of Mental Retardation” ?

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

Microcephaly + Microcephaly -

Cases Controls

Yes a b

No c d

Pregnancy Outcomes

Clinical or Serological

Evidence of Zika

during pregnancy

1. OR = ad/bc

2. OR as a good estimate of Relative Risk (especially with relatively rare diseases)

3. Hence RR~OR

Pe (RR-1)

Pe (RR-1) +14. PAR% =

Provides information regarding existence and magnitude of association between Zika infection in pregnancy and subsequent birth of a child with microcephaly!

Standard analysis of a case-control study

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:

– 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

• 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 ?