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2017: Re-emerging and
Emerging Infections
Richard Whitley, M.D.
South Carolina Chapter of the AAP
Asheville, North Carolina
August 12, 2017
Disclosures
• I am on the Board of Gilead Sciences and will not
discuss any of their products
• I have received remuneration from the NIH and IDSA
(Associate Editor JID)
• I serve on Data Safety and Monitoring Boards for clinical
trials sponsored by the NIH, GSK, and Merck
• My grant support is from NIAID, NIH
• I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation.
Objectives
• Appreciate the reappearance of vaccine
preventable childhood infections
• Understand the threat of mosquito borne
viral diseases, particularly in the Southern
US
• Know the potential for importation of
infectious diseases threats in the US
A New World of Infectious
Diseases
Re-Emerging (Vaccine Preventable)
Diseases
• Pertussis
• Mumps
• Measles
• Don’t Forget Influenza
PERTUSSIS
Highly contagious respiratory infection caused by Bordetella pertussis
Outbreaks first described in 16th Century
Bordetella pertussis isolated in 1906
Estimated 294,000 deaths worldwide in 2002
Increase in Pertussis Cases
U.S. Reported Pertussis Cases,
1990-2010**2010 data are provisional.
CDC, National Notifiable Diseases Surveillance System and Supplemental Pertussis Surveillance System and 1922-1949,
passive reports to the Public Health Service
Pertussis Cases by Age,
San Diego, CA
Reported Pertussis-Related Deaths
by Age Groups, U.S., 1980-2009
Age-group 1980-19891 1990-19991 2000-20092
0-1 month 38 68 152
2-3 months 11 16 23
4-5 months 5 5 2
6-11 months 7 4 1
1-4 years 13 2 2
5-10 years 1 6 3
11-18 years 0 0 3
>18 years 1 2 8
Total 77* 103 194
1 Vitek CR et al. Pediatr Infect Dis J 2003; 22(7):628-34.
2 National Notifiable Diseases Surveillance System, CDC, 2009
* Includes one case with unknown age
Pertussis Immunization
in the United States• Whole-cell vaccines / DTwP (1940s)
• DTaP (1990s)
– Infants at 2, 4, 6 months (1997)
– Toddlers at 15-18 months (1992)
– Pre-school at 4-6 years (1992)
• Tdap
– Adolescents at 11-12 years (2005)
– Adults who have not received (2005)
MUMPS OUTBREAKS
MUMPS 2017
CASES OF MEASLES USA
• 2010 63
• 2011 220
• 2012 55
• 2013 187
• 2014 667
• 2015 188
• 2016 70 (incomplete data set)
• 2017 108 (in progress)
Hemagglutinin (H) – 16 subtypes
(attachment, penetration)
Neuraminidase (N) – 9 subtypes
(release)
8 viral genes
(assembly, replication)
M2 protein
(penetration)
Influenza A Virus
Influenza Virus
A/Fujian/411/2002 (H3N2)
Neuraminidase
Hemagglutinin
Type of nuclear
material
Virus
type
Geographic
origin
Strain
number
Year of
isolation
Virus
subtype
Influenza Virus Strains
• Type A– moderate to severe illness
– affects all age groups
– affects humans and other animals (particularly migratory waterfowl)
• Type B– milder disease
– primarily affects children
– humans only
Impact of Influenza
• Approximately 36,000 influenza-
associated deaths during each influenza
season
• Persons 65 years of age and older
accounted for more than 90% of deaths
• The number of deaths and cost to society
from influenza is likely to increase as the
nation’s population ages
INFLUENZA ACTIVITY JUNE
2017
LRI CLINIC VISITS 2016-1017
INFLUENZA 2016-2017
INFLUENZA TYPES 2016-2017
Recently Approved Influenza
Vaccines• Quadrivalent live-attenuated influenza vaccine (LAIV4),
or Flumist Quadrivalent (MedImmune) Do Not Use
• Quadrivalent inactivated influenza vaccine (IIV4), or
Fluarix Quadrivalent (GSK)
• Trivalent cell-culture based inactivated influenza vaccine
(ccIIV3), or Flucelvax (Novartis)
• Trivalent recombinant hemagglutinin vaccine (RIV3), or
FluBlok (Protein Sciences)
• Quadrivalent inactivated influenza vaccine (IIV4), or
Fluzone Quadrivalent (sanofi pasteur).
Influenza
Antigenic Drift and Antigenic
ShiftHemagglutinin
Neuraminidase
Antigenic Shift:
Recombinant
changes in
antigenicity
Antigenic Drift:
Mutations result
in changes in
antigen shape
Influenza Vaccine 2017
• For 2017-2018, three-component vaccines are
recommended to contain:– an A/Michigan/45/2015 (H1N1)pdm09-like virus
– an A/Hong Kong/4801/2014 (H3N2)-like virus
– a B/Brisbane/60/2008-like (B/Victoria lineage) virus
• Four-component vaccines, which protect against
a second lineage of B viruses, are
recommended to be produced using the same
viruses recommended for the trivalent vaccines,
as well as a B/Phuket/3073/2013-like
(B/Yamagata lineage) virus.
Information for Healthcare
Providers• NNII (www.immunizationinfo.org)
• VEC (www.vaccine.chop.edu)
• IAC (www.immunize.org)
• CDC/NIP (www.cdc.gov/nip)
• AAP (www.aap.org)
• AAFP (www.aafp.org/)
• IVS (www.vaccinesafety.edu)
• Vaccine Page (www.vaccines.org)
• Every Child by Two (www.ecbt.org)
• PKIDS (www.pkids.org/)
THE WORLD OF INFECTIOUS DISEASES: IT IS OUR
WORLD
RE-EMERGING
INFECTIONS
EMERGINGINFECTIONS
20152010200520001995199019851980
HIV/AIDSMONKEY
POX
WESTNILE VIRUS SARS
PANDEMICINFLUENZA
MERS
EBOLA
CHIKUNGUNYA
DENGUEAnd E68, E71
H3N2INFLUENZA
and Zika
H9N5HDAI
MEASLES
PERTUSIS
Emerging Infections
• Respiratory Infections
– MERS
• Mosquito Borne Diseases
– West Nile
– Chikengunya
– Zika
• Contact/Bush Meat
– Ebola
Respiratory Tract Infections:
Coronaviruses: SARS/MERS
MERS CoronavirusOngoing 2017 MERS Outbreak
MERS Advisory
Mosquito Borne Diseases:
West Nile Virus
Zika
Chikungunya
Dengue*
* For another day
West Nile Virus Transmission
Cycle
Mosquito Vectors
• Predominantly Aedes aegypti and Aedes
albopictus
• Same mosquitos that transmit dengue and
zika
• Widely distributed throughout Americas
• Aggressive daytime bitersAedes aegypti Aedes albopictus
Ranges of A. aegypti and A. albopictus in the United States (March 2016).
Petersen LR et al. N Engl J Med 2016;374:1552-1563
WNV 2016
WNV NEUROINVASIVE
DISEASE: 2017
WNV Cases in the United
States
1999-2017
Neuroinvasive Non-Neuroinvasive Total Deaths (%)
2016 1,140 898 2,038 94 (4.6)
All 24,560 24,560 43,937 2,005 (4.6)
Zika: 2017
Zika Virus Transmission Cycle.
Petersen LR et al. N Engl J Med 2016;374:1552-1563
Areas in Which Human Zika Virus Infections Have Been Noted in the Past Decade (March 2016).
Petersen LR et al. N Engl J Med 2016;374:1552-1563
Attack Rates for Confirmed and Probable Zika Virus Disease per 1000 Population
Duffy MR et al. N Engl J Med 2009;360:2536-2543
Attack Rates for Confirmed and Probable Zika Virus Disease on Yap By Age
Duffy MR et al. N Engl J Med 2009;360:2536-2543
Clinical Characteristics of 31 Patients with Confirmed Zika Virus Disease on Yap Island
Duffy MR et al. N Engl J Med 2009;360:2536-2543
Cases of ZIKV Infection and the Guillain–Barré Syndrome in Colombia.
Parra B et al. N Engl J Med 2016;375:1513-1523
US Zika Cases
Zika CNS Disease
Zika Cases Identified in 2017
• Symptomatic Cases: Continental US
– 140 cases
– All from overseas travel
• Symptomatic Cases: US Territories
– 510 Cases
• 470 Puerto Rico
Microscopic Analysis of Brain Tissue
Mlakar J et al. N Engl J Med 2016;374:951-958
Human Clinical CHIKV Disease• Human infection is characterized by fever
(>38.9°C), rash, and polyarthritis
• 90-100% patients develop arthritis: very painful,
usually symmetrical, and involves more than one
joint
• Joints most commonly affected include: fingers,
wrists, elbows, toes, ankles, and knees.
• Injured joints are more susceptible to CHIKV
polyarthritis
• Tendon and muscle pain are also common
• ARTHRITIS LASTS FOR A LONG TIME AFTER
INFECTION HAS BEEN CONTROLLED
• To date there are no approved Vaccines or
Therapeutics against CHIKV
Chikungunya virus infection
• Majority (72-97%) of infected people
develop clinical symptoms
• Incubation period is usually 3-7 days
(range of 1-12 days)
• Primary clinical symptoms are fever and
polyarthralgia
Chikungunya virus in the United
States• Chikungunya virus is not currently found in the U.S.
• From 2006-2009, 106 laboratory-confirmed
chikungunya cases identified in travelers visiting or
returning to U.S., but none triggered a local
outbreak in U.S.
• With outbreaks in Caribbean, number of
chikungunya cases among U.S. travelers will likely
increase
• Imported cases may result in virus introduction and
local spread in some areas of the U.S.
CHIKV Outbreaks: Worldwide Epidemic
Three CHIKV Genotypes: Asian, West African, and East/Central/South African (ECSA)
Asian Genotype
ECSAA226V
ECSA
Asian
ECSAA226V
Chikungunya virus in the Americas*
• Seven Caribbean Countries
have reported locally acquired
cases
• > than 1,000 laboratory-
confirmed cases have been
reported
• Virus expected to spread to
new areas
*As of February 10, 2014
PREVENTION
Protect from mosquito bites
Ebola Virus Disease
Centers for Disease Control and Prevention
Office of the Director61
Ebola Virus
Prototype Viral Hemorrhagic
Fever Pathogen
Filovirus: enveloped,
non-segmented, negative-
stranded RNA virus
Severe disease with high
case fatality
Absence of specific
treatment or vaccine
>20 previous Ebola and
Marburg virus outbreaks
2014 West Africa Ebola
outbreak caused by
Zaire ebolavirus species
(five known Ebola virus
species)
62
Ebola Virus Zoonotic virus – bats the most likely reservoir, although
species unknown
Spillover event from infected wild animals (e.g., fruit bats, monkey, duiker) to humans, followed by human-human transmission
63
Ebola virus disease (EVD) cumulative incidence* —
West Africa, January 14, 2015
* Cumulative number of reported EVD cases to WHO
66
2014 Ebola OutbreakReported Cases in Guinea, Liberia, and Sierra Leone
This graph shows the cumulative reported cases in Guinea, Liberia, and Sierra Leone provided in WHO situation
reports beginning on March 25, 2014 through the most recent situation report on January 14, 2015.
67
EVD Cases and 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, Nigeria, Spain, and the United States have ended.
68
Reporting Date Total Cases Confirmed Cases Total Deaths
Guinea 13 Jan 15 2,825 2,525 1,829
Liberia 12 Jan 15 8,362 3,127 3,556
Sierra Leone 13 Jan 15 10,186 7,825 3,083
Mali 23 Nov 14 8 7 6
United Kingdom 29 Dec 14 1 1 0
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
TOTAL 21,408 13,510 8,483
Symptoms of Ebola• Initial symptoms are nonspecific - may include fever, chills, myalgias, and malaise.
• Patients can progress to develop gastrointestinal symptoms:– severe watery diarrhea, nausea, vomiting, abdominal pain
• Other symptoms: – chest pain, shortness of breath, headache or confusion, conjunctival injection, hiccups,
seizures, and cerebral edema
• Bleeding not universally present but can manifest later as petechiae, ecchymosis/
bruising, or oozing. Frank hemorrhage less common.
• Some develop diffuse erythematous maculopapular rash that can desquamate.
• Most common symptoms reported during current outbreak: – fever (87%)
– fatigue (76%)
– vomiting (68%)
– diarrhea (66%)
– loss of appetite (65%)
• Patients with fatal disease develop more severe clinical signs early during infection
and die between days 6 - 16 of complications (mean of 7.5 days).
• In non-fatal cases, patients may have fever for several days and improve, around
day 6.
• The case fatality proportion in West Africa is about 71% Source: Centers for Disease Control and Prevention. http://www.cdc.gov/vhf/ebola/hcp/clinician-information-us-healthcare-settings.html Accessed Oct. 14, 2014
Examples of Hemorrhagic Signs
Bleeding at IV Site
Hematemesis
Gingival bleeding
70
Ebola Virus Transmission
Virus present in high quantity in blood, body fluids, and excreta of symptomatic EVD-infected patients
Opportunities for human-to-human transmission
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)
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
71
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
72
Patient Recovery Case-fatality rate between 50-70% in the 2014 Ebola
outbreak
Case-fatality rate is likely much 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 antibodies
Antibody with neutralizing activity against Ebola persists greater
than 12 years after infection
Prolonged convalescence 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 reportedReferences: 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.
74
Ebola experimental therapeutics
Company Agent Mechanism In vivo postexposure
efficacy in NHPs*
Reference
Biocryst BCX4430 Putative inhibitor
of EBOV RNA
pol (as TP)
Broad spectrum
antiviral activity
100% protection
against related
Marburg virus
Warren et al,
Nature 2014
Mapp Bio/
LeafBio
ZMapp
(mixture of
MoAbs
produced in
tobacco plant)
Inhibition of
entry by
targeting the GP
env protein
100% protection Qui et al,
Nature 2014
(in press)
Tekmira TKM-Ebola
si RNA delivered
as lipid
nanoparticles
Mixture of
siRNAs targeting
L, VP24, and
VP35
100% protection Geisbert et al,
Lancet 2010
*Tested in cyno/rhesus monkey model with 100% lethality
Alios likely identified nucleosides active against Ebola
- clinical RSV nuc candidate (AL-8112/8176) might be active against Ebola
(Ebola sensitive to nucs active against paramyxoviruses)
GS-466547
(prodrug)
Lead Compound: Activity
Against Ebola
Compound
Anti-Ebola Activity; EC50 [uM]
HMVEC Huh-7Huh-7
(Yield)HeLa HFF-1 Macrophages
GS-441524 0.77 1.5 ND > 20 > 20 > 20
GS-466547 0.12 0.09 0.01 0.24 0.23 0.07
GS-441524
(parent)
Thank You