Hepatitis E and the English blood supply Mhairi Webster Microbiology Senior Scientist National Transfusion Microbiology Reference Laboratory With thanks to Dr Alan Kitchen
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
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
HEV in the English blood supply Joint NHSBT/PHE study in 2012-13 1 225,000 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
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
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 products 1 Detailed dietary questionnaire sent to all positive donors 1 Said B et al; Hepatitis E virus in England and Wales: indigenous infection is associated with the consumption of processed pork products. Epidemiology & Infection, 2014
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
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
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
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
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
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
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
HEV positive donors Blood donors deferred for 6/12 with automatic reinstatement 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
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
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
Blood donors Blood donors are not followed up but automatically reinstated 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
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 x10 6 IU/ml current - median 482 IU/ml, range 1-8.07 x10 5 IU/ml Pick-ups 2012/13 study 57/79 (72%) seronegative at pick-up current 133/179 (74%) seronegative at pick-up
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
What has changed Is the incidence of HEV in the population increasing? Assay used for screening is at least 10 1 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?
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