Impact of donor epidemiology and screening strategies on the … · 2019. 1. 15. · Screening of...

Impact of donor epidemiology and

screening strategies on the safety of

blood and plasma for fractionation

Yoshihiko Tani, MD, PhD

Japanese Red Cross Osaka Blood Center

IPFA 2nd Asia Workshop in Yogyakarta

March 03, 2017

Blood and Law

Blood and Blood components

Plasma derivatives (Alb, IVIG.etc)

Prescription Drugs

Specified Biological Products=

AS PRESCRIPTION DRUG

Pharmaceuticals and Medical Devices Act

GMP, GQP, GVP...

Quality Management System

Risk Management Plan

AS SPECIFIED BIOLOGICAL PRODUCTS (Human Blood)

Law Concerning Securing Stable Supply of Blood Product (Blood Law)

Minimum Requirements for Biological Products

Standards for Biological Materials

Pharmacovigilance is

implemented to blood

components

Haemovigilance

Blood Service and Regulation

National Government (Ministry of Health, Labour and Welfare)

Policy Making Authorization

• Promotion of Blood donation

• Domestic demand/supply of blood

• Promotion of appropriate use

• Secure stock of source plasma

• Blood collection

• Manufacturing of blood components

• Marketing

Blood Establishment (Japanese Red Cross Society)

Regional Blood Centers Block Blood CentersBlood Service Headquarters

Blood collection

DistributionManufacturing (testing, preparation)

Marketing Authorization Holder in charge of manufacturing

Approvals

Licensing

Statutory

Pharmaceuticals and Medical Devices Agency (PMDA)

Regulation Review Post-Marketing Safety Measure

Application, ADR reports

Assessment

Supervision

Blood Safety Measures

●National

Assay

●Personal Identification●Questionnaire （Archive for 41 yrs）●Reference of test records

●Specimen storage

Sep 1996（for 11yrs)

Donated Blood

Voluntary Donor

Plasma for Fractionation

●Pre-donation diversion

●Pre-storage leukocytes

reduction

Blood for Transfusion

●Inventory hold for FFP

（for 180 days）Hospitals

Patients

●Inventory hold （for 6 mo）

Plasma Pool●Virus Removal/Inactivation

Plasma Derivatives

●NAT

●Lookback study

●TTI Report

※Relief System for Infections Derived

from Biological Productas

●Call back

●Post donation information

●Serological Tests

●NAT（Individual）

ＨＥＶ-NAT in Hokkaido

JRCS⇒JBPO

Measures to Ensure Safety of Blood Supply

Transfusion

Reception upon

Blood donation

Tests

Preparation

Distribution

Blood collection

Safety Measures Target Pathogens

ID confirmation, Interview,

Questionnaires

Thorough skin disinfection

Diversion of initial blood

Serological testing／NAT for

for pathogens , ALT

Leukocytes reduction

prior to storage

Inventory holds(fresh frozen

plasma) : 6 months

Collection of information on

adverse reactions/infections

Retrospective surveys

bacteria, WNV, Malaria,

vCJD, Chagas, etc

Resident skin bacteria

HBV, HCV, HIV, HTLV-1,

Syphilis,B19/ HBV,HCV,HIV

bacteria such as

Yersinia enterocolitica

Information on infections

of blood donor

Screening of blood donations

1. Serological Test（CLEIA）HBsAgHBcAb*HCV-AbHIV-1/2-AbHTLV-1-AbTP-AbParvoB19-Ag(selective CMV-Ab)

2. Individual NATHBV,HCV,HIV(investigational HEV

:Exclusive in Hokkaido)

3. Biochemical testALT (Ineligible above 101 IU/L)

4. Blood typeABO typing, Rh typingIrregular antibodies(HLA typing)

Criteria for

HBcAb and HBsAb

HBcAb

C.O.I.<1 1<C.O.I

HBsA

b

200mIU/mL< eligible eligible

<200mIU/mL eligible ineligible

(since Aug.2012)

(since Aug.2014)

ＦＦＰ-480

ＢｌｏｏｄＤｏｎａｔｉｏｎ

ＲＢＣ-１ＦＦＰ120 ＲＢＣ-２ＦＦＰ240

ＰＣ＋ＰＰＰＰＰＰ

ＰｌａｓｍａｆｏｒＦｒａｃｔｉｏｎａｔｉｏｎ

ＷｈｏｌｅＢｌｏｏｄＡｐｈｅｒｅｓｉｓ

２００mL ４００mL

ＰＣ

FFP (Fresh Frozen Plasma)

FFP 120mL, 240mL from Whole Blood

Prepare within 8 hours after collection

FFP 480mL from Apheresis

(PPP: Platelet Poor Plasma)

Prepare within 6 hours after collection

Plasma for fractionation

Category C (for coagulation factors)

Fibrinogen, FVIII, FIX, etc

good for 1 year after collection

Category N (for non-coagulation factors)

Albumin, γ-globulin, etc

good for 4 years after collection

Annual Changes in volume of Plasma

100

300

500

700

900

1.100

2006200720082009201020112012201320142015

x１０3 Ｌ FFP Plasma for fractionation

JRCS Tracing System

◆Haemovigilance: Since January 1993

◆Medical Representatives nationwide: 150 persons

◆Repository Samples: Since September 19966 mL, frozen, 11 years

◆Nucleic amplification tests: Target viruses: HBV, HCV, HIV, Parvovirus B19, HEV, CMV, HTLV-1,

Dengue etc.

◆Storage of source plasma and FFP: Source plasma; since July, 2000for 6 months FFP ; since Jan. , 2004

◆Serological tests◆Microbiological tests

Specimen Storage: minus 30 ℃for period of 11 years

(10 years + 1 years )

Flow of Transfusion ADR case reporting

Medical Institutions/Hospitals

JRC Regional Blood Centres

JRCS Blood Service HQ Safety Vigilance Division

Pharmaceuticals and Medical Devices Agency

(PMDA)

Ministry of Health, Labour and Welfare

(MHLW)

JRCS Central Blood Institute

Informationacquisition

ADRsTTIs

VoluntaryReport

ADRsTTIs

Severe ADRsTTIs

MandatoryReport

Assessment

Statutory

Investigation/analysis

Analysisresults

Analysisreport

Severe ADRsTTIs

MandatoryReportLiterature &

Academic conferences

1.533

1.451

1.515

1.595

1.597

1.579

1.541

1.554

28

21

21

12

14

26

25

22

2

1

1

2

6

3

2

5

93

81

125

131

96

98

98

149

0 200 400 600 800 1.000 1.200 1.400 1.600 1.800

2015

2014

2013

2012

2011

2010

2009

2008

non-hemolytic hemolytic GVHD(doubt) Infection(doubt)

Transition of the number of adverse reactions

and infectious diseases

Descriptions of tests for adverse reactions and infectious diseases

(1) Non-hemolytic adverse reactions

anti-HLA antibody

anti-platalet antibody

anti-granulocyte antibody

anti-plasma protein antibody

Plasma protein deficit

(2) Hemolytic adverse reactions

ABO group and irregular antibody

(3) Bacterial infection

Blood culture test

Bacterial identification test

Endotoxin quantification test

(4) Viral infections

NAT

Serological test

(5) Post-transfusion GVHD

Micro-satellite DNA test

Chimerism test on recipient blood

TT-Viral Infections

Annual changes in the number of suspected TTI reported cases

54 6996

138 130

85 74 6145 36 40 50 52

27 14

61 40

86

8871

4941

38

2627 29

40 32

2635

1 2

4

5

2

1

1

1

1

1

23 27

66

53

54

50

30 46

23 28 21

30 25

17 25

2 6

8

10

8

6

8 3

4 6 6

1115

1118

0

50

100

150

200

250

300

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Others Bacteria

HIV HCV

HBV

200050p-NAT

200420p-NAT

2008CLEIA methodNew 20p-NAT

2012HBcAbcriteria revised

2014ID-NAT

(cases)

(year)

2003Look-back

Study

HBV 96Report from medical institution

Look back, Follow-up research etc.

52

44

HCV 7Report from medical institution

Look back, Follow-up research

3

4

HEV 19

Report from medical institution

Look back / Post-donation

information

7

12

HAV 1 Post-donation information 1

HIV 1 Look back 1

H.Parvovirus B19 6 Report from medical institution 6

Bacteria 12 Report from medical institution 12

Information sources for confirmed TTI cases (2004-2015)

14

12

78

7

11 11

98

4 4

01 1 1

21

01 1

00

5

10

15

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

HBV

HCV

HIV

cases

Transition of the number of TTI in Japan (donation year)

● The number of cases derived from the same donated blood is excluded.

2012.9Change of NAT/serology

test System（High sensitive）

HBValgorism

ID-NAT20P-NAT

2004.8 2008.8 2014.8

Annual TT-HBV confirmed cases by screening method and infectious status of donors

3,2 2,7 2,6

1,50,7

0,5

3.04,7

0,30,5

0

2

4

6

8

10

20p-NAT(old) 20p-NAT(new) HBcAb criteria change ID-NAT

WP

ID NAT＋WP

ID NAT－past infection

ID NAT＋past infection

ID NAT－

8.0 cases 8.6 cases 2.6 cases

48months

(2004.8～2008.7)

49months

(2008.8～2012.8)

23months

(2012.9～2014.7)

24months

(2014.8～2016.7)

0.5 cases

(cases/year)

95%LOD NAT screening

LOD (IU/mL)*

Sensitivity

ratio20P-NAT ID-NAT

2014.7.31before

2014.8.1after

HBV 64 4.3 15

HCV 248 3.0 83

HIV-1 836 18.0 46

HEV 1020** 7.9 129

＊Attached document ＊＊in-house PCR by Hokkaido BBC

About 10 days2 days

ID-NAT

HCV

HBV

Viral load, LOD of NAT, and window period

20 pool NAT 64 IU/mL

4 IU/mL

248 IU/mL

3 IU/mL

HBV：Sensitivity x15, WP shorten 10daysHCV： Sensitivity x83, WP shorten 2days

(Viral load)

(Days)Infection

Incidence of Post -Transfusion Hepatitis

1 1 1

2

1

4

1

4

2

1

1

1

0

1

2

3

4

5

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Genotype3 Genotype4

(all G4 cases were occurred in Hokkaido)

Annual changes of TT-HEV cases

2006- Investigational HEV-NAT exclusively in Hokkaido

2011Health insurance imbursement for

IgA-HEV-Ab testing

(cases)

(year)

Hokkaido

(1)

(1) (1) (1) (1)

(1)

(1)

(2)

(3)

( ) Look-back study derived cases

20 cases in 14 years from medical institutions: 8, look-back study cases: 12

Genotype 3: 17 cases, Genotype 4: 3 cases (only in Hokkaido)

Recovered with seroconversion: 15 cases

Persisted viremia: 5 cases (transplantation, hematological disorder)

ALT > 1000 IU/mL : 2 cases

No fulminant or fatal cases

Ribavirin: effective

Blood donors : early phase of infection without HEV-Ab

Infection rate : 50％

(calculated from TT-HEV cases and look-back study in Hokkaido)

Summary of TT-HEV cases

TT-Bacterial Infections

Safety measures for bacterial infection

Donor interview（dental treatment, diarrhea, etc.）

Skin disinfection

Diversion Pouch (to remove very first flow containing skin bacterial

flora) 2006-2008 gradually started

Leukoreduction（to remove bacteria such as Y.enterocolitica from RBC component）started in 2007

Shortest shelf life (4 days for PLT, 21 days for RBC, including collection day)

：Use the unit with low bacteria concentration

Visual inspection of Platelet for swirling before delivery and at transfusion site

Transfusion transmitted bacteria cases

Before diversion pouch/leukoreduction

For 10 years after diversion pouch/leukoreduction

RBC 3cases

(0)

B,cereusY.enterocolitica×2

0cases

(0)

PLT 2cases

(2)

S.pneumoniaeS.aureus

9cases

(0)

S. PneumoniaeS. Dysgalactiae ssp. Equisimilis x 3S. AgalactiaeS. pyrogenesS. Aureus x 2S. marcescensE. coli

( ) : fatal caseYear component Days incl. collection Detected bacteria

2008 IR-PLT-LR 4 Staphylococcus aureus

2008 IR-PLT-LR 4 Streptococcus dysgalactiae ssp. Equisimilis

2009 IR-PLT-LR 4 Serratia marcescens

2009 IR-PLT-LR 3 Streptococcus agalactiae


2012 IR-PLT-LR 4 Streptococcus pyogenes


2015 IR-PLT-LR 3 Escherichia coli

2015 IR-PLT-LR 4 Staphylococcus aureus

Leaflet for visual inspection of platelets before transfusion (2008)

Near miss cases of bacterial contamination

FY Facilities Visual abnormality ComponentDays incl.

collectionBacteria/Pathogen

2012

Blood center Swirling negative Platelet 4 Escherichia coli

Blood center Aggregation Platelet 4 Staphylococcus aureus

Hospitals Aggregation Platelet 4 Streptococcus agalactiae

Hospitals Aggregation Platelet 4 Staphylococcus aureus

Hospitals Line Clogging Platelet 4 Staphylococcus aureus

2013


Blood center Aggregation Platelet 4 Klebsiella pneumoniae

Hospitals Line Clogging Platelet 4 Staphylococcus aureus


2014


Blood center Aggregation Platelet 4 Lactococcus garvieae




2015

Blood center Aggregation Platelet 4 Citrobacter Koseri

Blood center Aggregation Platelet 4 Lactococcus garvieae


Summary of the TT-Bacteria cases

9 cases in 10 years after implementation of diversion pouch and leukoreduction

All cases were caused by platelet component (apheresis)

No fatal cases

No infectious case of RBC

Visual inspection is effective, because bacterial contamination is unavoidable

Acknowledgement

I thank Drs. Rikizou Taira and Naoko Goto (Japanese Red Cross Society Technical Department Safety Vigilance Division) for supporting and preparing for this presentation.

Thank you for your attention.


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