The risk and prevention of transfusion-transmitted HEV

1. HEV and Blood Donations
Dragoslav Domanovic, ECDC
1st ECDC Hepatitis E virus expert group meeting
09 – 10 December 2015, Stockholm, Sweden

2. Pig farms in Europe
Source: Eurostat

3. 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.

4. 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.

5. Prevalence of anti-HEV IgG (%) - blood donors
0.4
4.75 5.9
36
23.6
52
5.5
15.5
11
5.9 6.8
10.45
9
46
5.3
27
4.75
3.1 2.8
21
11
16
7.7
6
12
16
4.7
0
10
20
30
40
50
60

6. 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

7. 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 )

8. Transmission of HEV through transfusion
Author/country
Donor
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 85
ERY N.A. Lymphoma No disease - -
Mitsui, , Japan NA ? ERY/ WB? M/31 Haemodialysis Ac. Hep E 21 days N.A.
Boxall, UK M/40 3
ERY 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 days
Haïm-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/40
120 IU/ml
Immunocomp. Ch. Hep E
495 IU/mlPLT aph. 2

10. Survival in the anticoagulated blood during
processing and storage
Lack 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

11. Association between blood components and transmission
Hewitt et al, Lancet 2014

12. 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?

13. Clinical response in immunocompetent
transfusion recipient
ALT = -------------
HEV RNA =
Matsui T et al. Hepatology Research 2015; 45: 698 – 704.

14. 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.

15. 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 hepatitis
Neurological 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

16. 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.

17. 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

18. 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.

19. 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.

20. 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.

21. 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

22. 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.

23. 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.