Hepatitis E and the English blood supply

Mhairi WebsterMicrobiology Senior ScientistNational Transfusion Microbiology Reference LaboratoryWith thanks to Dr Alan Kitchen

Blood and Transplant

Hepatitis E virus• Small, non-enveloped virus, assigned to the hepeviridae

family – In most healthy individuals it is asymptomatic or causes

only mild symptoms – can have more serious consequences in

immunocompromised individuals• There are 4 genotypes which differ in route of

transmission and distribution– genotypes 3 & 4 considered to be zoonoses– genotype 3 found in UK– associated with food and transmission through blood

products

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HEV in the UK• HEV infections in England and Wales

– high seroprevalence rates upwards of 13%

– thought to be 60,000+ infections/year

– infections prevalent in England and Wales are genotype 3 – rarely cause illness

– no or very low reproductive capacity in humans

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HEV in the English blood supply• Joint NHSBT/PHE study in 2012-131

• 225,000 donations screened, in pools of 24, for HEV RNA– 95% LoD 22 IU/ml– donors from SE of England (logistical reasons)– not performed in real-time, a delay before HEV RNA

available. Products may already have been issued• If positive, unused blood components remaining in the

NHSBT inventory were discarded and those already issued were recalled

1 Hewitt et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet, July 2014

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HEV in donors• 79 viraemic donations picked up - 1:2848 donations tested

– 57 were seronegative at pick-up– 64% male– median age: male 51.5 yrs, female 49.5 yrs; majority in

40-60 yr group

• 54 (68%) of the 79 donor samples could be genotyped, all genotype 3

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Source of infection in donors• What is the source of the virus in England and Wales?• Given the nature of the virus and limited routes of

infection, dietary source most likely

• Genotype 3 infection in the UK (considered to be) associated with the consumption of pork products1

• Detailed dietary questionnaire sent to all positive donors

1Said B et al; Hepatitis E virus in England and Wales: indigenous infection is associated with the consumption of processed pork products. Epidemiology & Infection, 2014

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HEV in recipients• 129 blood components prepared from the 79 positive

donations

• 62 components transfused

• 43 recipients followed up

• 25 recipients had no evidence of infection (either seronegative 16/52 post/transfusion OR seronegative and HEV RNA negative 8/52 post/transfusion)

• 18 had evidence of infection – RNA and/or serology

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Observations on transmission outcomes

• Absence of detectable antibody and a high viral load in the donation rendered transmission more likely– product type also relevant– volume of plasma important

• Spontaneous clearance of viraemia without clinical disease was common

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Observations on transmission outcomes

• Recipient immunosuppression delayed or prevented seroconversion and extended the duration of viraemia

• 10/18 recipients developed prolonged or persistent infection. - only 1 recipient developed apparent but clinically mild

post-transfusion hepatitis (immunocompetent)– 3 of these recipients cleared persistent viraemia after

intervention with ribavirin or alteration in immunosuppressive therapy

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UK response to the presence of HEV in blood donations

• SaBTO (Safety of Blood Tissues and Organs) recommended selective testing to provide HEV negative blood components for certain patients – screening to be carried out on pools of 24 donations– recommendation to be reviewed in 3 years

• SaBTO/NHSBT wrote to clinicians to raise the awareness of this problem and to provide links to dietary advice to patients

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HEV negative blood components• NHSBT decision to issue as standard, HEV negative

components– For neonates and infants < 1yr– For intrauterine transfusion and neonatal exchange transfusion– Pooled granulocytes– Imported methylene blue treated FFP and cryoprecipitate

• SaBTO - HEV negative components are indicated for– Patients awaiting solid organ transplant, from 3 months before

planned date or from date of listing and for as long as the patient is taking immunosuppressants

– Patients awaiting allogeneic stem cell transplant, from 3 months prior and for 6 months post transplant or as long as immunosuppressed

– Patients with acute leukaemia, from diagnosis unless/until decision made not to procede with stem cell transplant

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Issues surrounding implementation

• Screening implemented by NHSBT late Feb 2016

• How many donations need to be screened to ensure the provision of sufficient products?

• Selective screening requires significant manual intervention to select sample tubes

• Management of HEV RNA positive donors

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Screening within NHSBT• Pools of 24, reactive pools resolved directly to individuals• Roche cobas HEV RNA assay run on current screening

system (6800/8800 systems)• Confirmation in NTMRL by independent HEV RNA assay

and serology– Fortress HEV IgG and IgM assays– Inhouse RNA assay 100% LoD 100 copies/ml– Based on WHO international standard

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HEV positive donors• Blood donors deferred for 6/12 with automatic re-

instatement

• Component donors deferred until RNA negative and IgG positive (>1 IU/ml)– Currently resampled at 6/52 if Ab positive at pick-up– 8/52 if Ab negative at pick-up– Constantly reviewed

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Screening outcomes• Up to 01/09/16 a total of 159 HEV RNA positive donors

have been identified and confirmed– 139 whole blood donors– 20 component donors– Approximately 255,000 donations screened - 1:1600

• 7 pick-ups were not initially confirmed using the NTMRL in-house HEV RNA assay– 4/7 were seropositive at pick-up– 6/7 found to be HEV RNA positive following sample

concentration by ultracentrifugation– 1/7 confirmed on the basis of a subsequent sample

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Component donors• Component donors have archive of previous donation

retrieved and a f/u sample bled at 6 or 8/52 from pick-up – 4/20 were Ab positive (IgM & IgG) at time of pick-up– HEV RNA level, median 243 IU/ml, range 17 – 24,085

IU/ml– 4/20 had RNA positive archive samples from previous

donations (pre screening samples)

• 18 f/u samples obtained to date from 15 donors– 4/18 were still HEV RNA positive– 16/18 had IgG at high level >1 IU/ml

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Blood donors• Blood donors are not followed up but automatically re-

instated at 6/12 from pick-up without any further testing– returning blood donors are flagged on Pulse, without

affecting donation status, so that the pilot tubes from their returning donation are sent to NTMRL for investigation of their serostatus for information only

– 43/139 were seropositive on pick-up– 31/43 were both IgG & IgM positive, 3/43 IgM only and

9/43 IgG only

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Comparison of outcomes to date• Numbers are higher than expected

– 2012/2013 study - 1:2848– current incidence - 1:1600

• Overall viral loads are lower than expected– 2012/13 study - median 3900 IU/ml, range 50 - 2.37

x106 IU/ml – current - median 482 IU/ml, range 1- 8.07 x105 IU/ml

• Pick-ups– 2012/13 study – 57/79 (72%) seronegative at pick-up– current – 133/179 (74%) seronegative at pick-up

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Comparison of outcomes to date• Male/female

– 2012/2013 – 64% male, 36% female, – current – 69% male, 31% female

• Age– 2012/13 - median age male 52 yrs, female 50 yrs– current – median age males 48 yrs, female 39 yrs

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What has changed• Is the incidence of HEV in the population increasing?• Assay used for screening is at least 101 more sensitive

than the assay used for the study; did the study underestimate incidence?– Detecting lower level RNA positives now?

• Screening covers all areas of the country, study only covered south east

• Change in source of infection– Meat supply?

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Evolving picture• Protocols are still being adjusted

• Number of donations screened daily and variety of products required to be HEV negative on issue is constantly changing – implications for Donation Testing and Manufacturing

• Potential increase in post transfusion infection enquiries now that ‘HEV negative’ products are issued –implications for Microbiology Services

• Ongoing work with hospitals to encourage the appropriate requesting and use of HEV negative products