Thomas M File, Jr MD MSc MACP FIDSA FCCP

Chair, Infectious Disease Division

Summa Health System Akron, Ohio;

Professor of Internal Medicine,

Chair ID Section

Northeast Ohio Medical University

Rootstown, Ohio

Emerging Infections

It is time to

“close the book on

infectious diseases.”

Congressional testimony by the

Surgeon General of the

United States, 1969

Congressional testimony by the Surgeon General of

the United States, 1969

EMERGING INFECTIONS

New,

Re-emerging, or

Drug-resistant

infections whose incidence in humans

has increased within the past 2 decades

or whose incidence threatens to

increase in the near future.

Institute of Medicine Report 1992

From:

Woolhouse M

Microbe 2006

1: 511

NEW INFECTIONS (>100)

sample

Chikungunya

Clostridium difficile (NAP 1)

Community associated Methicillin-resistant S. aureus

EBOLA

Hantavirus

Helicobacter

HIV

Hepatitis C

Human Herpes virus 6,7,8

Influenza H5N1; Influenza 2009 H1N1; H7N9

Lyme

MERS

Severe Acute Respiratory Syndrome (novel coronavirus)

SEVERE ACUTE RESPIRATORY

SYNDROME (SARS)

Started in Guangdong Province China(11/02);

Spread worldwide; profound impact on travel

Spread by close contact (air droplet)

Highest mortality in elderly and debilitated

Epidemic terminated July 03

No significant numbers of asymptomatic infection

No transmission prior to clinical illness

“We don’t know if we’re going to see anther SARS patient

or not…But I think we’re living in the age of the new normal

of emerging health threats and this preparedness for SARS is

going to pay off sooner or later, because if it’s not SARS, it

will be something else, and we’ll be ready for it” J. Gerberding (CDC, Sept, 26, 2003)

AVIAN INFLUENZA

Fall 2003-new outbreak of respiratory illness Young affected; high mortality

Stimulated worldwide Pandemic Preparedness Plans

Avian Influenza (H5N1) 2003-2015

SE Asia; China; Indonesia;Azerbaijan; Turkey; Iraq; Egypt, Nigeria, + others

Primarily contracted from poultry • Numerous countries with poultry infection

• (Asia, Africa, Europe)

• ONE in Western Hemisphere (Jan 2014)

AVIAN INFLUENZA

1st Case North America (Canada)

Died Jan 2014

young woman recently returned from Beijing

No known bird exposure

NEW OUTBREAK: Influenza

A(H1N1) MMRW Report, April 2009

MMWR, April 24, 2009 Swine Influenza A in two children in Southern

California

No exposure to pigs

MMWR, April 28, 2009 / 58(Dispatch);1-3 47 patients reported to CDC with known ages

(out of 64) the median age was 16 years (range: 3-81 years)

38 (81%) were aged <18 years

Of 14 patients with known travel histories • 3 had traveled to Mexico

• 40 of 47 patients (85%) had not been linked to travel or to another confirmed case

Source: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0428a2.htm

RECENT VIRAL OUTBREAKS

Requirement for Pandemic

Requirements

for Pandemic

SARS Avian Flu H1N1 (Swine)

Flu

Novel Virus + (Coronavirus) + (H5N1) + (Hsw1N1)

Disease in

Humans

+ + +

Degree of

spread Human

to human

+* - +**

*Transmissible only during symptomatic disease

**Transmissible prior to symptoms and many ‘subclinical ‘ cases

RECENT VIRAL OUTBREAKS Characteri

stic

SARS MERS EBOLA Chikungunya H7N9 Flu Enterovirus

D68

Onset Nov 2002;

Guangdong

Province China

Sept 2012 Feb

2014;

West

Africa

Dec 2013;

Caribbean

FLA

March 2013;

China

Aug-Dec 2014

Origin Civit Cat ? Camels Bats Arbovirus-

mosquitoes

Avian, Human Human

Transmission Person to Person Mostly

environmenra

l; low person

to person

Person

to

Person

Vector borne Poultry Droplet

# cases 8500 (3/09) 1042

(Feb/2015) 22,903

(Feb,201

5)

1,135,892

(Feb/2015)

540 (Feb, 2015)

83 since Dec

2014

1,121 (Dec 4)

Mortality 9.5% 37% 9194/22903

(40%) ;

9194/13969

(67%)

0.02% 30% 12 Deaths

reorted

Status Terminated 7/03;

Surveillance

Ongoing

(slowly) Ongoing Ongoing (‘not

peaked’)

Emerging

Evolving

Reducing

Ebola Virus Prototype Viral

Hemorrhagic Fever

Pathogen

Filovirus: enveloped,

non-segmented,

negative-stranded RNA

virus

Severe disease with

high

case fatality

Prior absence of

specific treatment or

vaccine

>20 previous Ebola and

Marburg virus outbreaks

2014 West Africa Ebola

outbreak (Guinea, Sierra

Leone, Liberia)

Largest outbreak in history

13

EBOLA CASES (WHO, Sept 4, 2015)

Ebola Virus Transmission

The virus is spread through

direct contact (through broken skin or mucous membranes) with a sick person's blood or body fluids (urine, saliva, feces, vomit, and semen)

objects (such as needles) that have been contaminated with infected body fluids

infected animals

Healthcare workers and the family and friends in close contact with Ebola patients are at the highest risk of getting sick because they may come in contact with infected blood or body fluids.

Human-to-Human Transmission

Infected persons are not contagious

until onset of symptoms

Infectiousness of body fluids (e.g., viral

load) increases as patient becomes

more ill

Remains from deceased infected

persons are highly infectious

Human-to-human transmission of

Ebola virus via inhalation (aerosols)

has not been demonstrated 17

Detection of Ebola Virus in Different Human Body Fluids over Time

18

Pathophysiology of EBOLA Virus

UpToDate 2014

viremia

3

IgM

ELISA IgM

0 10

IgG

IgM: up to 3 – 6 months

ELISA IgG

IgG: 3 – 5 years or more (life-long persistance?)

days post onset of symptoms

RT-PCR

Critical information: Date of onset of

fever/symptoms

Fever

EVD: Expected diagnostic test results over time

20

EVD Clinical Manifestations

Acute onset: typically 8-10 days after exposure

(range 2-21 d)

Stage I

Fever, chills, HA, myalgias, malaise,weakness

Diffuse erythematous Maculo papular rash (some)

GI symptoms common: N/V, diarrhea, Abd pain

Stage II (high mortality)

Hemorrhage

Hypotension; electrolyte Abn; Shock

Lab: Cytopenia; Abn LFTs; Coag Abn; Renal Abn

* Deceased NEJM Nov 27, 2014

Ebola Fighters: Time People of year 2014

EVD Diagnosis

Person Under Investigation (PUI):

Epidemiologic risk factors within the past 21 days • contact with blood or body fluids of a patient with

EVD; residence in—or travel to—an area where EVD transmission is active; or direct handling of bats or non-human primates from disease-endemic areas.

AND • Clinical criteria– fever > 100.4 F; plus symptoms such

as severe HA, myalgia, vomiting, diarrhea, abdominal pain, or unexplained hemorrhage;

Lab: IgM ELISA; PCR; Virus Isolation

Clinical Management of EVD: Supportive, but Aggressive

Hypovolemia and sepsis physiology

Aggressive intravenous fluid resuscitation

Hemodynamic support and critical care management if necessary

Electrolyte and acid-base abnormalities

Aggressive electrolyte repletion

Correction of acid-base derangements

Symptomatic management of fever and

gastrointestinal symptoms

Avoid NSAIDS

Multisystem organ failure can develop and may

require

Oxygenation and mechanical ventilation

Correction of severe coagulopathy

Renal replacement therapy

Reference: Fowler RA et al. Am J Respir Crit Care Med. 2014 24

Investigational Therapies for EVD Patients

No approved Ebola-specific prophylaxis or treatment

Ribavirin has no in-vitro or in-vivo effect on Ebola virus

Therapeutics in development with limited human clinical

trial data

• Convalescent serum

• Therapeutic medications

o Zmapp – chimeric human-mouse monoclonal antibodies

o Tekmira – lipid nanoparticle small interfering RNA

o Brincidofovir – oral nucleotide analogue with antiviral activity

Vaccines – in clinical trials; now in use • Chimpanzee-derived adenovirus with an Ebola virus gene inserted;

Attenuated vesicular stomatitis virus with an Ebola virus gene inserted

References: 1Huggins, JW et al. Rev Infect Dis 1989; 2Ignatyev, G et al. J Biotechnol 2000; 3Jarhling, P et al. JID 2007 S400; 4Mupapa, K et al. JID 199 S18; 5Olinger, GG et al. PNAS 2012; 6Dye, JM et al. PNAS 2012; 7Qiu, X et al. Sci Transl Med 2013; 8Qiu, X et al. Nature 2014; 9Geisbert, TW et al. JID 2007; 10Geisbert, TW et al. Lancet 2010; 11Kobinger, GP et al. Virology

2006; 12Wang, D JV 2006; 13Geisbert, TW et al. JID 2011; and 14Gunther et al. JID 2011. 25

Phase 1 clinical trial results suggest a bivalent

Ebola vaccine was safe and immunogenic in

healthy adults, according to the NIH

NEJM 2014:doi:1056 (pre print Dec 17, 2014)

EBOLA VACCINE

Patient Recovery

Case-fatality rate 71% in the 2014 Ebola outbreak

Fatality rate is lower with access to intensive care

Patients who survive often have signs of clinical

improvement by the second week of illness

Associated with the development of virus-specific AB

Antibody against Ebola persists greater than 12 years

Prolonged convalescence

Includes arthralgia, myalgia, abdominal pain, extreme

fatigue, and anorexia; some symptoms may persist for >21

months

Skin sloughing and hair loss has also been reported

References: 1WHO Ebola Response Team. NEJM 2014; 2Feldman H & Geisbert TW. Lancet

2011; 3Ksiazek TG et al. JID 1999; 4Sanchez A et al. J Virol 2004; 5Sobarzo A et al. NEJM 2013; and 6Rowe AK et al. JID 1999.

27

EVD Management

EBOLA concern in Akron, Ohio

OHIO: Monitored 164 contacts of

Fever in Traveler returning from

Caribbean

Returning traveler from the Caribbean(5 days)

Within 24 hours c/o pain to back of knees, both ankles and feet, wrists and hands-symmetric, no swelling nor erythema, lasted 3-4 days

Severe spinal pain, inability to stand upright -3 days

Fevers –constant for up to 72 hours 101-102F

Malaise, myalgia, fatigue for 1 week

2-3 days later, faint erythema to trunk, followed by photosensitivity rash to arms face legs-transient pruritus

No headaches, URI symptoms

Chikungunya

Viral infection

No vaccine or treatment

No person-to-person

transmission

Mosquito vectors

Aedes aegypti or Aedes albopictus

widespread

Mosquitoes can “hitchhike”

RECENT VIRAL OUTBREAKS Characteri

stic

SARS MERS EBOLA Chikungunya H7N9 Flu Enterovirus

D68

Onset Nov 2002;

Guangdong

Province China

Sept 2012 Feb

2014;

West

Africa

Dec 2013;

Caribbean

FLA

March 2013;

China

Aug-Dec 2014

Origin Civit Cat ? Camels Bats Arbovirus-

mosquitoes

Avian, Human Human

Transmission Person to Person Mostly

environmenral;

low person to

person

Person

to

Person

Vector borne Poultry Droplet

# cases 8500 (3/09) 1042

(Feb/2015) 22,903

(Feb,201

5)

1,135,892

(Feb/2015)

540 (Feb, 2015)

83 since Dec

2014

1,121 (Dec 4)

Mortality 9.5% 37% 9194/22903

(40%) ;

9194/13969

(67%)

0.02% 30% 12 Deaths

reorted

Status Terminated 7/03;

Surveillance

Ongoing

(slowly) Ongoing Ongoing (‘not

peaked’)

Emerging

Evolving

Reducing

Chikungunya

The mosquitoes

Aedes species; same types for dengue virus

Bite mostly during the daytime

Symptoms

Usually begin 3‒7 days after being bitten by an

infected mosquito

Most common symptoms are fever and severe

joint pains, often in the hands and feet

Other symptoms may include headache, muscle

pain, joint swelling, or rash

Chikungunya Sudden high fever (usually >102º F) which may be

continuous or intermittent

Severe joint pain that commonly involves the hands and

feet

Joint swelling

Back pain

Rash usually 2-5 days after fever starts

Other symptoms may include headache, body ache,

nausea, vomiting, and redness around the eyes. In

unusual cases, infection can involve the brain, eyes, heart,

kidney and other organs.

Fatal infections are rare, however many patients have

chronic joint pain, arthritis, loss of energy and depression

lasting weeks to years.

Differential diagnosis

Chikungunya vs Dengue viral fever

Dengue more pronounced retro-orbital pain

More commonly hypotension and mild

bleeding complications

Fatigue can last for months

Associated with higher mortality

Chikungunya-prominent Arthralgia

?influenza-like, but no URI symptoms

Diagnostic testing

Performed on the 3rd day given

persistent symptoms

CBC, mild lymphopenia, mild

thrombocytopenia

LFT not done

Mild CPK elevation

Chikungunya PCR+

Other options: paired sera for

Chikungunya IgM

Chikungunya

Prevention

No vaccine or medication to prevent infection

Reduce mosquito exposure

Use air conditioning or window/door screens

Use mosquito repellents on exposed skin. Repellents containing

DEET, picaridin, IR3535, and some oil of lemon eucalyptus and

para-menthane-diol products provide long lasting protection.

Wear long-sleeved shirts and long pants

Wear permethrin-treated clothing

Empty standing water from outdoor containers

Support local vector control programs

People at increased risk for severe disease should consider

not traveling to areas with ongoing chikungunya outbreaks

Novel betacoronavirus (HCoV)

MERS (Middle East Resp Syndrome

Sept 2012: 2 patients with severe

pneumonia (Saudi Arabia; Qatar) in

otherwise healthy

Sept 2015: 1216 cases (Middle East;

Travel from Middle East--UK, France,

Italy, US, Korea, 21 countries);

30-40% mortality

Similar to SARS virus

Source: bats, camels

Human to human (low)

NEJM Oct 17,2012

42

Novel betacoronavirus (HCoV) MERS

May 17, 2014: 3 cases US

2 from Saudi Arabia

• 1st May 2; 2nd May 11

–Both HCP worked in SA

3rd from exposure to 1st case (Illinois

male exposed to Indiana male)

WHO SHOULD BE EVALUATED FOR MERS

PATIENTS WHO MEET THE FOLLOWING:

FEVER AND PNEUMONIA OR ACUTE RESPIRATORY

DISTRESS SYNDROME AND EITHER:

HISTORY OF TRAVEL FROM COUNTRIES IN OR NEAR THE

ARABIAN PENINSULA1 WITHIN 14 DAYS OF SYMPTOMS OR

CLOSE CONTACT2 WITH A SYMPTOMATIC TRAVELER WHO

DEVELOPED FEVER AND ACUTE RESPIRATORY ILLNESS (NOT

NECESSARILY PNEUMONIA) WITHIN 14 DAYS AFTER TRAVELING

FROM RISK COUNTRIES OR

IS A MEMBER OF A CLUSTER OF PATIENTS WITH SEVERE ACUTE

RESPIRATORY ILLNESS (E.G., FEVER AND PNEUMONIA

REQUIRING HOSPITALIZATION) OF UNKNOWN ETIOLOGY IN

WHICH MERS-COV IS BEING EVALUATED

OR: CLOSE CONTACT2 OF A CASE OF MERS

NEWEST OUTBREAK!!

H7N9 Avian Influenza

Identified in China April 2013

As of Jan 2014: 207 cases; 22% mortality

Minimal during summer; new cases over winter

Exposure to birds

? Human to human (possible 2 cases)

Low pathogenicity in birds (Different than H5N1)

Virulence factor similar to 1918/19 strain

Probable reassortment of avian strains

Median Age-60s

Most in/and surrounding Shanghai

Appears to be susceptible to oseltamivir

Vaccine being developed

46

Travel Precautions to China

47

CDC does recommend that travelers to countries

with influenza A outbreaks in poultry or people

observe the following:

Avoid visiting poultry farms, bird markets and

other places where live poultry are raised, kept, or

sold.

Avoid preparing or eating raw or undercooked

poultry products.

Practice hygiene and cleanliness.

See a doctor if you become sick during or after

travel.

Painless chronic skin ulcer enlisted

person coming home from Iraq

Case: Patient presents to ER with

fever, cough, chest pain

The diagnosis is

most likely by?

a. Sputum culture

b. Blood culture

c. Sputum PCR

d. IgM ELISA

e. Urinary

Antigen

EMERGING INFECTIONS

“Humanity has but three great

enemies: fever, famine and war;

of three by far the greatest, by

far the most terrible, is fever.”

Sir William Osler