4/20/15. Overview. Ebola Virus Biology. Ebola Virus. The Ebola Disclosures: Spouse works for Merck, Inc. Nothing else to disclose







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The Ebola

2 0 1 4 - 5

i n s t i t u t i o n a l

Disclosures: Spouse works f o r Merck, Inc.

Nothing else t o disclose

David Henderson,

Describe the biology, virology and pathogenesis of Ebola Disease.

Describe the epidemiology of Ebola, both in Africa and: in countries.

Describe the US cases of Ebola Virus Disease, including the epidemiology, clinical signs and symptoms, clinical management, and outcome.

Describe prevention current En use. Discuss the available information concerning Ebola Virus Disease medical countermeasures,

O v e r v i e w

Ebola Virus Disease Biology Virology The Current West African Outbreak - Epidemiology

Ebola Virus Disease and Western Medicine - Cases outside Africa > Epidemiology > Diagnosis > Clinical findings Clinical management Outcome Prevention institutional Infection Control

Progress on the horizon promising countermeasures

Ebola V i r u s

Member of the family filamentous

negative-sense RNA virions that are capable of causing severe disease in humans and nonhuman and are often referred to as viral hemorrhagic fever

Five Species known.

Ebola Ebola zaire

Ebola Ebola Ebola tai forest

Ebola V i r u s Biology

Enzootic Cycle Epizootic Cycle




Ebola V i r u s T r a n s m i s s i o n

• Blood and Body


» Infeeted (e.g., f r u i t bats o r primates [apes and clearly be t r a n s m i t t e d via c o n t a c t w i t h blood,, or m e a t of infected

Ebola V i r u s T r a n s m i s s i o n 2

Virus present in high quantity in blood, body fluids, and excreta of patients. Transmission thought occur only after symptoms

develop; the viral burden clearly rises at symptom onset. The risk of transmission is more illness (when the Ebola virus levels are highest),

• One study evaluated 31 environmental specimens from an Ebola isolation ward. All these specimens negative by

among healthcare personnel Is associated with direct contact with infected persons (or the bodies of persons who from EVD), direct with body fluids from EVD patients, and occupational with

Ebola Virus Pathogenesis

r r e c t e d d e n d r i t i c cell Immune Cytokine \ release \ Inflammatory Response - Syndrome Vascular leak

Clinical Course o f Ebola


Progressive disease)

' f

Transmissible [ 8 to r f Weakness, - Vomiting, . . Myalgias, Cytokine Arthralgias -


OHM -DOS ffi -009


4 / 2 0 / 1 5

Ebola Virus Disease Cases

Guinea 18 Oct 14 1,553 1,312 926 Liberia 18 Oct 14 4,665 965 2,705 22 Oct 14 3,389 1,281 Nigeria** 15 Oct 14 20 19 Spain 21 Oct 14 1 1 0 Senegal** 15 Oct 14 1 1 0 States 24 Oct 14 4 4 1 Mali 23 Oct 14 1 1 1 TOTAL 10,141 5,692 4,922 Updated case at by WHO data from Health

outbreaks In Senegal Nigeria were declared

Outbreaks - Viral Discovert t o t h e Present

Source: Butler 0, L Ebola by the numbers; The size, spread and cost of an outbreak.


Sequencing of the Ebola Outbreak

isolates from May-June sequenced (395


changes; 8 of in highly conserved areas of the genome

No Evidence of significant functional change

surveillance elucidates Ebola virus o r i g i n and transmission

during the 2014 outbreak

E b o l a in t h e a i r ? A nightmare that c o u l d h a p p e n

Elizabeth Cohen. Medical

"It's the concern I've ever had in my public health said Or, Michael director of the Center f o r Disease Research and Policy at the University of Minnesota, "I can't imagine anything in my career and this includes that would be more devastating, t o the w o r l d respiratory transmissible virus,"


Malaria Typhoid Fever

Severe bacterial infection (e.g., sepsis, pneumonia). Presence of one of these infections does n o t exclude Ebola, especially in settings in which an individual has had a high-risk exposure.

Cases t o t e to the US:

Ebola Infections Documented Humanitarian



4 / 2 0 / 1 5



Source: European Centre of Disease Prevention and Control

Medical Evacuation and Repatriation




Yes Spain sierra (UK) HOT


4 Uteris (USA] rawed USA

Recovered Yes USA

2014 sierra (The Netherlands) HOT No The 14 s) HOT Recovered No Tie

Liberia (France) HOT Recovered Yes Sierra Madrid HOT Death Yes Spain

HOT Recovered Maryland (USA] HOT USA


Liberia Omaha (USA) Stable Yea USA 6 Sierra Irons Oslo hot Unknown Yes Norway

Death Yes Sudan

Guinea Verb (USA) USA

Centre Control,

C a s e s

t o t h e U.S.

U n i v e r s i t y o f N e b r a s k a C e n t e r M e d i c a l C e n t e r • Richard Sacra, MD Ashoka WHO Physician MSF Physician • Craig E m o r y U n i v e r s i t y M e d i c a l C e n t e r c l i n i c a l C e n t e r

Transmissions t h a t Have Occurred

Outside t h e Epicenter

Nigeria Patrick Sawyer, a lawyer

from Uberia to Nigeria (after reporting an exposure then becoming He infected 20 resulting in eight deaths (primarily in healthcare workers),

Thomas Eric Duncan a who became Ebola patient diagnosed in. the US. He infected two nurses who provided care for

Spain - Manuel Garcia Viejo, a Spanish Priest was repatriated after the diagnosis was established. He infected one who cared for him.

Source: CDC

Ebola Virus: Texas Health Positive. CDC Confirms

First Eb

Gas a




Boarded a a Developed Returned to pregnant Brussels, United Airlines symptoms same by woman to art Airlines flight to (abdominal ambulance; Ebola treatment flight t a Washington

then carried Brussels. changed nausea and

her to a to headache, abdominal

take her home, flew to Dallas, fever pain, projectile Went to E.R. vomiting and Sent home on fever. antibiotics.

September 30 October 8.

Tests Patient dies

positive for in a Dallas,

Ebola at Texas





the three which Ebola epidemic. Source; Gomes, MFC, el. Assessing the Spreading Risk Associated with the West African Ebola

Outbreak. Currents Outbreaks Sep 2. Edition I.

Ebola Virus

* Real Time PGR (RT-PCR)

Used to diagnose acute infection More sensitive than antigen detection * Identification of specific viral genetic

Performed in select CUA-certified laboratories

• RT-PCR sample collection

Volume: minimum volume whole blood Plastic collection tubes (not glass or heparinized tubes) * Whole blood preserved with EDTA is preferred

• Whole blood preserved with sodium polyanethol (SPS), citrate, or with clot activator is acceptable



Ebola RT-PCR

* If started days the negative result

* is unlikely consider other diagnoses

infection control precautions for EVD can be discontinued unless ciinical suspicion for EVD persists

If started days before the negative RT-PCR result

Interpret with caution

Repeat test at >72 hours after onset of symptoms Keep in isolation a suspected until repeat RT-PCR

hours after onset of symptoms negative


Clinical Observations

* Major issue is decreased vascular volumes and capillary leak syndrome due to both direct and

endothelial cell damage;

» Patients leak fluid into their spaces' at an alarming rate

At Emory of the patients gained as much as 40 pounds of water weight, yet remained profoundly hypovolemic > Their also lost as much as Electrolyte abnormalities are often

patients are often and

US: feome.


» Physicians at both Emory and found viral RNA In several body

Blood Urine > Stool Tracheal Secretions Skin

Did not detect contamination, though these specimens were until the day of patients' discharge,

Sources: patients Ebola virus In U.S.: learned, Week October B,

Clinical Observations

Aggressive supportive care is crucial t o


» Nursing care is labor-intense

Patients at all t h r e e centers needed

emotional support,

Some patients have needed physical

therapy nutritional support

(patients may be malnourished).

Sources: patients virus Injection In the learned. Presented at PA, fl-1?, 2014.




Case-fatality rate to date is 7 1 % for the 2014 Ebola outbreak Case-fatality rate is likely much lower with access to intensive care Patients who survive often have signs of improvement by the second of illness

Associated with the development of antibodies Antibody with neutralizing activity against Ebola persists greater than

12 years after infection Prolonged convalescence

> Includes arthralgia, myalgia, abdominal pain, extreme fatigue, and many symptoms resolve 21 months

> Significant arthralgia and myalgia may persist for >21 months Skin sloughing and hair loss has also been reported



in West African

Ebola Outbreak

General Neurological Cardiovascular Pulmonary Gastrointestinal Hematological

Fever (87%), fatigue (76%), arthralgia (39%), myalgia Headache confusion (8%). coma Chest pain (37%),

Cough dyspnea sore throat hiccups Vomiting diarrhea anorexia abdominal pain dysphagia (33%), jaundice

Any unexplained

vaginal bleeding gingival bleeding hemoptysis bleeding at injection site


Conjunctivitis rash (6%)


L a b o r a t o r y

Thrombocytopenia range)

Initial leukopenia f o l l o w e d by neutrophilia Elevations of transaminases: serum aspartate transferase (AST) > alanine amino-transferase (ALT) Coagulation abnormalities - PTT prolonged! proteinuria, Increased CPC Website - DAY I2 3 4567 33 34 30 43 57 61 75 SALIVA/SWAB URINE SEMEN SKIN/SWEAT VAGINAL lit Source: CDC

Immunological Findings

Critical Date of onset of f e v e r / s y m p t o m s



3 10 -1 Source; CDC

Challenges t o Successfully Managing

I m p o r t e d


* Effective exit and entrance screening o f

individuals arriving f r o m epidemic areas,

» Effective identification of patients in

Rooms and other acute settings.

Assurance t h a t institutions can provide safe for patients.

» Appropriate use of PPE, use of trained


Managing t h e waste stream,




Exit Screening Screening

Fever October 2014

• Presence of symptoms • Fever

• History of contact with • Presence of symptoms known Ebola patient

• History of contact with exit if screen known Ebola patient


• Refer for further evaluation, and quarantine, if warranted



» All

-> Must work with local and national public health authorities to determine whether or not to provide comprehensive care for EVD patients. > For institutions that to refer patients to

regional or tertiary centers, procedures for transport/transfer of patients to a where comprehensive care can be provided must be developed and implemented;

Institutional Planning f o r Managing

Patients Comprehensively

» An institutional effort - involves every department, • Components include (but not limited to:

Effective early screening for infection;

Safe to the hospital within the hospital (staff and infrastructure);

Effective and PPE;

Training retraining) of staff (physicians, nurses, technologists, trained

Simulation for procedures intensive care; Refresher training;

Standard operating procedures to safe safe laboratory practices;

> Internal and external communication

Keeping staff informed; managing hysteria, fear and dissention.


» All institutions

Must have effective strategies for screening for exposure/travel history of emergency room and outpatients, at the initial interaction must focused, precise clear (CDC checklist}; For patients who have any symptoms and positive

exposure/travel histories, institutions Must have:

The ability to place patients safely on isolation precautions

Streamlined procedures for urgent interaction with public health authorities to determine next steps;

Strategy to assure that all staff interactions PPE,

f o r Managing Ebola-lnfected


• Strategies for effective early for infection; > Algorithm for returning travelers - http://

www.cdc.gov/vhf/ebola/pdf/ebola-algorithm.pdf > for patients being evaluated for EVD

- http://www.e.de.gov/vhf/ebola/pdf/chec.klist-patients-evaluated-us-evd.pdf

> Algorithm to identify, to identify, isolate, inform for the. emergency room evaluation and management of with possible EVD - http://

www.cdc.gov/vhf/ebola/pdf/ed-algorithm-Source; CDC

Planning f o r Managing Ebola-lnfected


» An effort - involves every Physician staff

« Critical Care • Anesthesiology

• Medical and surgical subspecialty consultants Nursing

Clinical laboratory leadership and staff Facilities management

Environmental services

Sources, flf&oe, S, (Us


4 / 2 0 / 1 5

f o r


Strategies for transport



Control Considerations

Guidelines, are far too complex for description, * Prudence mandates an abundance of caution,

Specific CDC guidelines are available at the following sites;

General Information for healthcare workers and healthcare settings - http://www.cdc.gov/vhf/ebola/hcp/index,htmt General infection control guidelines -

> Information about Personal Protective Equipment (including donning and doffing) - http://www.cdc.gov/vhf/ebola/hcp/ procedures-for-ppe.html

Environmental infection control guidelines for http://


Institutional Infection Control Considerations

* Key Issues far

High-level units not required, but do offer advantages.

is labor-intense and requires many staff Use of the "buddy" system is key to

In our experience use of an independent, trained observer (a is key to safe use of PPE

of (and rigid adherence to) Standard Operating Procedures

SOP's are a target

SOP's should be tailored to the individual institution



Key Issues for consideration - 2

Highest level of risk is likely associated with and management of needles and sharp objects, Crucial to anticipate laboratory needs; laboratory

guidance not yet clear; where possible, testing is optimal

Dedicated equipment is also important

We have aggressively used hydrogen peroxide vapor decontamination of equipment and the environment. Practice, practice, dress rehearsals.


f o r

may Exposed t o Ebola 1 *

* of fluids

Needle stick, splashes t q eyes, or > Exposure t o body fluids directly o n skin;

Handling body fluids, as in a laboratory, w i t h o u t wearing personal protective equipment (PPE) o r w i t h o u t following recommended safety

Touching a dead body w i t h o u t correctly wearing PPE in a country w i t h widespread

Living and caring f o r , a person showing s y m p t o m s of

* risk

> Close c o n t a c t * * a person showing symptoms o f Ebola (e.g., in a household, health care facility, or the community (while not wearing PPE), In countries widespread Ebola transmission: direct contact

person showing symptoms o f Ebola while wearing PPE

Issued October available at:

"Close contact" being of the person with far a long without wearing PPE


CDC f o r Public Health

f o r Individuals w i t h o u t


Monitoring Restricted Public Activities

Restricted Travel

High risk Active M o n i t o r i n g

Yes Yes

Some risk Yes- Direct Active

Monitoring assessment assessment


M o n i t o r i n g f o r some; Direct Active f o r others

No No

No risk No No No

* Issued October at


Risk Levels f o r {including

may have been t o Ebola 2 *

not zero) risk—

Having been a country w i t h widespread Ebola transmission w i t h i n t h e previous 2 1 days and having no k n o w n exposure;

In t h e r o o m f o r a brief period o f t i m e (without direct contact) w i t h a person showing o f Ebola;

> Having brief skin contact w i t h a person symptoms o f Ebota w h e n t h e person was believed t o be n o t very contagious;

countries w i t h o u t widespread Ebola contact w i t h person showing symptoms of Ebola while wearing PPE

Travel o n an airplane w i t h a person showing o f Ebola

Contact w i t h a person who is. showing symptoms AFTER that person was. in contact w i t h a person w i t h Ebola

Contact w i t h a person w i t h Ebola BEFORE t h e person was showing symptoms Having traveled t o a country w i t h Ebola outbreak MORE than 2 1 days ago Having been in a country w h e r e there is no widespread Ebola transmission

(e.g., the United States), and having no other exposures t o Ebola


4 / 2 0 / 1 5


Operating Procedures Should

Constant "Work in Progress"

Procedures should be constantly reevaluated for risk-points;

Failure mode and effects analysis is a powerful tool for such assessments; Instances of protocol violation should precipitate

Root Analyses (RCA's) Creativity is key to risk mitigation; Encourage questioning: "How can we do this

better or

What kinds of quality care can be delivered without having the physician enter the room? All team members have an equal voice Practice,

Safe Clinical

CDC developed guidance for laboratory workers and. healthcare personnel who collect or handle specimens The guidance includes information about the appropriate steps for collecting, transporting, and specimens from patients who are suspected to be infected with Ebola

Specimens should NOT be shipped to CDC without consultation with and local/ state health departments

Not ail authorities are comfortable with these recommendations; or example American Society for Microbiology has recommended that only testing be used.



Practices -


All three US containment facilities have employed point-of-care testing in the care of EVD patients. • Point care tests that have been used include;,

Clinical chemistry

Clinical hematology, including coagulation tests Arterial blood gases

> Urinalysis (automated)

> diagnostic test (automated)

Ebola - Medical

Combination of three humanized mouse monoclonal antibodies directed against coat glycoprotein

Documented efficacy in

Small, RNA Human 1 trials progress

4430 Nucleoside analogue,' RNA Prophylactic efficacy in a model of Marburg Virus Has broad-spectrum antiviral activity;

works as a viral RNA polymerase Inhibitor

In vitro activity against In trials evaluating efficacy against other Viral RNA polymerase already

licensed in Japan for

Prophylactic efficacy a mouse model of Ebola




Replication incompetent chimpanzee adenovirus vector containing gene for Ebola glycoprotein

Efficacy in animal trials; now In Phase 1 human testing; Phase 1 tests are complete; awaiting


Replication competent horse vesicular stomatitis virus vector containing

for Ebola glycoprotein

Human Phase 1 trials in progress

Phase Trial of



Fully Enrolled

20/20 participants have received the vaccine; no immediate safety issues; formal data about safety and should be i n late November 2.014,



.- .


Chimpanzee adenovirus vaccine generates acute and durable

protective against


John C Annie W C



fied virus have been evaluated as vaccine vectors In primates and human clinical trials5-"-'1; low worldwide are not human sera4. Here evaluated monovalent (EBOV GP) or bivalent (EBOV plus ebolavirus ebolavirus vaccines protection against acute EBOV challenge and durable protection using

and approaches.

- b o o s t s t r a t e g y ( C h i m p a d e n o v a c c i n e ; m o d i f i e d vaccinia A n k a r a b o o s t ) * P r o t e c t e d 4 / 4 Rhesus m a c a q u e s f r o m l e t h a l Ebola i n o c u l a t i o n


(AP) An re In

If phase a p p e a r s b o t h f o r s a f e t y a n d efficacy, a l a r g e r t r i a l w i l l be b e g u n .

Early t r i a l s i n t h e US, C a n a d a , a n d Kenya

G o i n g F o r w a r d . . .

public health infrastructure, Humanitarian assistance,

• Careful implementation of safe and strategies, Meticulous attention to Infection control.

> Public health interventions - contact tracing and follow-up. > Effective internal and external communication.

Decisions usually involve risk

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