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• W3046602120 abstract "Transfusion-associated graft-versus-host disease (TA-GvHD) is a rare but largely fatal complication of transfusion characterised by fever, rash, diarrhoea, hepatitis and pancytopenia 2–30 days after transfusion. Diagnosis is confirmed detecting persistent donor lymphocytes from a transfused component in affected tissue biopsy or peripheral blood of recipients.1-3 Diagnosis can be challenging due to competing differentials and lack of leucocytes. TA-GvHD pathophysiology is extrapolated from case reports/case series and experimental mouse models. Current thinking is that transfused lymphocytes that are not eliminated by the recipient immune system proliferate and attack recipient organs, which are recognised as foreign, including recipient bone marrow.4, 5 Three main factors appear to influence risk: the lymphocyte load in the product [reduced by leucoreduction (LR)], immune competence (specifically impaired cellular mediated immunity) and shared human leucocyte antigen (HLA) type between recipient and donor (related or unrelated). Components implicated have largely been (fresh) red cells, historically fresh whole blood, platelets, and fresh (never frozen) plasma.6 However, cases continue to be described in patients with and without these risk factors, demonstrating how our ability to predict this complication remains limited.6 Universal pre-storage leucoreduction of blood was introduced in the UK in 19997 and has become standard in Western Europe over the past 20 years.8 This policy change is credited with reducing the number of cases reported to haemovigilance systems in recent years by reducing the lymphocyte load in the product.5 Approaches to further reduce harm currently rely on identifying patients at risk due to underlying immunocompromise or products known or suspected (e.g. family donations) to be HLA matched. In these circumstances, irradiation of blood components is recommended in the previous British Committee for Standards in Haematology (BCSH) guidelines.9 Irradiation of blood components using gamma- or X-rays has been shown to prevent proliferation of transfused lymphocytes in the recipient by inactivating lymphocytes via cross-linking DNA.5 Universal irradiation of blood components could avoid the need to differentiate between recipients and simplify stock management. However, irradiation affects the quality of red cell concentrates (particularly), with rises in potassium concentration and haemolysis over time.10, 11 By limiting the shelf life, universal irradiation of red cells would be both wasteful (due to the reduction in lifespan) and risks a potentially inferior product avoidably being transfused. Irradiation to order is performed commonly in the USA, where transfusion services are very differently organised, with many academic centres having the ability to secondarily process blood components4 – further comments on the applicability of this guidance to USA transfusion practice can be found later in this Commentary. In the UK, where irradiators are usually located in the blood service, irradiated units must be specifically ordered and risks maintaining a dual inventory to avoid delays. As inventory management is not the focus of this guideline and this aspect is not addressed. Fortunately, blanket irradiation is practical for platelets, as the quality of the product and shelf life is unaffected.4, 12, 13 This is performed by a number of blood services, although not universally throughout the UK. Decision-making and formulating recommendations in this area are difficult. The feared adverse event is rare (making data collection challenging) and has a high fatality rate. Randomised controlled trials are neither feasible nor ethical and the evidence that exists is observational or based on laboratory data. The British Society of Haematology (BSH) has updated their guidance on indications for use of irradiated blood components based on recent and historic publications, and relevant UK Serious Hazards of Transfusion (SHOT) reports.14 The authors emphasise that their guideline aims for risk reduction or mitigation rather than elimination – as previously noted, TA-GvHD has been observed in the absence of standard risk factors. TA-GvHD has been linked with fresh blood components in reported cases, possibly due to a reduction in T-cell viability or antigen expression.2 The new guidance recommends red cell units >14 days after collection (if irradiated units unavailable in urgent situations) and similar advice was recently incorporated into Canadian guidelines also.15 Modern medicine now includes an array of treatments that induce immune defects raising the question regarding whether irradiation of blood components is indicated for recipients. These clinical practice changes include the expansion of indication of pharmaceutical agents already in use (e.g. alemtuzumab in multiple sclerosis, as immunosuppressive therapies after solid organ transplantation), and novel therapies [chimeric antigen T-cell therapy (CAR-T)]. A strength of this guideline is that it examines these situations in this update and attempts to provide guidance for these complex patients, based on the degree of immune competence expected in the recipient. The recommendation that irradiation is not required even if anti-lymphocyte globulin or alemtuzumab are used in solid organ transplantation may make inventory management easier for hospital transfusion laboratories and simplify shared-care arrangements. Immune incompetence in fetuses and neonates is well described. Historic cases of TA-GvHD were described in the past following intrauterine transfusion (IUT) and neonatal exchange blood transfusion.16 The recommendation for irradiation of components in these circumstances has not changed although the recommendation for small volume ‘top-up’ transfusions for post-natal transfusions following IUT has been removed. The authors' rationale is that this is less likely with the advent of modern processing methods plus the absence of affected cases of TA-GvHD in those patients in this category who did not received irradiated components. Irradiation of blood components for neonates or infants in other circumstances without a known or suspected defect of cellular immunity is still not recommended. Helpfully, in this latest revision, the authors define cellular immunity defects. The rise in plasma potassium in red cell components following irradiation is a potential risk for neonatal recipients, given their vulnerability to hyperkalaemia. This is exacerbated by a large volume transfusion such as exchange red cell transfusion hence, the recommendation to transfuse as close to time of irradiation as possible (24 h) remains. Shared donor and recipient HLA alleles (especially where the donor are homozygous for the shared allele) is a longstanding known TA-GvHD risk factor.4 Therefore, the recommendation to irradiate cellular blood components donated by close family members or from volunteer HLA matched donations (e.g. HLA matched platelet donations) remains unchanged. Any policy that requires prescribers to order a specific product carries the dual risks of omission (not ordering when indicated) and commission (ordering when not required). Unsurprisingly, the former is common. SHOT data on omissions reassuringly shows no cases have been associated with TA-GvHD, consistent with the assumption that this is an uncommon phenomenon and the incidence fell following universal leucoreduction, which mitigates risk further that leucocyte reduction does mitigate the risk, given that the incidence fell after the introduction of universal leucoreduction in the UK. However, given the rarity of TA-GvHD, overall evidence is insufficient to remove the need for irradiation for most indications. What feasible alternatives to irradiation does the future hold? Filtering to decrease the number of leucocytes mitigate the risk of TA-GvHD may be one approach. An intriguing study by Chun et al.17 demonstrated a reduction in the residual leucocyte count in the product, although not sufficient to confirm a reduction in TA-GvHD and came at the expense of approximately 20% of the red cell content. Pathogen reduction (by amotosalen- or riboflavin-based methods), developed to reduce the risk of bacterial and other infectious transfusion transmitted infections, presents another strategy. Due to nucleic acid cross-linking, it can result in reduced lymphocytes able to proliferate.18 Data from a manufacturers' laboratory study suggest it may do so more efficaciously5 and pathogen-reduced platelets do not need to be irradiated. However, pathogen reduction is still in development for red cells where the greatest disadvantage to irradiation lies. While frustrating to those tasked with writing guidelines, the lack of recent data in many ways is encouraging, as it suggests that the phenomenon of TA-GvHD has remained rare and that current risk reduction methods are effective. Changes in this area are more likely to be driven by changes in blood component processing than abandoning the feasible risk-reduction methods that have served us well to date. As noted and well described by our colleague Dr Ní Loingsigh, TA-GvHD is a highly lethal adverse event with limited treatment options.4 As such, there has been much emphasis in the global transfusion medicine community on averting this hazard. From the preventative standpoint, irradiation of cellular blood components has emerged as the most effective means to inactivate residual T lymphocytes within cellular blood components, thereby halting their engraftment in transfusion recipients. Some institutions,19 and Japan as a country,20, 21 are applying universal irradiation for their cellular blood components. However, given the potentially deleterious side-effects of irradiation on stored blood components22 and the reduction in ‘shelf life’ of some irradiated units,4 it may not always be practical nor feasible to irradiate every cellular blood component in a blood bank's inventory.23 Thus, several practical questions regarding irradiation remain, particularly in the USA, with those at the forefront being: (i) when should blood banks irradiate products according to available evidence or best clinical practice?; (ii) which products qualify for irradiation?; and (iii) which patient populations need products to be irradiated? To cause no harm, we have to balance the limited risk of irradiation for most patients versus the substantial risk of non-irradiated cellular blood components for susceptible patients. Unfortunately, we cannot recognise all such patients by routine clinical methods. T-cell mediated immunosuppression may be harmful, even when subtle and not progressing to clinically apparent TA-GvHD. If in doubt, we should generally decide in favour of irradiation. In summary, Foukaneli et al.14, on behalf of the BCSH Blood Transfusion Task Force, have composed a vital and highly practical update on the use of blood component irradiation to prevent TA-GvHD. This document should be of great value to blood banks and transfusion services across the globe, be they small community practices or highly complex tertiary care centres. The authors should be congratulated for their diligent work and the valuable contribution this guidance offers. Intramural Research Programme (Z99 CL999999) of the NIH Clinical Center at the National Institutes of Health. None. Sorcha Ní Loingsigh, Christopher A. Tormey, Willy A. Flegel and Jeanne E. Hendrickson wrote and edited the paper." @default.
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• W3046602120 title "Preventing transfusion‐associated graft‐versus‐host disease with blood component irradiation: indispensable guidance for a deadly disorder" @default.
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