HEV and Blood DonationsDragoslav Domanovic, ECDC

1st ECDC Hepatitis E virus expert group meeting09 – 10 December 2015, Stockholm, Sweden

Pig farms in Europe

Source: Eurostat

HEV and Blood Transfusion

Blood donors are infected with HEV3 by consuming uncooked or undercooked pork,

game and shellfish that are considered main sources of zoonotic infections.

HEV3 (4) present in transfused blood has been recognized as an additional

source of HE in humans.

Transfusion transmissible pathogen

• Present in the asymptomatic donor’s blood;

• Survives in the blood during processing and storage;

• Responsible for a clinically apparent outcome in at least a proportion of recipients who become infected.

Prevalence of anti-HEV IgG (%) - blood donors

Austral

ia

Brazil (2

.0 - 7

.5)

Canad

a

China (

30 - 4

2)

France

France

3 (To

ulouse

)

German

y (Hess

e)

German

y (Th

uring

ia)

German

y (Berl

in-Bran

denb

urg)

German

y (NRW, Lo

wer Sa

xony, H

esse)

DE (Nort

h Schl

eswig-

Holstei

n)

India (

6.9 - 1

4.0)

Italy (

Lazio)

Italy (

Abruzzo

)Jap

an

Netherl

ands

Russia

Spain

(Gran

ada)

Spain

( Mad

rid)

Spain

(Cata

lonia 1

)

Spain

(Cata

lonia2

)USA

1USA

2USA

3

Engla

nd

South

West

Engla

nd

Scotla

nd0

10

20

30

40

50

60

0.44.75 5.9

36

23.6

52

5.5

15.511

5.9 6.810.45 9

46

5.3

27

4.75 3.1 2.8

21

1116

7.7 612

16

4.7

Incidence HEV3 RNA - blood donors EU

Year Countries Technique No. tests Ratio of positives Ref.

2011 England PCR 42000 1:7040 Ijaz et al.2013 Scotland PCR 43560 1 :14520 Cleland et al. 2011 Germany RT-PCR 18100 1:4525 Baylis et al.2011 Sweden RT-PCR 95835 1:7986 Baylis et al.2011 Germany RT-PCR 16125 1:1241 Vollmer et al.2011-2012 Netherlands RT-PCR 45415 1:2672 Slot et al.2012-2013 England RT-PCR 225000 1:2848 Hewitt et al.2012 France RT-PCR 53234 1:2218 Gallian et al.2013 Spain TMAA 9998 1:3333 Sauleda et al.

PCR: Polymerase Chain Reaction; RT-PCR: Real Time Polymerase Chain Reaction; TMAA - transcription mediated amplification assay 

Reported cases of TTI HEV infection

~ 40 cases of HEV transmission through blood product recipients in Europe/Japan

6 cases of molecularly confirmed TTI HEV in non-endemic countries (Matsui, Hepatology Research 2015)Acute & chronic hepatitis: Clinically apparent post transfusion hepatitis 1:18 7/10 immunosuppressed: HEV PCR positive 3 months after exposure (Hewitt et al, Lancet 2014 )

Transmission of HEV through transfusion

 Author/countryDonor

Blood product

Patient

G/A HEV gt G/A Viral load Disease Clinical dg. Lab. dg Clearance

Matsubayashi , Japan, F/24 4

FFP recovered   N.A. OHS Ac. Hep E 37 days 85ERY   N.A. Lymphoma No disease - -

Mitsui, , Japan NA ? ERY/ WB? M/31   Haemodialysis Ac. Hep E  21 days N.A.

Boxall, UK M/40 3ERY   NA. Lymphoma   Ac. Hep E 34 days 89 days PLT-pool     Liver cirrhosis  No inf. - -

Colson, France, M/24 3 ERY M/7 N.A. Kidney tumour Ac. Hep E  42 days  Matsubayashi,Japan, M/39 4 PLT – aph. M/64 1259 IU/ml NHL, Auto. HSCT Ac. Hep E 22 days 97 daysHaim-Boukobza,France F/53 3 PLT- recovered M/81 17,000 IU/ml AI thrombocytop. Ac. Hep E 10 weeks 26 weeks

Hauser, France F/32 3

FFP – Aph. PI 1 M/36 N.A. Kidney transpl.  Ch.Hep E  NA NA 

FFP – Aph. PI 2 M/61 N.A. Liver transpl.   Ch.Hep E NA  NA 

FFP – Aph. PI 3 N.A. N.A. Deceased - - -Coilly, France, M/41  3 ERY M/55 3162 IU/ml Liver transpl. Ac hep.E  ~37

days ~ 90 days 

Huzly , Germany, M/40 3 PLT aph.1

M/40120 IU/ml 

Immunocomp. Ch. Hep E   

495 IU/mlPLT aph. 2    

Survival in the anticoagulated blood during processing and storageLack of survival studies of HEV in blood and blood components• in CPD (citrate-phosphate-dextrose) preservative and SAGM (saline

adenine glucose mannitol) additive solutions • at + 4o C (erythrocytes), +20o C (thrombocytes) and – 30o C (fresh

frozen plasma)Indirect proof of HEV survival in blood donations = evidence of transmission through transfusion• HEV survives in all types of blood components• Data of the storage date of blood components associated with HEV

transmission are not published• Components with high plasma content (FFP and apheresis platelets)

most frequently involved in transmission

Association between blood components and transmission

Hewitt et al, Lancet 2014

Low frequency of clinical cases of transfusion-transmitted HEV

• Underreporting • Unrecognition• Miss-diagnosis• Non-recognized asymptomatic cases • Non-developed disease?

– Neutralizing Ab in recipient blood?– Neutralizing Ab in transfused blood

components?– Low viral load in the transfused blood

component?

Clinical response in immunocompetent transfusion recipient

ALT = -------------HEV RNA =

Matsui T et al. Hepatology Research 2015; 45: 698 – 704.

Preventive measures

• HEV RNA laboratory screening test• Pathogen inactivation not fully effective and not

available for all three types of blood components• Vaccination: Hecolin (hepatitis E vaccine produced in E. coli, Xiamen Innovax Biotech, Xiamen, China) well tolerated and effective for genotypes 1 and 4. Data are not available on Hecolin efficiency in high-risk groups and also in relation to genotype 3. WHO’s Global Advisory Committee on Vaccine Safety recommended phase 4 postmarketing study to further assess the safety profile.

TTI HEV3 summary 1

• HEV3 is transfusion-transmissible pathogen• Some MS show a high incidence of asymptomatic HEV3 infection in

blood donors• Several cases of proved transfusion-transmitted HEV3 infection have

been reported• Possible consequences

Acute or chronic hepatitisNeurological complications not reported after TTI HEV

• Probably many cases of post-transfusion hepatitis E are unrecognised• Population at risk – immunocompromised patients – SOT esp. LT

recipients – • Preventive measures available

HEV and blood donation – summary 2

• As HEV3 appears gradually becoming the dominant cause of new hepatitis cases, and in the absence of effective pathogen inactivation for all types of blood components, there is a recognized need for HEV testing at an early stage, alongside routine tests for other hepatitis viruses, at least for high-risk individuals.

Status of HEV blood safety measures in EU MS – EU Commission DG SANTE D4 survey

No legal requirement to test blood donations for hepatitis E in the EU

Hepatitis E discussion at CAs meeting in April 2015 revealed different approaches in those MS that described their current situation

Agreed that it would be useful to understand the current situation related to HEV and blood donations in all MS through a simple email survey

Results circulated to the group in August 2015

Participation: All MS and LI and NO participated

Questions

A. Notification of hepatitis E Is it mandatory for health professionals to notify cases of hepatitis E infection to a central authority monitoring the general population in your country?

B. Measures to prevent transmission of hepatitis E by blood transfusion

1. Have you, as NCA, implemented mandatory measures to reduce the risk of hepatitis E transmission by blood transfusion in your country?

2. Has the blood service itself chosen to implement measures to reduce the risk of hepatitis E transmission by blood transfusion in your country?

3. If you answered YES to 1 or 2 above, please describe the measures and the circumstances in which each they are taken.

4. If you answered NO to questions 1 and 2, do you plan to introduce any national measures in the future? If YES, please describe.

The results: Notification

In 15 Member States it is mandatory for health professionals to notify cases of hepatitis E infection to a central authority monitoring the general population.

In the others, as well as in LI and NO, it is not mandatory to notify.

The results: Testing

Only one Member State, LU, reported having implemented a mandatory testing measure to reduce the risk of hepatitis E transmission by blood transfusion at a national level; all plasma donations for production of SD fresh frozen plasma are screened by PCR HEV RNA since December 2014.

The results: Donor Deferral

FR: Since January 15th 2015, at least 20% of the total volume of plasma produced for transfusion is HEV free. The French Blood Service advises hospitals to use these HEV free units for certain immunosuppressed patients.

AT: some blood establishments have tested, or still test blood donors for HEV-NAT and use the results for product release.

DE: some blood establishments have tested or still test blood donors for HEV genome to obtain more data on the prevalence and also on virus load in the positive tested donations.

FI: instead of using fresh frozen plasma, Octaplas is exclusively used, and is tested for HEV-RNA

The results: Donor Deferral

RO: mandatory Regulation on Standards for Prospective Donor Selection states that persons with hepatitis A and E will be deferred during the illness and for 3 months after recovery

CZ: obligatory ban on blood donation during acute HEV and a convalescence period of 1 year.

Other MS: Generic exclusions of potential donors with acute or recent infections, or a history of unspecified hepatitis, cover exclusion of HEV infected individuals.

The results: Future Plans

Most MS, together with LI and NO, do not currently plan to introduce any national measures

8 MS (AT, DE, EL, HR, MT, PL, PT and UK ) are actively exploring or planning initiatives.

• These mostly focus on gathering data on prevalence, or planning to gather such data, and on scientific discussions regarding testing or viral inactivation for specific patient groups.