Fulminant Transfusion-Associated HEV Infection Despite Screening, England, 2016-2020





HEV and Blood Donation

Hepatitis E virus (HEV) infections can have severe, even fatal implications for immunocompromised blood and platelet recipients. In England, all blood donations are screened for HEV but at present, in addition to the UK, only Ireland and the Netherlands perform universal donor screening. Some countries perform selective screening for components that are supplied for plasma fractionation or used for immunocompromised patients, but many countries have elected not to perform any screening on the basis of low risk and cost-effectiveness.

 

A recent study by Harvala, Reynolds, Brailsford and Davison in 20221 looked at the prevalence of HEV RNA in apheresis and whole blood donors in England between 2016 and 2020. It sought to determine the risk of non-detection of HEV and reassess the extent and impact of transfusion-transmitted infections in the presence of a national screening protocol. HEV RNA testing was performed in pools of 24 donations (Cobas MPX for use on the 6800/8800 systems, Roche Diagnostics).

 

What did the study find?

Screening and transmission – A total of 6,297,904 blood donations, including 350,323 apheresis and 5,947,581 whole blood donations were screened for HEV RNA in England by NHS Blood and Transplant (NHSBT). This screening identified and intercepted 1727 RNA-positive donations. Overall, HEV RNA was detected in 1:2000 donors (varying from 1:1258 in 2016 to 1:2591 in 2017) and 1:3647 donations (varying from 1:1258 in 2016 to 1:2591 in 2017).

 

A total of 107 HEV RNA positive apheresis platelet donations were identified during the 5-year study period. Retrospective individual HEV RNA testing of the donors’ previous donations (98 in total) identified nine HEV RNA positive donations. These donations were undetected by pooled screening due to the low viral loads (all around/below 37 IU/mL) and the components were supplied for clinical use. Lookback investigations identified 18 recipients of the platelet components produced from these indicated donations. All the components were traced via lookback investigations, and information was received on ten of the recipients. Two of these recipients were shown to have acquired their infection via transfusion.  Transmissions were confirmed by sequence analysis.  All suspected transfusion-transmitted infections investigated in England by NHSBT are reported to the NHSBT/UKHSA epidemiology unit and to the UK’s hemovigilance scheme, SHOT (https://www.shotuk.org). Between 2016 and 2020, 6 cases of possible transfusion-transmitted HEV were reported and investigated by NHSBT. Two cases were confirmed (as above), with one further probable transmission, which could not be confirmed.

 

Predicting the risk of non-detection – Incidence was assumed to be equal to the HEV RNA positivity rate in donors. To estimate risk, incidence was multiplied by the duration of the window period in years for HEV NAT using 0.019 years corresponding to 7 days and 0.038 years corresponding to 14 days. These parameters were based on expert opinion in the absence of any published values. The annual risk was calculated for apheresis and whole donations per million donations tested. It was combined with the estimated number of apheresis and whole blood donations each year, to give an approximate number of HEV RNA-positive donations that wouldn’t be detected by the current screening protocol.

 

The annual HEV incidence and estimated risk of non-detection were noted to fluctuate year on year for both apheresis and whole blood donors. Risk for both groups of donors increased two-fold if a window period of 14 days instead of 7 days was used. The study predicted that between 12 and 23 apheresis platelet donations and between 177 and 354 whole blood donations positive for HEV RNA would not have been detected over the 5-year study period. Despite uncertainty in the parameters, this predicted risk is very similar to the true risk demonstrated so far for apheresis donations: 9 apheresis donations positive for HEV RNA were not detected by initial pooled screening between 2016 and 2020. Although the model predicted that the screening is missing a much larger number of whole blood donations, this doesn’t directly equate to transmission risk. Infectious HEV is considered to partition into the plasma component of a donation. The residual plasma volume in a unit of red cells is 7-fold lower than in a platelet product, which may therefore, reduce the transmission risk of red cell transfusions.

 

Implications for the Blood Service

With only two confirmed cases of transfusion-transmitted HEV infection in 5 years, one could argue that the pooled screening strategy has largely eliminated infectious HEV from the blood supply in England. However, the residual risk calculations argue against this. While pooled HEV screening is generally effective at identifying donations with low-level viraemia, it repeatedly missed donations with a HEV RNA levels below 37 IU/mL. Similar findings were obtained in Germany, where all HEV RNA positive donations exclusively identified by individual NAT screening had viral loads below 25 IU/mL.2,3 This is important because even low levels of HEV RNA can lead to a severe, even fulminant infection in the recipient. It is worth remembering that the minimum infectious dose of HEV RNA resulting in an infection in a recipient of blood transfusion, remains unknown.

 

The study by Harvala et al1 is also a reminder to clinical and transfusion communities of the response required in the event of a confirmed HEV infection.  Active lookback investigations are needed to follow-up asymptomatic recipients who have received blood components that contained HEV RNA.  The study showed that individuals with a HEV infection can be asymptomatic for weeks without the presence of HEV antibodies but subsequently develop very atypical symptoms (i.e., multiorgan failure).  The outcome in some patients can be fulminant.  Recipient testing must include both HEV RNA and HEV serology to exclude or confirm a transmission event.

 

References 

1 Harvala H, Reynolds C, Brailsford S, Davison K. Fulminant Transfusion-Associated Hepatitis E Virus Infection Despite Screening, England, 2016-2020. Emerg Infect Dis. 2022 Sep;28(9):1805-1813.

2 Vollmer T, Diekmann J, Knabbe C, Dreier J. Hepatitis E virus blood donor NAT screening: as much as possible or as much as needed? Transfusion. 2019 Feb;59(2):612-22.

3 Cordes AK, Goudeva L, Lütgehetmann M, Wenzel JJ, Behrendt P, Wedemeyer H, et al. Risk of transfusion-transmitted hepatitis E virus infection from pool-tested platelets and plasma. J Hepatol. 2021 Aug 27.


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