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