Challenges for the maintaining the microbiological safety of the UK blood supply

Donor selection and donation testing

Ensuring blood safety depends on donor selection, safe venesection, and the storage, processing and testing of donations. Potential donors are screened to not only ensure that it is safe and appropriate for them to donate, but also to identify those behaviours that are associated with higher risk of infection with a transmissible agent. These include higher risk sexual behaviours, injecting drug use and potential exposure to infections through travel. If a potential donor is considered at risk, then they are deferred, either temporarily or permanently. In the absence of identified risk, blood samples from donors are tested for the presence of specific pathogens or antibodies. Blood components (red blood cells, platelets and plasma) might be subjected to additional mitigations, such as leucocyte reduction, which became routinely applied to blood components in the UK in 1999 to minimise the risk of transmission of variant Creutzfeldt–Jakob disease (vCJD). The UK has moved toward a more individualised risk-based approach for donor selection, which keeps patient safety at the heart of any decision.¹⁰ The rules are, wherever possible, evidence based on risk and behaviours and adapted in light of local epidemiological data. In other areas, the risks of TTIs have been further reduced by introduction of testing for hepatitis E virus (HEV) and improved testing of blood for hepatitis B virus (HBV) to reduce the risk of transfusion from those donors whose levels of circulating HBV DNA are below the limit of detection but might still infect the recipient.⁵

Measures to minimise the risk of transfusion-transmitted infection

Currently, mandatory tests are performed on each blood donation for a variety of infectious agents (Table 1). Universal screening for antibodies to the HBV core protein (anti-HBc) to identify past or occult infections with HBV has recently been introduced. In addition, additional selective screening methods are used for new donors or for those who have recently travelled. However, for some infections, there are no appropriate tests; thus, reducing risk depends on excluding potential donors on the basis of screening questions and/or physical approaches, such as leucocyte reduction or pathogen inactivation technologies. Therefore, to reduce the risks of transfusion transmission of prion-associated diseases (for which there are no recognised appropriate tests available), screening criteria are used (Box 1), although these indications for deferral are being reviewed.

Surveillance for transfusion transmitted infections

During 2020, of the 1.7 million blood donations screened in the UK, 176 were confirmed positive for HBV, hepatitis C virus (HCV), HIV, human T lymphotropic virus (HTLV) or treponemal antibodies, and were discarded.¹¹ Three-quarters were detected in donations from new donors. Of the donations, 458 tested positive for HEV and were discarded. Of the 44 donors with recent infections, 12 did not fully disclose deferrable risks at the time of donation.¹¹ Thus, donor screening will not identify all potential donors at risk of having a transmissible infection.

The UK operates an active haemovigilance scheme to monitor all adverse outcomes of transfusions (Serious Hazards of Blood Transfusion (SHOT)).⁸ For TTIs, there is a legal duty to report cases to the Medicines and Healthcare Products Regulatory Agency (MHRA). In 2021, 2,194,215 units of blood components (1,607,174 red cells and 284,927 platelets) were issued to UK hospitals. During that time, the UK Blood Services investigated reports from hospitals of 115 suspected bacterial incidents and 10 suspected viral incidents: of the bacterial incidents, none were confirmed as TTIs and, of the viral TTIs, there were two cases of possible HCV. Between 1996 and 2021, 42 confirmed transfusion-transmitted viral infections were documented in the UK, involving 35 donors. Among these, HBV (n=12) and HEV (n=12) were the most commonly reported proven viral TTIs. All except two HEV transmissions were reported before HEV RNA screening was introduced in April 2017.

Bacterial screening of platelet components as a risk-reduction measure by UK blood services identifies infection in 0.05% or less of those tested. These components are discarded and, over the past 5 years, there have been no reported and/or confirmed cases of TTI related to bacteria or malaria.^12,13

Although these data are reassuring, there is no room for complacency. Collection of data through reporting of adverse events will miss infections that do not initially present symptomatically. Furthermore, we have seen even severe disease undiagnosed at the time because infections were not suspected clinically. Reported cases will inevitably be an underestimate of the true number of incidents because some cases will not be recognised, correctly attributed to the transfusion or reported.

Human error

Evidence from the SHOT report⁸ indicates that human error might be responsible for adverse events at all stages of the vein-to-vein journey from donor to patient. However, we are not aware of instances where human error has led to a TTI.

Accuracy of donor responses

Implicit for the safety of donation is that questions in the donor health check questionnaire are answered accurately. There are several reasons why the responses might not be accurate, but levels of intentional misrepresentation are thought to be low.¹⁵ Evidence suggests that volunteer donors are good at assessing risk and do understand the importance of providing pre-donation information.¹⁰ However, non-compliance with the questionnaire represents a significant proportion of those potential blood donors with potentially transmissible infections.^16–19 Some potential donors who are at risk of having a potential transmissible agent do not realise that their behaviour is considered a risk.²⁰ Thus, non-disclosure, for whatever reason, of relevant risk behaviour remains a small, but important cause of potentially infectious donations.

Testing does not identify all potentially infectious donation

Current testing strategies rely on a combination of approaches, using mini-pools for nucleic acid-based testing (NAT) and using individual donations for serological testing. Mini-pools allow a larger number of samples to be tested and might make such strategies more cost-effective. Current strategies do not always detect those donations in which the amount of infectious material is below the limit of detection using current techniques but might still transmit infection.

There are many other infections with the potential to be transmitted by transfusion, such as human parvovirus-19, human herpesvirus-8 and hepatitis A virus. With these viruses, the risk is low and, thus, testing might not be cost-effective in the UK, although it might cost-effective in other jurisdictions where the epidemiology is different. The rationale is varied and relates to the severity of disease, the epidemiology of the infection, the use of donor selection criteria and exclusion of those donations that are at risk, the characteristics of the test and cost-effectiveness. Other causes of failure to identify potentially infectious donations include human and technical error, although reported cases are rare.²¹

Some infectious agents cannot be detected using currently available techniques

Some blood-borne infections, such as prions, cannot as yet be detected using validated technologies licenced for large volume use; thus, there is a reliance on the donor health check to identify and exclude higher risk donors.

New and emerging infections

Many factors, including increasing travel and climate change,^22–24 mean that some TTIs, such as West Nile virus or Zika virus, currently rarely seen in the UK, are likely to become more prevalent in the UK population. Outbreaks of infections, including Ebola virus¹⁴ and most recently monkeypox virus, have occurred where the potential transmission risk arises from the ability of the virus to establish a moderate and sustained viraemia during the prodromal asymptomatic stage of infection.²⁵

Contamination of blood or products following collection

Acquired infectivity or contamination are possible during any stage of the journey of the blood from donor phlebotomy to recipient transfusion, although these events are rare. Stringent aseptic techniques and closed systems have removed much of the risk. Measures such as pathogen reduction technologies and/or bacterial sampling techniques could help remove these risks and reduce the risk to the recipients. Platelets are currently stored at 22°C to maintain optimum viability and, thus, present a greater risk of infection compared with blood (stored at 4°C).²⁶

Horizon scanning

SaBTO relies on the joint unit managed by NHS Blood and Transplant (NHSBT) and the UK Health Security Agency, which reports through JPAC to alert the Committee of emerging infections relevant to blood, tissues and organ donation safety. The unit monitors European and global updates on infections that pose a risk to the UK, including babesia, Chikungunya virus, Crimean-Congo haemorrhagic fever, dengue, malaria, pandemic and avian influenza, tick-borne encephalitis, West Nile virus and Zika virus.²² Predicting the future is never easy (at least accurate prediction is rarely achievable) and, although this approach is necessary, it cannot be relied on to identify all emerging and new infections. Thus, warnings of a possible epidemic of monkeypox virus were not considered even though, with the benefit of hindsight,²³ outbreaks were postulated nearly a decade ago, as a consequence of the falling rates of smallpox vaccination. A further challenge is that the risk behaviour of blood donors might differ from that of the general population²⁴; thus, simple extrapolation to the blood donor could give rise to misleading conclusions.

For those transfusion-transmissible viruses for which universal screening has been implemented, estimating transfusion risk is well established using models based on the incidence of infection in the donor population and the infectious window period. However, this approach is not applicable to emerging infectious agents because the incidence of infection in the donor population is not known and an assay window period is not applicable. Two models are available for estimating the risk: the Biggerstaff-Petersen model and the European Upfront Risk Assessment Tool (EUFRAT), with different strengths and limitations; thus, more work is needed to develop a robust model.^14,25

Inevitably, some predictions will not be borne out: for example, xenotropic murine leukemia-related virus was reported to be associated with prostate cancer and chronic fatigue syndrome, and present in the blood of asymptomatic blood donors. It was later shown that the virus did not affect humans but was a laboratory contaminant from cell lines.²⁵

Enhanced recognition and reporting

There can be no doubt that the number of TTIs reported is an underestimate. Healthcare professionals must be continually reminded that TTIs should be considered and that reporting is mandatory.

Improving donor questionnaires

Designing questionnaires for blood donors is problematic: there must be continuous review and, where appropriate, revision. Language must be clear, and questions must be unambiguous, must not cause offence and must be available in formats that are appropriate for all potential donors. The need to avoid discrimination must be balanced with blood safety²⁷ but, in our view, the safety of the blood supply must take priority. Pre-donation computer-based questionnaires might be associated with increased compliance.²⁸

Improved laboratory detection

Improved detection of donations with potentially transmissible infections will reduce TTIs. Better use of current technologies and early introduction of new technologies both have a role. Currently, NAT testing is carried out on pooled samples to reduce cost. Introduction of individual testing could reduce the risk of missing potential infections but will increase cost and might have logistical implications. Similarly, reducing the cut-off points for defining positives will result in a trade-off between excluding infected samples and discarding non-infectious samples. New technologies, such as next-generation sequencing, allow potential identification of new infections and are under evaluation as a means to provide more comprehensive screening of a wider range of potential blood-borne viruses and bacteria in blood donations.

Pathogen reduction/inactivation technologies (PITs)

These technologies primarily target nucleic acids and, therefore, can inactivate viruses, bacteria, and parasites in plasma and platelets. There are several commercially available technologies for platelet inactivation.²⁹ These technologies can inactivate a range of microbial infections and, thus, could offer some benefit from both known and unknown infections. PITs might also minimise the risk of transfusion-associated graft-versus-host disease and avoid the need to provide irradiated blood components for patients at risk. There are concerns that PITs might affect the haemostatic quality of platelets. An alternative measure for reducing the risk of bacterial contamination of platelets is the use of cold storage at 4°C, as for red cell units. There is considerable interest in the enhanced haemostatic effectiveness of such platelets in patients with major haemorrhage.

Keeping prescribing to the minimum clinically needed

It is axiomatic that the best way to avoid the risks of transfusion is not to give a transfusion where it is not needed or where safer alternatives are available.³⁰ For example, some patients are given a transfusion to improve haemoglobin levels for whom oral iron would be as effective,⁶ and the use of tranexamic acid reduces major bleeding and need for transfusion in surgery.³¹ Other examples include the inappropriate use of fresh-frozen plasma or platelets in an attempt to improve clotting where these are not indicated.³² Thus, clinicians should ensure the use of blood, blood products and components is kept to the minimum that is clinically indicated.