3/25/2018

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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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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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*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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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

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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

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Ma

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Jun

e

Sep

t

De

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rch

Jun

e

Sep

t

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Jun

e

Sep

t

De

c

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Jun

e

Sep

t

De

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ber

Ma

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Jun

e

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tem

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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

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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)

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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

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May, 2015

July, 2016

Dec. 2015

Aug. 2013-July 2014

Molecular mapping of ZIKV spread; Worobey; 2017

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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

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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

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# 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

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017

5/7

/2017

5/2

1/2

017

6/4

/2017

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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

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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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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

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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

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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