Proposal to Cease Testing Blood Donations for CMV

Proposal to Cease Testing Blood Donations for CMV Status Public Executive summary (200 words) In response to SaBTO recommendations for replacing CMV seronegative cellular blood components with leucodepleted blood components, an implementation project has been established pending approval from the Board. The proposed implementation date of January 2018 is considered a realist timeframe for this approach. Communication with clinicians indicates the acceptance of leucodepleted components as CMV safe, replacing the selection of CMV seronegative components. Information has been obtained regarding international practices and use of leucodepletion with respect to CMV. This paper sets out key information on the proposed replacement of CMV seronegative blood products with leucodepleted blood products, provides recommendations of the optimal strategy to achieve this, and takes into consideration patient groups that may be affected. Action requested (bulleted list) The Board is asked to: Note the implementation plans for the introduction of CMV safe blood products Approve the proposal to cease production of all CMV seronegative blood products that undergo leucodepletion and consider these products as CMV safe Approve the proposal to continue the production of CMV seronegative red cell and platelet components for intra-uterine transfusions and neonates Approve the proposal to continue the production of CMV seronegative granulocyte components for CMV seronegative patients Approve the proposal to continue the production of CMV seronegative blood components for seronegative and seropositive pregnant women that require transfusions throughout pregnancy Agree the recommendation to continue to implement CMV PCR as a screening method for early detection for all haemopoietic stem cell and solid organ transplant recipients Purpose of paper (1 paragraph) For over 30 years, there has been an ongoing debate regarding the use of CMV seronegative blood components versus the use of leucodepleted blood components. To date, the use of CMV seronegative blood products has been implemented to reduce the risk of transfusion-transmitted cytomegalovirus in patients considered at risk. Leucodepletion has been performed on all blood products in the UK since 1999. This paper provides an overview on the use of CMV seronegative blood products in comparison to the use of leucodepleted blood components. This paper provides an assessment of patient groups that are considered at risk of CMV and considers advantages to ceasing of CMV testing in the UK. Background Cytomegalovirus (CMV) is a pervasive, cell-associated prototypic virus that is a member of the betaherpesvirus subfamily (Ziemann and Hennig, 2014; Ljungman, 2004). CMV mostly causes asymptomatic infection or mononucleosis-like-infection in an immunocompetent host; however, in an immunocompromised host it can result in chronic and persistent infection with devastating outcomes (Seed et al., 2015). Patient groups that are considered at risk of life-threatening transfusion-transmitted CMV infection includes CMV seronegative patients undergoing haematopoietic stem cell transplantation and solid organ transplantation, low birth weight and premature neonates, foetuses that require intrauterine transfusion, CMV seronegative pregnant women, and highly immunocompromised patients, such as those with malignant disease (Ziemann and Hennig, 2014; SaBTO, 2012). CMV infection is frequently encountered throughout childhood and an estimated 50 60% of the adult population in the United Kingdom (UK) are CMV positive (SaBTO, 2012). CMV infection can be transmitted both horizontally and vertically (Crough and Kannah, 2009). Horizontal transmission occurs through contact with body fluids, such as urine and saliva, sexually through genital secretions, blood transfusion, and hematopoietic stem cell and organ transplant (SaBTO, 2012; Sia and Patel, 2000). Vertical transmission occurs from mother to child, via delivery and breast milk (Crough and Kannah, 2009). Additionally, congenital CMV infection is highly prevalent and may arise through a primary maternal infection during pregnancy (Crough and Kannah, 2009). Following exposure to CMV and the initial infection, the virus remains in a dormant state (Ljungman, 2004). Seroconversion of the host occurs between 6 8 weeks and mounts an immune response, producing CMV specific immunoglobulin (IgG) (Seed et al., 2014). In the UK, there is an estimated seroconversion rate of 1% per annum (SaBTO, 2012). CMV therefore has a window period, in which there may be underlying viremia and high viral load (Liberman et al., 2011). Subsequently, a CMV seropositive individual is considered to have been infected, whilst at the same time considered potentially infectious due to the life-long persistence of the virus (SaBTO, 2012). Transfusion-transmitted CMV infection is regarded as a potential threat to the safety and sufficiency of the blood supply for a multitude of reasons (Roback, 2002). Firstly, transfusion-transmission of CMV that is present in blood and blood components can result in the infection of naà ¯ve recipients (Ziemann and Hennig, 2014; Ljungman, 2004). Secondly, transfusion-transmitted CMV is acknowledged as a primary source of infection, in which donor infectivity is an underlying reason, that may result in CMV disease (Ljungman, 2004). Thirdly, CMV seropositive recipients that are exposed to blood products containing CMV may cause reactivation of the latent virus or reinfection from a new strain (Ziemann and Hennig, 2014; Ljungman, 2004). However, the risk of transfusion-transmitted CMV infection has been significantly reduced through the implementation of leucodepletion and production of specific CMV negative blood and blood products (Ziemann and Hennig, 2014). Since November 1999, all blood products (unless state otherwise) produced by the UK blood service are leucodepleted (Guidelines for the Blood Transfusion Services in the United Kingdom, 2013). Initially, this was a response taken to reduce the risk of variant Creutzfeldt-Jakob (vCJD) disease in blood transfusions; however, this risk reduction strategy has proven beneficial in additional areas of transfusion science and blood safety (Guidelines for the Blood Transfusion Services in the United Kingdom, 2013). The UK specification for leucodepletion is: more than 90% of leucocyte-depleted components should contain less than 1 x 106 leucocytes and more than 99% of components should contain less than 5 x 106 leucocytes (SaBTO, 2012). The specification for 99% of components is regarded as the level in which blood components are deemed CMV safe (SaBTO, 2012). Leucodepletion has considerably reduced the risk of transfusion-transmitted CMV, to a level that mirrors the selection of CMV negative blood products (Ljungman, 2004; Bowden et al., 1995). However, it has yet to be shown to what extent the techniques are comparable and how this may affect patient groups considered at risk of CMV infection (Ljungman, 2004). It is important to note that whilst leucodepletion removes most white cells from blood products, it is not 100% effective (Kumar, 2006). Therefore, there is a residual risk of CMV transmission in blood products of recently infected donors (Kumar, 2006). This occurs in the window period of the virus from 6 8 weeks to 1 year following seroconversion, in which the virus may be present in the remaining plasma or white cells (SaBTO, 2012; Ziemann et al., 2010; Drew and Roback, 2007). CMV transmission can occur in both donors that have an active infection, including primary or reactivated, or latent infection (Azevedo, 2015). The leading mechanism of transfusion-transmitted CMV infection is through mononuclear cells that are believed to harbour a latent infection (Ljungman, 2004). CMV is thought to persist in circulating monocytes, in which an estimated 1 in 10,000 and 1 in 100,000 peripheral blood monocular cells carry CMV (SaBTO, 2012). Pennington et al (2001) conducted a study that provided evidence to suggest that leucodepletion filters are highly effective in removing mononuclear cells and may reduce CMV levels to 0.1 viral copies per mL in leucodepleted blood. Furthermore, blood products that have been leucodepleted are monitored continuously, using flow cytometry, to assess efficiency (SaBTO, 2012). Moreover, the prospect of having a component issued that contains a leucocyte count above the UK specification can be calculated (SaBTO, 2012). In regards to testing for transfusion-transmitted CMV, there are two main methods that are used. This includes serological testing and Nucleic Acid Technology (NAT) testing (SaBTO, 2012). Serological testing involves the use of antibody screening which is accomplished through the use of enzyme immunoassay (EIA) tests that detect total CMV antibody (Ross, 2011). Screening for CMV infection using serology is the most prevalent method used and is based on the agglutination principle (Ross, 2011; Ljungman, 2004). The method offers several advantages as it is fast, highly sensitive, and highly specific, constituting an ideal screening test (Ross, 2011). This method, however, is associated with two key limitations. Firstly, the window period presents a challenge in regards to activation of the primary infection and seroconversion (Ljungman, 2004). Secondly, there is a risk of obtaining false negative screening results (Ljungman, 2004). Therefore, there is a risk that CMV may be transmitted via a CMV seronegative component (SaBTO, 2012). In addition to serology, NAT testing is used to detect CMV DNA and subsequent infection (Ross, 2011). Several qualitative and quantitative assays are available for this method (SaBTO, 2012). This screening method is associated with variation in the sensitivity and specificity of available assays (Roback et al., 2003;2001). Studies have highlighted inter-laboratory variation for samples containing low viral load (Pang et al, 2009; Wolff et al., 2009). As a result, a CMV DNA reference has been developed for comparison of results when sensitivity is a challenge (Ross, 2011). To produce a supply of CMV negative blood and blood components, several donations are screened each year. Overall, an estimated 25 40% of donors are CMV antibody positive, dependent on age. The production and use of CMV negative blood components forms a significant undertaking for the blood service. According to the report released by the Advisory Committee on the Safety of Blood, Tissues, and Organs (SaBTO) in March 2012, in the last 5 years, the number of CMV negative platelets and red cells has increased. The report notes that NHSBT charge  £7.76 for CMV negative red cells and platelets, covering the inventory and screening costs. This amounts to a total of  £2.5 million per annum, in which  £230,000 is dedicated to apheresis platelets and  £2,270,000 to red cells. The number of donations that are screened is greater than the number of donations that are issued as CMV negative. In addition, not all donations screened will deliver a negative result. Subsequently, it has been proposed that the use and production of CMV negative components is reviewed. SaBTO recommends the use of a single inventory and accepting leucodepleted blood products as CMV safe. This is outlined in section 6. Proposal 6.1 This proposal has been written to ask the blood centre to consider ceasing CMV testing for an agreed list of blood products and in its replacement, support the use of leucodepleted blood components that are considered CMV safe. 6.2 The proposal of ceasing CMV testing for the replacement of leucodepleted components that are considered CMV safe is associated with several advantages. Inventory management Management of a single inventory would offer an advantage to blood banks and hospitals. This would be a preferred method to the current used for ease of access. NHSBT must ensure CMV negative components are available across the country on multiple NHS sites. To achieve this, NHSBT spend approximately  £95,000 n the delivery of CMV negative components. Wastage The Belgian Blood Service have produced a report that states implementation of pathogen reduction in platelets to inactivate CMV may result in an overall decrease in the wastage of platelets. A 1.5% reduction is estimated, which would result in a saving of  £0.22 million. Improved compliance with safety initiatives Reduction in the wastage of blood products and implementation of a single inventory would enable the target of 80% platelets by apheresis to be met sooner. Furthermore, this would support transfusion related acute lung injury (TRALI) prevention, as the number of male platelet donors would increase due to enhanced recruitment strategies. This would further enable costs of HLA antibody screening of potential female platelet donors to be avoided. Reduction in hospital blood bank workload Because of the removal of CMV seronegative components, the workload in hospitals and blood banks would decrease. Staff would no longer have to spend time ordering or checking platelets as CMV negative components. This would have a direct positive impact on the stock management. Staff that may potentially be free from the responsibility associated with CMV negative products will be able to invest their time elsewhere, to improve the efficiency of the blood service. Reduction in clinical errors The Serious Hazards of Transfusion (SHOT) have reported from 2000 to 2010, 1040 reports were filed stating special requirements were not met. Of these, 83 were attributed to the inappropriate selection of blood components that were not CMV negative. 65 were attributed to selection of blood components that were both CMV negative and irradiated components. However, none of these cases reported CMV transmission. 6.3 The proposed implementation date of this project is January 2018. Further clinical guidance is to be requested from SaBTO who will instruct in the implementation plan of this proposal. 6.4 Consideration must be given to specific patient groups that are considered at risk of CMV infection. This includes: Haematopoietic stem cell transplant patients Leucodepleted blood products can be used for all patient groups post haemopoietic stem cell transplantation Patients receiving transfusions and may need a transplant also may receive leucodepleted products CMV PCR should be used to assess CMV infection for patient groups to enable early detection and treatment Intra-uterine transfusions and neonates CMV negative components should be provided for intra-uterine transfusions and neonates (up to 28 days post expected due date) All blood products produced at a reduce size for neonates should be CMV seronegative Pregnant patients CMV seronegative blood products should be provided to pregnancy women, regardless of CMV status. Components should also be provided for transfusions throughout pregnancy, for example in the case of haemoglobinopathies. HIV and immunodeficient patients These patients should receive leucodepleted blood as there is no evidence to suggest a benefit with the use of CMV seronegative components Organ transplant patients Organ transplant patients should receive leucodepleted blood only CMV PCR should be used to assess CMV infection for patient groups to enable early detection and treatment Granulocytes Granulocyte components provided should be CMV seronegative for all patients as these components cannot be leucodepleted 6.5 Potential impact on blood centre employees includes the reduction in workload. Considerations needs to be given towards how this workload can be replaced. Consideration also needs to be given towards the possibility of redundancy, as a successive effect of this proposal. 6.6 The board must be aware of the clinical and financial benefits of this proposal; however, the board should also be aware of potential limitations regarding the operation of the proposal. The board should also be aware of potential legal repercussions should someone become infected with CMV through a blood component. 6.7 Stakeholders that will need to be involved include both internal and external. Internal stakeholders will include the manager of the NHSBT site and the head of testing. External stake holders will need to raise public awareness regarding the change in production of seronegative CMV components. Doctors will also need to be aware of the changes implemented to CMV negative components and be aware of who this applies for. E.g. certain patient groups will still receive CMV seronegative components. References A. Ross, S., Novak, Z., Pati, S. and B. Boppana, S. (2011). Overview of the Diagnosis of Cytomegalovirus Infection. Infectious Disorders Drug Targets, 11(5), pp.466-474. 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