Hepatitis E Virus in Transfusion and Transplantation Lorna Williamson NHS Blood and Transplant, England.

HEV in UK 1.Number of reported infections in population increasing 2.1 in 2850 blood donors positive in study in First UK transmission 2006; then three cases Literature: –Case series of chronic carriage/progression to chronic liver disease in immunosuppressed –Worsening of pre-existing liver disease –Other clinical features as well as hepatitis –One transmission via transplanted liver UK situation & state of knowledge both rapidly evolving

HEV natural history Hyper-endemic in developing world (water), genotypes 1 and 2 Increasing in W Europe, genotypes 3 and 4; linked to pork, wild boar, venison Incubation period 40 days; virus in blood for 3 weeks; then IgM and IgG with viral clearance; virus in stool for 2 more weeks Asymptomatic or mild symptoms; jaundice rare: ? BUT fulminant/chronic if immunosuppressed Susceptibility to re-infection unclear

Prevention and treatment Thorough cooking of pork products Hand hygiene in food handlers No vaccine licenced in Europe Most cases need no specific treatment In immunosuppressed, ribavirin for 3 months effective; ?interferon

HEV infection in UK Evolving Clinical cases increasing (PHE enhanced surveillance/new phylotype): –England: 600/yr in 2012 to 800/yr in 2014 –Scotland 13/yr in 2011 to 160/yr in 2014 –N Ireland 3 cases in 10 years to 9/yr in 2014 Attack rate: %/yr = 1 in 500/yr. Prevalence of immune antibody: – 13% England/4% Scotland (?now higher) –Increases with age –May have fallen over last 20 years

HEV reported infections in England

Viraemia rates from blood donor studies CountryYearRNA positive France in 2218 Netherlands20131 in 1761 Netherlands in 2671 Germany20111 in 1240 Scotland in 14,520 England in 2848

UK transfusion transmissions # 1: 2006 #2: 2011 #3: 2012 #4: 2014 Lymphoma Discovered via lookback Stem cell transplant recipient Ca. bladder Ca. prostate (129 donor exposures) Liver disease Encephalo pathy Red cellsFFP Cleared virus Died other causes Cleared virus Cleared virus

Risks in specific transfusion recipients No clinical cases reported via transfusion: –Pregnancy –Neonates & infants –Haemoglobinopathy patients –HIV positive people (though HEV is described) BUT low awareness of HEV amongst clinicians

NHSBT/PHE donor/recipient study (Hewitt et al Lancet 2014) Only donor/recipient study so far Donors 1 in 2848 virus positive 18/43 recipients had evidence of HEV (40%)- 6 had antibody and 12 RNA Transmission from red cells, FFP, platelets, granulocytes Transmission rates higher if high viral load/large plasma volumes (small nos)

HEV in immunosuppressed Small case series reporting progression to chronic carriage/liver disease in up to 60% of infected solid organ transplants Chronic liver disease also reported in stem cell transplant recipients (case reports) Chronic carriage in some HIV positive people May make chronic liver disease acute

Effect of immune suppression on recipient outcome (Hewitt et al Lancet 2014) NONE/MILDMODERATESEVERE n= 8n=6n=4 10 weeks of infection 18 weeks of infection 30 weeks of infection Anti-HEV in 8Anti-HEV in 5Anti-HEV in 2/3 Viral clearance in 8 Viral clearance in 3/4 Viral clearance in 2/3 Clinical hepatitis: 1 Clinical hepatitis: 0

Clinical features other than hepatitis Mainly studied by Dalton et al in Exeter; SW England Neurological: Guillain-Barré, neuropathies Renal, pancreas, thyroid Low platelets, high lymphocytes Remain to be confirmed in other series

Strategies to provide ‘HEV-safe’ blood components Donor selection by occupation or diet No (vegetarians only 7%) Test donors for HEV RNA Yes Create donor panel with immune anti-HEV No Pathogen inactivation of FFP or platelets Uncertain

RNA HEV testing of blood donors 2 CE marked suppliers Can be done in pools Confirmatory assay available Would generate 3-4 positive donors/day –Manageable impact on supply –Donors would be informed, deferred & retested before return to donation –Lookback if previous recent donations ? < 4 months

International situation re blood donor screening Netherlands- decision not to test (1 in 500 pos) France: testing for Octaplas manufacture; otherwise being discussed Ireland: request for funding to test entire blood supply for 5 years Other EU countries: reviewing data Not an issue for N America, Australia, Japan

Pathogen inactivation No licensed systems for red cells Platelets –Mirasol- no information, little routine use –Intercept- no information, no transmissions FFP –Intercept - 2 transmissions –Methylene blue - no information –Solvent detergent - evolving situation

Solvent-detergent FFP Pooled product, licensed medicinal (Octaplas) UK guideline: Recommended for plasma exchange for TTP & some inherited clotting disorders Wales: all patients receive SDFFP (also Ireland) Scotland: TTP only England: mixed economy, some use in paeds Transmissions reported from Canada Octapharma now requesting tested plasma and will set safe levels for pools Could become safe option for high risk patients

Organ and stem cell transplant recipients appear to be at highest risk of serious clinical sequelae They might acquire HEV from blood, from diet, and from the transplant

Transmissions from organs and stem cells One reported transmission from a liver transplant (not in UK) One stem cell donor with acute HEV Approx one organ donor/year calculated to be virus positive

Risks to recipients of tissues No transmissions reported from tissue products Processing removes most plasma No immunosuppression needed Rarely transfused Hence tissue transplantation low risk

Risks to recipients of gametes and embryos No transmissions reported Processing of sperm removes plasma Egg = single cell Recipients not immunosuppressed No specific transfusions Hence seen as low risk procedure

Acknowledgements Pat Hewitt, Richard Tedder, Samreen Ijaz, NHSBT/PHE Bloodborne virus laboratory Su Brailsford, NHSBT/PHE epidemiology team James Neuberger, NHSBT organ donation & transplant team