fatalities by product type
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3/25/2018
1
Brian Custer, PhD, MPHBlood Systems Research Instituteand University of California, San Francisco
TRANSFUSION-TRANSMITTED INFECTIONS – CURRENT ISSUES AND EMERGING CONCERNS35THANNUAL NCASM MEETINGMARCH 3, 2018
Risks of major TTVs linked to interventions, and accelerating rate of EIDs of concern to blood safety
Perkins HA, Busch MP. Transfusion-Associated Infections: 50 Years of Relentless Challenges and Remarkable Progress. Transfusion, 2010; 50(10):2080-99
ZIK
V
Recent arbovirus threats
Fatalities by Product Type
http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/ReportFatalities Reported to FDA Following Blood Collection and Transfusion Annual Summary for FY2016aProblem/TransfusionDonationFatalities/UCM459461.pdf
Evaluating an EID threat to blood safety3 basic questions need to be answered:
Is it in the blood supply?
• Requires the agent have an asymptomatic or ‘silent’ phase
• Requires a way to measure the agent in donors during epidemics
• Estimation of donor risks: prevalence, incidence, duration of detection• Estimation of risk by blood component type
• Temperature, preparation, storage duration effects on infectivity?• Is antibody in the infected donor or co-transfused components protective?
Is it transfusion-transmitted and what is the risk?• Is transmission risk dependent on stage of infection or VL in the
donor/component• Do recipient antibodies from prior infection protect from TT
If transmissible by transfusion, does it have a clinical impact in transfused recipients?
• Is TT disease more or less severe than usual routes of infection
Reducing the Risk of Transfusion-Transmitted Infections
• Donor history• Donor (mini-medical) examination• Testing• Diversion Pouches• Leukoreduction• Post donation information• Donor deferral registries• Limit exposures to transfusion – appropriate indications
• Pathogen reduction/inactivation
HIV viremiaduring early infection
HIV RNA (plasma)HIV Antibody
11
0 10 20 30 40 50 60 70 80 90 100
HIV p24 Ag
16 22
Ramp-up viremia
DT = 21.5 hrs
1st gen2nd gen
3rd gen
p24 Ag EIA -
HIV MP-NAT -
HIV ID-NAT -
Peak viremia: 106-108 gEq/mL
“blip” viremia
Viral set-point:
102 -105 gEq/mL
Closing the WP through improved screening tests
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2
0 5 10 15 20 25 30 60 65
days
103
106
103
106
103
106
viral load
geq/ml
35 40
Kleinman SH Transfusion 2009:49:2454-89
day 38
day 65
1 geq/20 ml
day 3
day 21
eclipse phase
day 15
day 24
day 6
HBV-DNA
HCV-RNA
RNAHIV-Ag Anti-HIV
Anti-HCV
HBsAg
What is the infectious window period?
0
5
10
15
20
25
30
35
40
45
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
No
. of
NA
T y
ield
do
no
rs
HIV HCV
HIV and HCV NAT RNA +/Ab – “Yield” Donors, ARC 1999-2008
244 HCV (1:270,000)
32 HIV (1:2,000,000)
N = 57TT HIV Cases
NAT
9
• Monitor HBV, HCV and HIV in US blood donors by developing and maintaining a complete database including data from participating blood centers representing nearly 60% of the US blood supply
Develop consensus definitions for concordant positives and NAT yields
Daily data exports, QC, data sharing, identification of key units for LRCC
• Perform relevant data analyses; report results
Prevalence
oBy sex, donation status, age, self-reported race/ethnicity, DHHS reporting region
Incidence and Residual Risk
10Transfusion-Transmissible Infections Monitoring System
(TTIMS)
• Perform recency testing on HIV plasma samples from donors with HIV concordant positive donations
• Conduct viral genetic sequence analyses on plasma samples for HIV (NAT yield and seropositive), HCV (NAT yield) and HBV (NAT yield) positive blood donors to determine genotypes and drug resistance (where applicable) of donor infections.
• Lead and support collection and analysis of risk factor data in donors with confirmed infections (cases) and donors who test false positive (controls).
• Risk factors by sex, age groups, self-reported race/ethnicity, donation status, DHHS reporting regions
• Compare risk factor data to those obtained in the REDS-II Viral Marker Prevalence and Donor Risk Factor Study.
Transfusion-Transmissible Infections Monitoring System
(TTIMS)
12TTIMS: 4 Centers of Donations for 24 Months
TTIMS – Sep 2015 - Aug 2017
Year ARC BSI NYBC OB All Centers
Total by Center
9,683,685 1,889,756 748,546 1,608,307 13,930,294
Percentby Center
69.5% 13.6% 5.4% 11.5% 100.0%
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3
*HIV Consensus Positives include HIV Controllers
13TTIMS: Overall Consensus Positive RatesHIV, HBV and HCV prevalence per 100k donations with 95% CI
Sept 2015 - Aug 2017
Consensus Positive Rate in Donations (NAT Yield + Concordant Positive)*
Positives Rate/100k 95% CI
HIV 365 2.6 (2.4 - 2.9)
HBV 912 6.5 (6.1 - 7.0)
HCV 2,762 19.8 (19.1 - 20.6)
A Typical Incidence Assay Dynamic
False-Recent Results
Busch et al. AIDS 2010 24:2763-27
Optimizing the Performance of Recency Assays
• Sedia Limiting Antigen (LAg) Avidity test
• Mean Duration of Recent Infection (MDRI) for HIV clade B:
~130 Days (95% CI 118 – 142 days)
• False Recent Rate (FRR): 1.6%
• Normalized Optical Density (ODn) using internal calibrators for each run
False-Recent Results
Duong et al. PLoS One. 2015 Feb 24;10(2) e0114947
HIV Recency Testing of US Blood Donors
Objective
Classify HIV-positive donors as having recently acquired or longstanding infection
Convenience sample of available plasma specimens from HIV concordant positive donations (confirmed NAT + serology reactive) from all participating organizations Pre-TTIMS Period – existing specimens stored under routine procedures by testing labs/blood
centers
TTIMS Period plasma units retrieved from whole blood donations, aliquoted and placed in repository as part of TTIMS
Analyses
Overall proportion with recently acquired HIV by year and various demographic and donation groups
Categorical groups compared for differences in proportions using χ2 statistics
p < 0.05 considered significant
Period Total
Pre-TTIMS Period 1/2010 – 8/2015 645
TTIMS Period 9/2015 – 3/2017 214
LAg Testing Results by Year
Donation YearRecentn (%)
Total Tested
2010 21 (32.3) 65
2011 48 (28.4) 169
2012 42 (28.0) 150
2013 34 (29.3) 116
2014 33 (34.7) 95
2015* 21 (24.1) 87
2016 34 (25.6) 133
2017 (through Q2)
13 (29.6) 44
No evidence of significant differences by year
* Includes period before and during TTIMS
0
10
20
30
40
50
60
70
80
90
100
2010 2011 2012 2013 2014 2015 2016 2017
Proportion Recent
Pe
rce
nt
LAg Testing Results by Demographics
Donor Characteristic
Recentn (%)
Total p-value
Donation History
Repeat 137 (36.4) 376< 0.0001First-time 109 (22.9) 483
Sex
Male 209 (30.4) 6870.021Female 37 (21.5) 172
Age Group
16-19 71 (44.9) 158
< 0.0001
20-29 119 (35.6) 334
30-39 21 (14.5) 145
40-49 19 (15.2) 125
50+ 16 (16.5) 97
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4
TTIMS HIV Molecular Surveillance
HIV, HBV, HCV1. For HIV, a fragment of 1275 base pairs (bp) of polymerase including the Protease (PR) and Reverse Transcriptase (RT) genes2. For HCV, a fragment of 363 bp in the core gene3. For HBV, a fragment of 2015 bp, including the envelope and polymerase genes
Followed by Next Generation Sequencing (NGS) using MiSeq
Reporting of HIV genotypes and drug resistance
To be reported: HCV and HBV genotypes (and neutralization/drug resistance)
Delwart et al. J Infect Dis. 2012 Mar 15;205(6):875-85.
HIV Subtypes in Initial TTIMS Period
HIV Drug Resistance Mutations
K103N is a nonpolymorphic mutation selected-for in patients receiving Nevirapine and Efavirenz
Flight Traffic Patterns
• https://www.youtube.com/watch?v=G1L4GUA8arY
On an average day over 8,000,000 people travel by airplane
World Distribution and Spread of WNV
Clade 1a
Clade 1b
Clade 1c
Lignage 1
Lignage 2
U.S. WNV Blood Donor Screening Timeline
1Lanciotti, RT, Roehrig JT, Deubel V, Smith J, Parker M, Steele K, et al. Science, 19992Pealer LN, Marfin AA, Petersen LR, Lanciotti RS, Page PL, Stramer SL, Stobierski MG et al. N Engl J Med. 20033Busch MP, Caglioti S, Robertson EF, McAuley, JD, Tobler LH, Kamel H et al. New England J Med, 2005Stramer SL, Fang CT, Foster GA, Wagner AG, Brodsky JP, Dodd RY. N Engl J Med. 2005
4Kleinman SH, Williams JD, Robertson G, Caglioti S, Williams RC, Spizman R et al. Transfusion. 20095Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 20096Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 2013
1 TTI
reported4
MP NAT
adopted3
ID NAT
triggering
adopted3
23 TTIs
reported2
WNV found
in Queens, NY1
1999 2006
1 TTI
reported5
20082002 2003 2004
6 TTIs
reported3
1 TTI
reported3
All transfusion-transmitted infections (TTIs) traced to WNV RNA(+) / Antibody(-) transfusions,
except for 2013 case in which donation had very low VL with IgM and IgG
ID NAT
triggering
enhanced4
ID NAT
triggering
enhanced4
2012
1 TTI
reported6
3/25/2018
5
2003230
2004125
2005123
2006112
2007162
200879
200980
No WNV positive cases during winter months
201076
WNV Positive Donations 2003-2012, CTS N=1370
201148
0
61
130
36
3000000
811
39
46
14
52000000
4
21
51
42
50000000
3
28
53
24
40000000
9
28
75
37
10
21000011
17
31
21
7
1000000
7
2428
19
200000002
13
35
24
500000002
15
35
27
10000000
16
83
118
48
31
40
0
20
40
60
80
100
120
140
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
c
Ma
rch
Jun
e
Sep
t
De
cem
ber
Ma
rch
Jun
e
Sep
tem
ber
De
cem
ber
Ma
rch
Jun
e
Sep
tem
ber
De
cem
ber
2012353
101
102
103
104
105
WN
V R
NA
(g
Eq
pe
r m
L)
Days following infectious mosquito bite
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
RNA IgM
IgG
MP-NAT
ID-NAT
3.4
9.5
5.8
IgM SC
IgG SC
6.1
6.9 days
13.2
3.9
7.7
1x ID-TMA
6x ID-TMA
MP-TMA
detection
Window Periods for acute WNV infection
parameters, and need for targeted ID-NAT
Busch et al, JID, 2008
REDS-III Dengue Study Sites and Epidemic ActivityRecifeand Rio de Janeiro
0
100
200
300
400
500
600
700
800
900
1 3 5 7 9 1113151719212325272931333537
Num
ber
of c
ases
Weeks
Dengue Epidemic in Recife
2011
2012
Dengue Epidemics in Recife
(2011-2012)
Nu
mb
er o
f cas
es
pe
r w
ee
k
Weeks
Dengue Epidemics in Rio de Janeiro (2008-2012)
Sabino et al, JID 2016Busch et al, JID 2016
DENV-4 in Brazilian Donors & Recipients
37.5% (6/16) infected
vs. 0.93% of control recipients
16 to 16 susceptible recipients
42 DENV RNA + units into 35 recipients
0.80% confirmed RNA positive in
Recife
0.51% confirmed RNA positive
in Rio
39,134 donors consented
Record review finds no significant differences between cases and controls re: morbidity or mortality
Sabino EC et al.JID. 2015;213:694-702.
1:200 1:125
2%
9%
IgM Rate6.2%
NAT
9.1 days (95%CI: 4.4-13.9 days) period of detectable RNA by ID-NAT
Busch et al, JID 2016
1 case of clinical dengue diagnosed for every 3 infections
853 cases of reported clinical disease per NAT yield donation
30
Zika virus (ZIKV)
• Arbovirus surveillance (Dick et al. 1952):
• Isolated from the blood of a sentinel rhesus monkey (placed in the forest in 1947)
• Isolated from a pool of Aedes africanus mosquitoes in Ziika forest, Uganda (1952)
• Humans:
• Serosurveillance: detection of neutralizing antibodies in human sera collected from East Africa (Smithburn et al. 1952)
• Isolated from a human in Nigeria in 1954
• First isolation of the virus itself from ZIKV-infected human (Simpson et al. 1964)
3/25/2018
6
31
ZIKV is a Flavivirus related to DENV
Classification:
• Flaviviridae family
• Flavivirus genus
• West Nile virus
• Dengue
• Japanese encephalitis
• Yellow fever
• Spondweni virus clade
Structure:
• 50 nm in diameter
• Enveloped: cell membrane
derived
• Capsid: icosahedral
symmetry
• + single stranded RNA
~11kb
Asian strains
East Africa
West Africa
32
May, 2015
July, 2016
Dec. 2015
Aug. 2013-July 2014
Molecular mapping of ZIKV spread; Worobey; 2017
33
Transmission Cycle of ZIKV
Transmission cycle of ZIKV
aegypti, albopictus, stegomyia, polynesiensis, africanus, apicoargenteus, furcifer, hensilli, luteocephalus, and vitattus , etc.
Vector: Aedes mosquitoesSylvaticUrban Different Aedes mosquitoes can transmit
ZIKV including:
Aedes aegypti
• Nervous mosquito
• Feeds on Humans meal
• Year round
Aedes albopictus
• Calm
• Feeds on multiple animals
• Diapause in winter
Figure 2. Distribution of ZIKV mosquito vector
Map estimates which US cities face the highest risk from ZIKV
http://www.sciencealert.com/this-map-estimates-which-us-cities-face-the-highest-risk-from-zika-virus
34
Distribution of suspected and confirmed ZIKV cases by epidemiological week and sub-region
Americas, 2016 – 2017
South America
Caribbean
Central America
Graphic from PAHO Regional Report: April 27, 2017
Why ZIKV Transfusion Transmission Concerns?
• Up to 80% of ZIKV infections asymptomatic/illness is generally mild • public health surveillance based on clinical case reporting is insensitive
• ZIKV can result in severe congenital syndromes & Guillain-Barré syndrome
• ZIKV RNA detected in asymptomatic blood donors
• ZIKV transfusion transmission reported – 4 cases (Brazil); 3 donors
• ZIKV may persist in whole blood longer than plasma
• 1-3 months vs weeks (diagnostic assays)
• Unknown impact of travel/sexual contact
• ZIKV interventions are available
• 2 investigational screening assays on newly available platforms
• Licensed pathogen inactivation for plasma/platelets; investigational methods in development (red cells/whole blood)
• FDA classification as a Relevant Transfusion-Transmitted Infection
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4 ZIKV TTIs; all reported via PDI (3-5 days) Brazil
Underlying Condition
Symptoms Sex Age Component
Liver transplant
None M 55 Platelet pool#
Trauma Thrombo-cytopenia
M 38 RBCs
Myelofibrosis None F 54 Apheresisplatelets*
AML/bone marrow
transplant
None F 14 Apheresisplatelets*
*same donation
37
# Barjas-Castro et al, Sept 15 2016, NEJM; neg pre-tx; genetic linkage* Motta et al, June 21 2016, Transfusion; genetic linkage
Weekly Detection Rate of ZIKV RNA in Blood Donated in Puerto Rico
This project has been funded in wholeor in part with Federal funds from theBiomedical Advanced Research and Development Authority, Office of theAssistant Secretary for Preparednessand Response, Office of the Secretary,Department of Health and HumanServices, under Contract #HHSO100201600010C.
365 (0.53%)68,380 tested
ID-N
AT o
nly
IgM
neg
(n=14
)
MP-N
AT re
activ
e
IgM
neg
ativ
e
(n=192
)
MP-N
AT re
activ
e
IgM
posi
tive
(n=26
) ID-N
AT o
nly
IgM
posi
tive
(n=93
)
102
104
106
108
1010
RN
A c
op
ies/m
l
Black symbols = Peurto Rico (n=306)Red symbols = Continental US (n=19)
Staging of ZIKV NAT yield cases with valid IgM results
0
1
2
3
4
5
8/1
4/2
016
8/2
8/2
016
9/1
1/2
016
9/2
5/2
016
10/9
/2016
10/2
3/2
016
11/6
/2016
11/2
0/2
016
12/4
/2016
12/1
8/2
016
1/1
/2017
1/1
5/2
017
1/2
9/2
017
2/1
2/2
017
2/2
6/2
017
3/1
2/2
017
3/2
6/2
017
4/9
/2017
4/2
3/2
017
5/7
/2017
5/2
1/2
017
6/4
/2017
6/1
8/2
017
7/2
/2017
7/1
6/2
017
7/3
0/2
017
8/1
3/2
017
8/2
7/2
017
9/1
0/2
017
9/2
4/2
017
10/8
/2017
10/2
2/2
017
54 ZIKV Confirmed Positive US Blood DonationsData collected under IND
To Nov 4, 2017No. Screened
No. Reactive No. Confirmed
13,580,225 4691:30,000
541:251,500
PPV: 11.5%Specificity: 99.997%
Alt NAT pos or eqv/IgM neg 10
Alt NAT pos or eqv/IgM pos 7
Alt NAT neg/IgM pos 37
41
Zika RNA positive donor enrollment and follow-up activities
Month 9 Month 126
Extended Follow-up• Characterization of humoral and cellular immunity• Discriminate recent vs remote infections• Detect ZIKV reinfections
6 symptomatic travelersSerum + for 3 days; WB + for 2 months
5 Asymptomatic donorsPlasma - 10 days (range 7–37)WB -22 days (range 14–100)VL higher in whole blood
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8
Longer persistence of ZIKV RNA in whole blood and RBC blood compartments than in plasma and body fluids
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
Plasma
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
PBMC
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
Red blood cells
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
Urine
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
Whole Blood
0 1 2 3 4 5 6100
101
102
103
104
105
106
107
Visit
ZIK
V IU
/mL
Saliva
1. Testing whole blood extends detection period for diagnosis of clinical cases and monitoring pregnant women and travelers.
2. Impact on donation policy: to extend deferral period or consider NAT testing whole blood.3. Considerations for testing for solid organ, tissue and semen donations 4. IS RBC-ASSOCIATED VIRUS INFECTIOUS?
44
Chikungunya VirusMakonde language: “to dry up or be contorted”
Alphavirus
3 genotypes
• West African
• East/Central/Southern/East African (ESCA)
• Asian
Like dengue
• Man-mosquito-man transmission cycle
• Aedes aegypti is the traditional urban vector
• Also spread by Aedes albopictus
46
substantial morbidity and mortality:
• DENV 1990s S America and the Caribbean• WNV 1999 endemic now in the continental US• CHIKV in 2013 S America and the Caribbean• ZIKV emerged in March 2015 Brazil• YFV outbreak in Dec 2015 in Angola => DRC- Vaccination reserve depleted
- 20% standard vaccine dose used- Dec 2016 expanded to rural areas of Brazil; sylvatic cycle mosquitoes and NHPs; human incidental hosts=> Concern for adjacent large urban centers with unvaccinated populations
YFV-17D vaccine complicationsCDC, MMWR 2010;59:34-7
• Viremia detected 3-7 days post-vaccination
• Associated disease incidence 0.4/100,000 vaccine recipients
• Single TT-cluster
• 89 military trainees rec’d vaccine 4 days prior to donation
• Retrieval actions occurred; however, 3 platelets, 2 FFP and 1 pRBCs were transfused to 5 recipients
• 4 surviving recipients – no complications; 3 developed IgM suggesting TT of vaccine virus
48
3/25/2018
9
Babesiosis
• Malaria-like illness caused by Babesia spp.
• Asymptomatic fatal• Non-specific symptoms (malaise, fever, etc.)• Hemolytic anemia• Onset 1-9 weeks after exposure
• General mortality 5-9%
• 21% immunocompromised
• At risk: infants, elderly, immunocompromised, asplenic, red cell disorders
• But risk groups not limited to above
Fang and McCullough, 2016, Trans Med ReviewsHerwaldt et al., 2011, TTB in the US, Ann Intern Med
Meldrum et al., 1992, Babesiosis in NY, Clin Infect Dis49
50
• June 2012-Sept 2014 tested donations from 4 states (CT, MA, MN, WI) by investigational antibody (AFIA) and DNA (PCR)
• Determined parasite loads (qPCR) and infectivity (parasitemia in hamsters) • Followed donors for Ab/DNA clearance• Hemovigilance system used compared rates of TTB: screened vs unscreened blood
Possible Mitigation Strategies for TT-EIDs
Curtail donations in outbreak areas
Defer donors from areas experiencing outbreaks
Enhanced donor deferral
Enhanced post-donation notification
Temporary quarantine of donations with proactive post-donation call back
Serological screening
Nucleic Acid Amplification Technology (NAT) screening
Photochemical inactivation of platelets/plasma/(RBC)
Assessing the risk of transfusion-transmission for newly
discovered pathogens
Lanteri et al, Transfusion 2016
Are There Consistent Patterns to Potential TT-EIDs?
Disease Agent
Attribute Syp
hilis
HB
V
HC
V
HIV
HT
LV
HH
V-8
CM
V
Mala
ria
Ch
ag
as
Leis
hm
an
ia
Bab
esia
HE
V
DE
NV
WN
V
vC
JD
SF
V
HA
V
Parv
ovir
us
ZIK
V
Viral agent
Chronic, persistent
infection
Detectable in plasma
Transmitted sexually
High incidence/
transmission in MSM
High incidence/
transmission in IDU
Vector-borne
Traditional TTID Agents Emerging Infections/Agents
Adapted from Stramer and Dodd, 2013
3/25/2018
10
Summary
• There is a continuing need to manage (prevent) transfusion-transmitted infections
• Testing has reduced residual risks to remarkably low levels• Testing approaches are not available for all of the known threats
• Infections continue to emerge at an alarming rate
• Technology can now identify more microbes than diseases• There is hope that threats can be anticipated
• Is there a solution?• Continued vigilance and potentially pathogen reduction/inactivation
AcknowledgementsBSRI / BSI
Roberta Bruhn
Michael Busch
Dan Hindes
Claire Quiner
Zhanna Kaidarova
Mars Stone
Nelly Gefter
Inder Sing
Sheila Keating
Dylan Hampton
Eric Delwart
Eda Altan
Sonia Bakkour
Eric Peters
Hany Kamel
Jackie Vannoy
Graham Simmons
CTS
Phillip Williamson
Sherri Cyrus
Val Winkelman
Tracy Fickett
FDA
Steve Anderson
Alan E. Will iams
Manette Niu
Peter Marks
NHLBI
Simone A. Glynn
Shimian Zou
NYBC
Debra Kessler
Lisa Milan-Benson
Carlos Delvalle
OneBlood
Rita Reik
German Leparc (retired)
Tisha Foster
Adam Rosenzweig
Shalet Verghese
Mihai Buba
Marjorie Doty
Kenzie Gaston
Megan Grant
ARC
Susan Stramer
Whitney Steele
Ed Notari
Roger Dodd
Diane Nelson
James Haynes
David Krysztof
Rebecca Townsend
Rahima Fayed
Greg Foster
Barbara Deisting
Quality Analytics
Jaye Brodsky
Marjory Manske
Maureen Barr
CDC
Lyle Petersen
Brad Biggerstaff
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