Antibiotic Overview, Antibiotic Resistance, and Emerging Pathogens

9/27/15 Emerging Infections: Ebola & Chikungunya
Chikungunya Virus
Elizabeth Race, MD, MPH
Infectious Diseases / HIV Medicine
AIDS Healthcare Foundation, Dallas, Texas
Chikungunya Virus:
A Newly Re-emergent Infectious Problem
Fever/Rash/Arthritis
•  Arbovirus originally identified in 1950s in E. Africa, in
sylvatic cycle involving primates and forest mosquitoes
-Triad of fever/rash/arthritis is characteristic of
•  Clinical descriptions first in 1970s in South Africa
Chikungunya, O’nyong-nyong, Ross River, Mayaro,
and Sindbis viruses
•  Limited outbreaks periodically in SE Asia, with a larger one
in 2001-2003 in Indonesia (after 20-year hiatus)
•  Explosive outbreak in 2005-present, in Indian Ocean
islands & Indian subcontinent, involving millions of cases
•  Imported cases in Europe, North America among travelers
to Indian Ocean sites
-Symptoms generally appear after 2-3 days incubation
a) fever, chills, myalgia
b) polyarthralgia mainly affecting small joints
c) maculopapular rash
-Arthritis generally resolves in a few weeks, but may
persist for months, or years in some cases.
Aedes albopictus
• 
Genus Alphavirus; Family Togaviridae
•  First isolated from the blood of a febrile
patient in Tanzania in 1952
•  Identified repeatedly in west, central and
southern Africa and many areas of Asia
• Transmitted by A. aegypti, A.albopictus,
others; vertebrate hosts include primates
Charrel R et al. N Engl J Med 2007;356:769-771
1 9/27/15 World Distribution of the Aedes albopictus
Togaviridae, genus Alphavirus
Charrel R et al. N Engl J Med 2007;356:769-771
Chikungunya
•  Acute
chikungunya fever typically lasts a few days to
a couple of weeks, but some patients have prolonged
fatigue lasting several weeks
Infection can cause a debilitating illness,
most often characterized by fever, headache,
fatigue, nausea, vomiting, muscle pain, rash,
and joint pain. The term ‘chikungunya’ is
Swahili for ‘that which bends up.’
• 
• Up to 10% may develop chronic joint symptoms
• Death is very uncommon
•  No vaccine or preventive drug; recommendation:
vector control, vector avoidance
Skin manifestations in CHIKV in travelers
Hochedez P, Jaureguiberry S, Debruyne M, Bossi P, Hausfater P, Brucker G, et al. Chikungunya infection in
travelers. Emerg Infect Dis. 2006 Oct
From: Medicine 2007;86:123-137
2 9/27/15 Chikungunya
tenosynovitis, arthritis
MRI: arthritis, tenosynovitis
From: Medicine 2007;86:123-137
Chikungunya Outbreaks:
•  India (14 states), Malaysia, Indonesia, Sri
Lanka, Maldives, Nicobar Islands
•  Imported cases reported in multiple countries:
– Australia
– Japan
– Taiwan
– Europe: UK, France, Italy, Spain
– USA
Figure: WHO; http://www.who.int/csr/don/Regional_Chykungunya_largeb.jpg
Chikungunya Infection in Travelers
During 2005-’06, 12 cases of CHIK
fever were dx’d serologically and
virologically at CDC in travelers who
arrived in the US from areas known to
be epidemic or endemic for CHIKV
Hochedez P, Jaureguiberry S, Debruyne M, Bossi P, Hausfater P, Brucker G, et al. Chikungunya infection in
travelers. Emerg Infect Dis. 2006 Oct
Chikungunya Virus: Summary
•  Caused by virus inoculated via mosquito bites
–  Increased risk May-October (rainy season)
–  Increased risk in urban and village areas
•  Symptoms: Sudden onset of fever, rash on trunk and limbs,
back pain, and severe joint pain / arthritis in multiple joints
•  Treatment: analgesics, NSAIDS, corticosteroids; chloroquine
has been used in a few refractory cases
African Tick-Bite Fever
Rickettsia africae
•  Countermeasures
–  Prevent mosquito bites
–  Use insect repellent
–  Sleep under a permethrin-treated bed net
3 9/27/15 Spotted Fever Group
Mediterranean spotted fever
- Rickettsia (R.)
conorii
Rickettsialpox
- R. akari
African tick bite fever
- R. africae
Queensland tick typhus
- R. australis
Japanese spotted fever
- R. japonica
Flinders Island spotted fever - R. honei
California flea rickettsiosis
- R. felis
Siberian tick typhus
- R. sibirica
Israeli spotted fever
- not named
Astrakhan fever
- not named
Disease: African Tick-Bite Fever
•  Rickettsial infections: R africae & R conorii
•  Transmitted by ticks
•  1992: Kelly et al isolated R africae from a
patient in Zimbabwe (Lancet 340:982-983)
•  Exported from southern Africa [ &
Guadeloupe] to US 1997
(Am J Trop Med Hyg1999;60(5):865-7; France 1998 (CID 1998;27(2):
316-23); France 2001 (NEJM 2001;344(20);1504-10) Italy 1999 (EJCMID
2002;21(2): 133-6) Norway 2003 (CID 2003;36(11):1411-7)
African Tick Bite Fever
• 
• 
• 
• 
• 
• 
• 
• 
• 
Seroprevalence of R. africae in ticks approx. 27-50%
Amblyomma ticks (found on cattle & ungulates)
Exposure: walking through brush/cattle areas
Usual incubation period 6-7d, varies, most in 2 wks
Fever, H/A, adenopathy, occ. RUQ pain, rash
Single or multiple eschars (vesicular)
Diagnosis: PCR, MIF, Western Blot, culture
Complications unusual
Therapy: doxycycline (possibly single-dose)
Amblyomma variegatum (female).
Parola P, Raoult D. et al. Am J Trop Med Hyg 1999;60:888-93.
Tick Borne Rickettsial Lesions:
“Tache noire”
PHILIPPE PAROLA, GUY VESTRIS, DOMINIQUE MARTINEZ, BERNARD BROCHIER, VERONIQUE ROUX,
DIDIER RAOULT. Am. J. Trop. Med. Hyg., 60(6), 1999, pp. 888–893
Four Inoculation Eschars (Arrows) on the Legs of a Patient Who Presented with
African Tick-Bite Fever after Returning from a Safari in South Africa
Raoult D et al. N Engl J Med 2001;344:1504-1510
4 9/27/15 Figure 1. Fibrinoid necrosis of a vessel in the dermis (arrow) with
perivascular inflammatory infiltrates mainly composed of
polymorpho-nuclear leukocytes (hematoxylin-eosin-saffron; orig.
magnification ×250).
Hubert Lepidi,Pierre-Edouard Fournier,& Didier Raoult,Université de la Méditerranée, Marseille, France Vol.12,No.
9 Sept2006
Figure 3. Inoculation eschar from a patient with African tick-bite
fever showing numerous dermal inflammatory infiltrates mainly
composed of polymorphonuclear leukocytes (immunoperoxidase
staining with an anti-CD15 antibody; original magnification ×100).
Hubert Lepidi,Pierre-Edouard Fournier,& Didier Raoult,Université de la Méditerranée, Marseille, France Vol.12,No.
9 Sept2006
Clinical Characteristics of
R.africae infection
Figure 5. Immunohistochemical detection of Rickettsia africae in
the inoculation eschar of a pt with African tick-bite fever. Note
location of the bacteria in the endothelial and inflammatory cells of
a blood vessel in the dermis (arrow);monoclonal rabbit anti-R.
africae antibody used at a dilution of 1:1,000 & hematoxylin
counterstain; orig. magnification ×250.
•  Fever > 38.5
•  Neck myalgias
•  Inoculation
eschars
•  Multiple eschars
•  Lymphadenopathy
•  Rash (vesicular)
•  Death
• 
• 
• 
• 
• 
• 
• 
88%
81%
95%
54%
43%
46% (45%)
0%
Raoult D, et al. NEJM 2001;344:1504-10.
Hubert Lepidi,Pierre-Edouard Fournier,& Didier Raoult,Université de la Méditerranée, Marseille, France Vol.12,No.
9 Sept2006
Rickettsial Disease in the
Returning Traveler
•  R.africae > murine typhus (R.typhae) >
mediterranean spotted fever > scrub typhus
•  Also RMSF, epidemic typhus, N. Asian,
Queensland tick typhus
•  Approx. 3rd most likely etiology of fever
in the returning traveler after malaria and
typhoid fever
Treatment of African Tick Bite Fever
(Lyme, RMSF, Ehrlichia)
doxycycline
Jensenius M, et al. Clin Infec Dis 2004;39:1493-9; Intl J Infec Dis 2004;8:139-46.
5 9/27/15 Viral Hemorrhagic Fevers
Emerging Infections: Ebola Virus Disease
Flaviviridae
(dengue, yellow fever,
TBE encephalitides)
Arenaviridae
(Lassa, Junin, Machupo, Guanarito)
Enveloped
RNA viruses
Bunyaviridae
(CCHF, RVF,
Hantaviruses)
Filoviridae
(Ebola, Marburg)
Ebola Taxonomy
Scientific Classification
Copyrighted
Dr. Fre:derick A. Murphy, D.V.M., Ph.D. 1976.
Order: Mononegavirales
Family: Filoviridae
Genus: Ebola like viruses
Species: Ebola
Subtypes
–  Ebola-Zaire, Ebola-Sudan,Ebola-Ivory Coast
•  disease in humans
–  Ebola-Reston
•  disease in nonhuman primates
• 
Ebola virus and Marburg virus are most well known and studied
• 
Other viruses: Sudan virus, Bundibugyo virus, Tai Forest virus, Reston virus,
Ravn virus
Viruses without borders
Ebola Virus
q 
Prototype Viral Hemorrhagic
Fever Pathogen
§  Filovirus: enveloped,
non-segmented, negativestranded RNA virus
§  Severe disease with high
case fatality
§  Absence of specific
treatment or vaccine
q 
>20 previous Ebola and
Marburg virus outbreaks
q 
2014 West Africa Ebola
outbreak caused by
Zaire ebolavirus species
(five known Ebola virus
species)
36
6 9/27/15 Epidemiology and ecology are intimately linked
Ebola Virus
q 
Zoonotic virus – bats the most likely reservoir, although
species unknown
q 
Spillover event from infected wild animals (e.g., fruit bats,
monkey, duiker) to humans, followed by human-human
transmission
37
Current Ebola virus outbreak
Figure. Ebola virus disease (EVD) cumulative
incidence* — West Africa, October 18, 2014
* Cumulative number of reported EVD cases per 100,000 persons since December 22, 2013.
MMWR 2014;63(43):978-981
(graphics: BBC)
40
2014 Ebola Outbreak, West Africa
EVD Cases and Deaths*
Reporting
Date
Total Cases
Confirmed
Cases
Guinea
27 Oct 14
1,906
1,391
997
Liberia
25 Oct 14
6,535
2,515
2,413
Sierra Leone
27 Oct 14
5,235
3,700
1,500
Nigeria**
15 Oct 14
20
19
8
Spain
27 Oct 14
1
1
0
Senegal**
15 Oct 14
1
1
0
United States
24 Oct 14
4
4
1
Mali
23 Oct 14
1
1
1
13,733
7,632
4,920
TOTAL
Total Deaths
Updated case counts available at http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html.
*Reported by WHO using data from Ministries of Health
**The outbreaks of EVD in Senegal and Nigeria were declared over on October 17 and 19, respectively.
WHO Ebola Response Team. N Engl J Med 2014. DOI: 10.1056/NEJMoa1411100
http://www.nejm.org/doi/full/10.1056/NEJMoa1411100?query=featured_ebola#t=articleResults
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7 9/27/15 EVD Cases (United States)
q 
EVD Cases (United States)
As of October 24, 2014, EVD has been diagnosed in the United
States in four people, one (the index patient) who traveled to Dallas,
Texas from Liberia, two healthcare workers who cared for the index
patient, and one medical aid worker who traveled to New York City
from Guinea
q 
§  Index patient – Symptoms developed on September 24, 2014 approximately
four days after arrival, sought medical care at Texas Health Presbyterian Hospital
of Dallas on September 26, was admitted to hospital on September 28, testing
confirmed EVD on September 30, patient died October 8.
As of October 31, 2014, four U.S. health workers and one
journalist who were infected with Ebola virus in West Africa
were transported to hospitals in the United States for care
§  All the patients have recovered and have been released from the
hospital after laboratory testing confirmed that they no longer
have Ebola virus in their blood
§  TX Healthcare Worker, Case 2 – Cared for index patient, was self-monitoring
and presented to hospital reporting low-grade fever, diagnosed with EVD on
October 10, recovered and released from NIH Clinical Center October 24.
§  TX Healthcare Worker, Case 3 – Cared for index patient, was self-monitoring
and reported low-grade fever, diagnosed with EVD on October 15, recovered and
released from Emory University Hospital in Atlanta October 28.
§  NY Medical Aid Worker, Case 4 – Worked with Ebola patients in Guinea, was
self-monitoring and reported fever, diagnosed with EVD on October 24, currently
in isolation at Bellevue Hospital in New York City.
Information on U.S. EVD cases available at http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/united-states-imported-case.html.
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44
Modes of Transmission
Ebola Virus Transmission
q 
Virus present in high quantity in blood, body fluids, and
excreta of symptomatic EVD-infected patients
q 
Opportunities for human-to-human transmission
3 most common
modes of infection:
§  Direct contact (through broken skin or unprotected mucous
membranes) with an EVD-infected patient’s blood or body fluids
§  Sharps injury (with EVD-contaminated needle or other sharp)
§  Direct contact with the corpse of a person who died of EVD
§  Indirect contact with an EVD-infected patient’s blood or body
fluids via a contaminated object (soiled linens or used utensils)
q 
1.  Unsterilized needles
2.  Suboptimal hospital
conditions
3.  Personal contact
Ebola can also be transmitted via contact with blood, fluids,
or meat of an infected animal
§  Limited evidence that dogs become infected with Ebola virus
§  No reports of dogs or cats becoming sick with or transmitting
Ebola
http://www.ecplanet.com/pic/2003/12/1071257871/ebola.jpg
45
Detection of Ebola Virus in Different
Human Body Fluids over Time
Human-to-Human Transmission
q 
Infected persons are not contagious until onset of
symptoms
q 
Infectiousness of body fluids (e.g., viral load) increases as
patient becomes more ill
§  Remains from deceased infected persons are highly infectious
q 
47
Human-to-human transmission of Ebola virus via inhalation
(aerosols) has not been demonstrated
48
8 9/27/15 Personal Protec,ve Equipment (PPE) Risks to healthcare workers
•  Health workers treating patients with suspected/
confirmed illness at higher risk of infection
–  Only time people transmit disease is when they
are symptomatic
–  Overwhelmingly viremic when symptomatic
•  General public is generally safe
•  Updated guidance for hospital-based
healthcare workers released 10/20/14
•  Guiding principles:
–  Rigorous training so all are practiced
and competent with PPE, including
taking on and off
–  No skin exposure when PPE is worn
–  Supervision by trained monitor when
taking PPE on and off.
EVD Risk Assessment
Ebola Virus Pathogenesis
q 
Direct infection of tissues
q 
Immune dysregulation
q 
Hypovolemia and vascular collapse
§  Electrolyte abnormalities
§  Multi-organ failure, septic shock
q 
**CDC Website to check current affected areas: www.cdc.gov/vhf/ebola
Disseminated intravascular coagulation (DIC)
and coagulopathy
Lancet. Mar 5, 2011; 377(9768): 849–862.
52
Ebola Pathogenesis
•  Enters Bloodstream
–  skin, membranes,open wounds
•  Cell Level
–  docks with cell membrane
•  Viral RNA
–  released into cytoplasm
–  production new viral proteins/ genetic material
Copyright: Russell Kightley Media, Australia
Ebola Pathogenesis, cont
•  Viral cores
– 
– 
– 
– 
– 
stack up in cell
migrate to the cell surface
produce trans-membrane proteins
push through cell surface
become enveloped by cell membrane
•  ssRNA- Genome Mutations
–  capable of rapid mutation
–  very adaptable to evade host defenses and environmental change
•  New viral genomes
–  rapidly coated in protein
–  create cores
•  Theory
–  virus evolved to occupy special niches in the wild
9 9/27/15 Clinical Features
Early Clinical Presentation
q 
Acute onset; typically 8–10 days after exposure
(range 2–21 days)
q 
Signs and symptoms
q 
§  Hypovolemic shock and multi-organ failure
§  Hemorrhagic disease
§  Death
§  Initial: Fever, chills, myalgias, malaise, anorexia
§  After 5 days: GI symptoms, such as nausea, vomiting, watery
diarrhea, abdominal pain
§  Other: Headache, conjunctivitis, hiccups, rash, chest pain,
shortness of breath, confusion, seizures
§  Hemorrhagic symptoms in 18% of cases
q 
Nonspecific early symptoms progress to:
Other possible infectious causes of symptoms
q 
Non-fatal cases typically improve 6–11 days after
symptoms onset
q 
Fatal disease associated with more severe early
symptoms
§  Fatality rates of 70% have been reported in rural Africa
§  Intensive care, especially early intravenous and
electrolyte management, may increase the survival
rate
§  Malaria, typhoid fever, meningococcemia, Lassa fever and other
bacterial infections (e.g., pneumonia) – all very common in Africa
55
Hemorrhagic Manifestations
Clinical Manifestations by Organ System
in West African Ebola Outbreak
Organ System
Clinical Manifestation
General
Fever (87%), fatigue (76%), arthralgia (39%), myalgia (39%)
Neurological
Headache (53%), confusion (13%), eye pain (8%), coma (6%)
Cardiovascular
Chest pain (37%),
Pulmonary
Cough (30%), dyspnea (23%), sore throat (22%), hiccups (11%)
Gastrointestinal
Vomiting (68%), diarrhea (66%), anorexia (65%), abdominal pain
(44%), dysphagia (33%), jaundice (10%)
Hematological
Any unexplained bleeding (18%), melena/hematochezia (6%),
hematemesis (4%), vaginal bleeding (3%), gingival bleeding
(2%), hemoptysis (2%), epistaxis (2%), bleeding at injection site
(2%), hematuria (1%), petechiae/ecchymoses (1%)
Integumentary
Conjunctivitis (21%), rash (6%)
56
•  Skin hemorrhages:
petechiae, purpura, ecchymoses
•  Gingival bleeding
•  Nasal bleeding
•  Gastro-intestinal bleeding:
hematemesis, melena, hematochezia
•  Hematuria
•  Increased menstrual flow
WHO Ebola Response team. NEJM. 2014
57
Examples of Hemorrhagic Signs
Hematemesis
Gingival bleeding
Bleeding at IV Site
59
10 9/27/15 Laboratory Findings
q 
Thrombocytopenia (50,000–100,000/µL range)
q 
Leukopenia followed by neutrophilia
q 
Transaminase elevation: elevation serum aspartate aminotransferase (AST) > alanine transferase (ALT)
q 
Electrolyte abnormalities from fluid shifts
q 
Coagulation: PT and PTT prolonged
q 
Renal: proteinuria, increased creatinine
62
EVD: Expected diagnostic test results over
time
Diagnosis
Critical information: Date of onset of fever/symptoms
IgM
IgG
viremia
0
3
10
Timeline of infection Diagnostic tests available Within a few days after onset
§  Antigen-capture enzyme-linked
immunosorbent assay (ELISA)
testing
§  IgM ELISA
§  Polymerase chain reaction
(PCR)
§  Virus isolation
§  Serology: IgM and IgG days post onset of symptoms
Later in disease course or after
recovery Fever
RT-PCR
Retrospectively in deceased
patients ELISA IgM
ELISA IgG
IgM: up to 3 – 6 months
§  Immunohistochemistry testing
§  PCR
§  Virus isolation IgG: 3 – 5 years or more (life-long persistance?)
63
Ebola Virus Diagnosis
q 
Other Ebola Virus Diagnostics
Real Time PCR (RT-PCR)
q 
§  Performed in select CLIA-certified laboratories
q 
Virus isolation
§  Requires Biosafety Level 4 laboratory;
§  Can take several days
§  Used to diagnose acute infection
§  More sensitive than antigen detection ELISA
§  Identification of specific viral genetic fragments
q 
Immunohistochemical staining and histopathology
q 
Serologic testing for IgM and IgG antibodies (ELISA)
§  On collected tissue or dead wild animals; localizes viral antigen
RT-PCR sample collection
§  Detection of viral antibodies in
specimens, such as blood, serum,
or tissue suspensions
§  Monitor the immune response
in confirmed EVD patients
§  Volume: minimum volume of 4mL whole blood
§  Plastic collection tubes (not glass or heparinized tubes)
§  Whole blood preserved with EDTA is preferred
•  Whole blood preserved with sodium polyanethol sulfonate (SPS),
citrate, or with clot activator is acceptable
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11 9/27/15 Research on filoviruses requires maximum containment: biocontainment laboratory designa,ons Laboratories
q 
CDC has developed interim
guidance for U.S. laboratory
workers and other healthcare
personnel who collect or handle
specimens
q 
This guidance includes information
about the appropriate steps for
collecting, transporting, and
testing specimens from patients
who are suspected to be infected
with Ebola
q 
Specimens should NOT be
shipped to CDC without
consultation with CDC and local/
state health departments
Biosafety level 1 (BSL-1)
Organisms (agents) not known to cause disease in healthy human adults.
Biosafety level 2 (BSL-2)
Agents known to pose a potentially moderate risk to health
Herpes simplex virus, rabies virus
Biosafety level 3 (BSL-3)
Agents known to cause serious or potentially lethal disease as a result of exposure
by inhalation
West Nile virus, SARS
Biosafety level 4 (BSL-4)
Agents known to pose a high risk of lethal disease, which may be transmitted by the
aerosol route, and for which there is not vaccine or therapy.
Ebola virus
Information available at:
http://www.cdc.gov/vhf/ebola/hcp/interim-guidance-specimen-collection-submissionpatients-suspected-infection-ebola.html
Packaging & Shipping Clinical Specimens to CDC for Ebola
Testing
68
Interpreting Negative Ebola RT-PCR
Result
q 
If symptoms started ≥3 days before the negative result
§  EVD is unlikely à consider other diagnoses
§  Infection control precautions for EVD can be discontinued unless
clinical suspicion for EVD persists
q 
If symptoms started <3 days before the negative
RT-PCR result
§  Interpret result with caution
§  Repeat the test at ≥72 hours after onset of symptoms
§  Keep in isolation as a suspected case until a repeat RT-PCR ≥72
hours after onset of symptoms is negative
http://www.cdc.gov/vhf/ebola/hcp/packaging-diagram.html
69
Clinical Management of EVD:
Supportive, but Aggressive
q 
Investigational Therapies for EVD Patients
q 
§  Therapeutics in development with limited human clinical trial
data
•  Convalescent serum
Electrolyte and acid-base abnormalities
•  Therapeutic medications
§  Aggressive electrolyte repletion
§  Correction of acid-base derangements
q 
Symptomatic management of fever and gastrointestinal
symptoms
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
§  Avoid NSAIDS
q 
No approved Ebola-specific prophylaxis or treatment
§  Ribavirin has no in-vitro or in-vivo effect on Ebola virus
Hypovolemia and sepsis physiology
§  Aggressive intravenous fluid resuscitation
§  Hemodynamic support and critical care management if
necessary
q 
70
•  Chimpanzee-derived adenovirus with an Ebola virus gene inserted
Multisystem organ failure can develop and may require
•  Attenuated vesicular stomatitis virus with an Ebola virus gene
inserted
§  Oxygenation and mechanical ventilation
§  Correction of severe coagulopathy
§  Renal replacement therapy
1Huggins,
References:
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 1999 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.
Reference: Fowler RA et al. Am J Respir Crit Care Med. 2014
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12 9/27/15 Historical Vaccine Challenges:
NEJM Webcast October 22, 2014
Strain Variation
q 
•  In 2005, Jones & his colleagues, Dr. Heinz Feldmann of
Winnipeg and Dr. Thomas Geisbert at Fort Detrick, Maryland
announced that they had successfully vaccinated monkeys
against the deadly Ebola virus
Not effective:
§  Ribavirin
§  Corticosteroids
§  Activated Protein C
§  Heparin
•  This Ebola vaccine was based on the 1976 strain of the Zaire
species and protected from the 1995, but not the other 2
species that affect humans.
Most promising agent:
- small interfering RNA (“Tekmira”)
Hampton, Tracy. Vaccines Against Ebola and Marburg Viruses Show Promise in Primates Studies. Maedical News
and Perspectives. JAMA. Vol. 294 No. 2 July 2005. Jones, Steven. Live attenuated recombinant vaccine protects
nonhuman primates against Ebola and Marburg viruses. Nature Medicine. Vol. 11 No. 7 July 2005.
NEJM Webcast October 22, 2014
NEJM Webcast October 22, 2014
•  Homes of nurses who developed fever did not need
special cleaning, only the home of patient zero
needed decontamination
•  Infectivity is near zero on surfaces
•  No airborne transmission; so N95 or PAC mask
is adequate
•  There was no need to clean the plane the second
infected nurse was traveling on, since she was
feeling well when she boarded the plane
•  Cover all skin. Designate a supervisor to watch
employees put on & take off PPE; stop &
decontaminate gown or gloves with bleach if
gown visibly contaminated before removal
•  Best to test by RT-PCR on or after 3rd day of
symptoms
•  Lifetime immunity
Practical Considerations for Evaluating
Patients for EVD in the United States
Patient Recovery
q 
Case-fatality rate 71% in the 2014 Ebola outbreak
§  Case-fatality rate is likely much lower with access to intensive
care
q 
q 
§  Ask patients with symptoms about a history of travel to West
Africa in the 21 days before illness onset
§  Know the signs and symptoms of EVD
§  Know the initial steps to take if a diagnosis of EVD is suspected
Patients who survive often have signs of clinical
improvement by the second week of illness
§  Associated with the development of virus-specific antibodies
§  Antibody with neutralizing activity against Ebola persists greater
than 12 years after infection
q 
CDC encourages all U.S. healthcare providers to
q 
Prolonged convalescence
CDC has developed documents to facilitate these
evaluations
§  The EVD algorithm for the evaluation of a returned traveler
§  Includes arthralgia, myalgia, abdominal pain, extreme fatigue,
and anorexia; many symptoms resolve by 21 months
§  Significant arthralgia and myalgia may persist for >21 months
§  Skin sloughing and hair loss has also been reported
•  Available at http://www.cdc.gov/vhf/ebola/pdf/ebola-algorithm.pdf
§  The checklist for evaluation of a patient being evaluated for EVD
•  Available at
http://www.cdc.gov/vhf/ebola/pdf/checklist-patients-evaluated-usevd.pdf
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.
77
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13 9/27/15 EVD Algorithm for
Evaluation of the
Returned Traveler
**CDC Website to check current affected areas: www.cdc.gov/vhf/ebola
Algorithm available at http://www.cdc.gov/vhf/ebola/pdf/ebola-algorithm.pdf
Checklist available at http://www.cdc.gov/vhf/ebola/pdf/checklist-patients-evaluated-us-evd.pdf
79
Interim Guidance for Monitoring and
Movement of Persons with EVD Exposure
q 
EVD Summary
CDC has created guidance for monitoring people exposed
to Ebola virus but without symptoms
RISK LEVEL
PUBLIC HEALTH ACTION
Monitoring
Restricted
Public Activities
Restricted
Travel
Direct Active Monitoring
Yes
Yes
SOME risk
Direct Active Monitoring
Case-by-case
assessment
Case-by-case
assessment
LOW risk
Active Monitoring
for some;
Direct Active Monitoring
for others
No
No
NO risk
No
No
No
HIGH risk
q 
The 2014 Ebola outbreak in West Africa is the largest in
history and has affected multiple countries
q 
Think Ebola: U.S. healthcare providers should be aware of
clinical presentation and risk factors for EVD
q 
Human-to-human transmission by direct contact
§  No human-to-human transmission via inhalation (aerosols)
§  No transmission before symptom onset
q 
Early case identification, isolation, treatment and effective
infection control are essential to prevent Ebola
transmission
www.cdc.gov/vhf/ebola/hcp/monitoring-and-movement-of-persons-with-exposure.html
82
Basic Research
•  The assembly of Ebola virus nucleocapsid requires virionassociated proteins 35 and 24 and posttranslational
modification of nucleoprotein
•  Report describes distinct VP35 and VP24 proteins mechanism of
regulation for filovirus assembly
•  suggests new approaches for viral therapies and vaccines for Ebola
and related viruses
•  Detection of antibodies against the four subtypes of Ebola
virus in sera from any species using a novel antibody-phage
indicator assay
For more information, please contact Centers for Disease Control and Prevention
1600 Clifton Road NE, Atlanta, GA 30333
Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348
Visit: www.atsdr.cdc.gov | Contact CDC at: 1-800-CDC-INFO or www.cdc.gov/info
•  assesses the presence of specific antibodies in serum
•  describes development of a novel assay for the detection of
seroconversion irrespective of Ebola virus subtype or animal
species
The findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the Centers for Disease Control and
Prevention.
Centers for Disease Control and Prevention
Office of the Director
CS252465
83
14 9/27/15 References
• 
Reemergence of Ebola Virus in Africa; Anthony Sanchez et al,EID Volume 1 * Number 3 July-September 1995
http://www.cdc.gov/ncidod/EID/vol1no3/sanchez.htm
• 
Viral Hemorrhagic Fever, Healthlink, Medical College of Wisconsin, 2000
http://healthlink.mcw.edu/article/955159073.html
• 
Isolation and Phylogenetic Characterization of Ebola Viruses Causing Different Outbreaks in Gabon
Emerging Infectious Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention ,February 5, 1997
http://www.cdc.gov/ncidod/EID/vol3no1/courbot2.htm
• 
Hemorrhagic fevers; Julia Barrett, Gale Encyclopedia of Medicine, Gale Research, 1999
http://www.findarticles.com/cf_dls/g2601/0006/2601000652/p1/article.jhtm
l
Key Issues in the Prevention and Control of Viral Hemorrhagic Fevers Clarence J.Peters, MD, Special Pathogens Branch/Division of Viral and
Rickettsial Diseases, National Center for Infectious Diseases/Centers for Disease Control and Prevention, 1997
http://www.cdc.gov/od/ohs/sympsium/symp43.htm
• 
Scientific Stock Images Library; Russell Kightley Media,Australia
http://www.rkm.com.au/imagelibrary/index.html
• 
Outbreak of Ebola Hemorrhagic Fever ---Uganda, August 2000--January 2001,
Morbidity and Mortality Weekly Report, Vol 50, No 05;73, 02/09/2001 / 50(05);73-7
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5005a1.htm
• 
Ebola-Reston Virus Infection Among Quarantined Nonhuman Primates -- Texas, 1996
Morbidity and Mortality Weekly Report, Vol 45, No 15;314 ,April 19, 1996 / 45(15);314-316
http://www.cdc.gov/mmwr/preview/mmwrhtml/00040920.htm
The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein,
Huang Y et al, Mol Cell. 2002 Aug;10(2):307-16. PMID: 12191476 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12191476&dopt=Abstract
Detection of antibodies against the four subtypes of ebola virus in sera from any species using a novel antibody-phage indicator assay.; Meissner
F et al , PMID: 1235035
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12350354&dopt=Abstract
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